515 results on '"Minden MD"'
Search Results
2. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis
- Author
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Wong, W W-L, Dimitroulakos, J, Minden, MD, and Penn, LZ
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- 2002
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3. Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells
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Xia, Z, Tan, MM, Wei-Lynn Wong, W, Dimitroulakos, J, Minden, MD, and Penn, LZ
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- 2001
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4. Antileukemic action of buthionine sulfoximine: evidence for an intrinsic death mechanism based on oxidative stress
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Hedley, DW, McCulloch, EA, Minden, MD, Chow, S, and Curtis, J
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- 1998
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5. Quality of life following bone marrow transplantation: a comparison of patient reports with population norms
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Sutherland, HJ, Fyles, GM, Adams, G, Hao, Y, Lipton, JH, Minden, MD, Meharchand, JM, Atkins, H, Tejpar, I, and Messner, HA
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- 1997
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6. A novel energy dependent mechanism reducing daunorubicin accumulation in acute myeloid leukemia
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Hedley, DW, Xie, S Xiu-Yan, Minden, MD, Choi, CH, Chen, H, and Ling, V
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- 1997
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7. Azacitidine (AZA) prolongs overall survival in older patients with acute myeloid leukemia (AML) with poor prognostic karyotypes compared with conventional care regimens (CCR)
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Doehner, H, Vyas, P, Seymour, JF, Santini, V, Stone, RM, Minden, MD, Al-Ali, HK, Del Castillo, TB, Morrill, J, Songer, S, Weaver, J, Skikne, BS, Beach, CL, and Dombret, H
- Published
- 2019
8. Clonal proliferation and long-term culture of malignant lymphoma cells under serum-free culture conditions
- Author
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Dai Yucheng, Wang XH, Wang C, Jamal N, Biondi A, Minden MD, and Messner HA
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- 1990
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9. BCL2 Splice Isoform Switching Promotes Leukemia Stem Cell Survival and Sensitivity to a Novel Pan BCL2 Inhibitor
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GOFF D, SMITH KM, SHIH AY, COURT RECART A, SADARANGANI A, GERON I, CHUANG R, BALAIAN L, WEI J, KITADA S, ZHAI D, GOTLIB J, MINDEN MD, SCHAIRER A, LEU H, MA W, JIANG Q, RUSERT J, DAO KHT, SHAZAND K, VOLAR M, DE BORJA R, MCPHERSON JD, HUDSON TJ, BARRETT CL, FRAZER KA, WENTWORTH P, MORRIS SR, GOLDSTEIN LSB, PELLECHIA M, REED JC, JAMIESON C., MARTINELLI, GIOVANNI, GOFF D, SMITH KM, SHIH AY, COURT-RECART A, SADARANGANI A, GERON I, CHUANG R, BALAIAN L, WEI J, KITADA S, ZHAI D, GOTLIB J, MINDEN MD, MARTINELLI G, SCHAIRER A, LEU H, MA W, JIANG Q, RUSERT J, DAO KHT, SHAZAND K, VOLAR M, DE BORJA R, MCPHERSON JD, HUDSON TJ, BARRETT CL, FRAZER KA, WENTWORTH P, MORRIS SR, GOLDSTEIN LSB, PELLECHIA M, REED JC, and JAMIESON C
- Subjects
SPLICE VARIANT - Published
- 2011
10. MLL translocations specify a distinct gene expression profile that distuinguishes a unique leukemia
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Armstrong, SA, Staunton, JE, Silverman, LB, Pieters, Rob, den Boer, Monique, Minden, MD, Sallan, SE, Lander, ES, Golub, TR, Korsmeyer, SJ, and Pediatrics
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- 2002
11. LYL1 (lymphoblastic leukemia derived sequence 1)
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Minden, MD, primary and Meng, Y, additional
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- 2011
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12. Shiga-like toxin purges human lymphoma from bone marrow of severe combined immunodeficient mice
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LaCasse, EC, primary, Saleh, MT, additional, Patterson, B, additional, Minden, MD, additional, and Gariepy, J, additional
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- 1996
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13. THE EFFECTS OF RETINOIC ACID ANALOGS ON THE BLAST CELLS OF ACUTE MYELOBLASTIC-LEUKEMIA IN CULTURE
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TOHDA, S, primary, SHUDO, K, additional, and MINDEN, MD, additional
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- 1994
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14. Alterations of p53 and c-myc in the clonal evolution of malignant lymphoma
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Chang, H, primary, Benchimol, S, additional, Minden, MD, additional, and Messner, HA, additional
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- 1994
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15. Expression of the Kit and KitA receptor isoforms in human acute myelogenous leukemia
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Piao, X, primary, Curtis, JE, additional, Minkin, S, additional, Minden, MD, additional, and Bernstein, A, additional
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- 1994
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16. THE ROLE OF STROMA CELLS ON THE PROLIFERATION AND C-KIT EXPRESSION OF ACUTE MYELOBLASTIC-LEUKEMIA CELLS
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TOHDA, S, primary, ASHMAN, LK, additional, and MINDEN, MD, additional
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- 1993
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17. Role of interleukin-6 in the proliferation of human multiple myeloma cell lines OCI-My 1 to 7 established from patients with advanced stage of the disease
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Hitzler, JK, primary, Martinez-Valdez, H, additional, Bergsagel, DB, additional, Minden, MD, additional, and Messner, HA, additional
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- 1991
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18. Associations between quality of life, fatigue, and cytokine levels in patients aged 50+ with acute myeloid leukemia.
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Panju AH, Danesh A, Minden MD, Kelvin DJ, Alibhai SM, Panju, Abbas H, Danesh, Ali, Minden, Mark D, Kelvin, David J, and Alibhai, Shabbir M H
- Abstract
Goals Of Work: Quality of life (QOL) is significantly impaired in patients with acute myeloid leukemia (AML), and fatigue is the most common and disabling symptom; effective treatment measures have yet to be found. Cytokines, biomarkers of inflammation, may moderate both health outcomes, but published data are limited. We looked at the role of cytokines in modulating QOL and fatigue in an older AML population.Patients and Methods: We recruited 34 English-speaking patients (23 men, 11 women) aged 50 or older with AML within 1 year of diagnosis. QOL and fatigue were assessed with validated questionnaires. Blood was simultaneously drawn for quantitative measurement of a 13-cytokine panel. Repeat measurements were done 4-6 weeks later (n = 28 patients). Spearman correlations between health measures and cytokine levels were examined at baseline, as were changes in variables between time points. A potentially clinically important correlation was defined as an r > or = 0.30.Results: At baseline, potentially clinically important correlations were noted between global QOL and interferon (IFN)-gamma (r = -0.376, p = 0.031), interleukin (IL)-2 (r = -0.340, p = 0.053), IL-5 (r = -0.368, p = 0.035), IL-8 (r = -0.312, p = 0.077), and TNF-alpha (r = -0.326, p = 0.064). A similar correlation was observed between IL-6 and fatigue (r = 0.332, p = 0.059). Between time points, there were no potentially important correlations between changes in global QOL and any cytokine. However, potentially important correlations with fatigue were seen with both IL-5 (r = 0.344, p = 0.073) and IL-10 (r = 0.326, p = 0.091) between time points.Conclusions: These preliminary data provide support for a larger controlled study of cytokines, fatigue, and QOL in patients with AML. [ABSTRACT FROM AUTHOR]- Published
- 2009
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19. Mutation of the p53 gene in human acute myelogenous leukemia
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Slingerland, JM, primary, Minden, MD, additional, and Benchimol, S, additional
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- 1991
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20. Analysis of molecular events in leukemic cells arrested at an early stage of T-cell differentiation
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Yumura-Yagi, K, Hara, J, Terada, N, Ishihara, S, Tawa, A, Takihara, Y, Champagne, E, Minden, MD, Mak, TW, and Kawa-Ha, K
- Abstract
We analyzed the rearrangement and expression of T-cell receptor (TCR) genes, including the recently identified TCR delta gene, in 21 patients with T-lineage leukemia/lymphoma. Among 8 patients with CD3-, CD4-, and CD8- (group I), 2 patients showed germline configuration of the TCR delta, gamma, beta, and alpha genes and 1 patient demonstrated only TCR delta gene rearrangement. All nine patients with CD3-, CD4+, and/or CD8+ (group II) showed concomitant rearrangements of the TCR delta, gamma, and beta genes. TCR alpha gene rearrangement was also observed in two patients. Three of four patients with CD3+ (group III) showed rearrangement of the TCR alpha gene with deletion of both alleles or of a single allele of the TCR delta gene. With Northern blot analysis, full-length transcripts of the TCR delta gene were detected in 3 of 15 examined patients. All were restricted to group I or group II. In contrast, full-length transcripts of TCR beta and alpha were observed mainly in samples from groups II and III. Based on these findings, rearrangement of the TCR delta gene may be the earliest event in T-cell differentiation, preceding rearrangements of the other TCR genes.
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- 1989
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21. The T-cell receptor delta chain locus is disrupted in the T-ALL associated t(11;14)(p13;q11) translocation
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Champagne, E, Takihara, Y, Sagman, U, de Sousa, J, Burrow, S, Lewis, WH, Mak, TW, and Minden, MD
- Abstract
Two T-ALL patients carrying a t(11;14)(p13;q11) translocation were analyzed. Southern blotting experiments demonstrated that both patients had rearranged their J delta genes and that the translocation involved the delta locus in both cases. In one patient, cloning, restriction mapping, and sequencing showed that the translocation occurred on a D delta 1-D delta 2-J delta 2 rearranged gene. In addition, the rearrangement on chromosome 11 occurred in both patients within a segment of less than or equal to 2 kb showing the presence in this region of a point of recurrent recombination.
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- 1989
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22. Clonogenic hemopoietic precursors in bone marrow transplantation
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Messner, HA, Curtis, JE, Minden, MD, Tritchler, D, Lockwood, G, Takahashi, T, Lepine, J, Jamal, N, Tweeddale, M, and Wandl, U
- Abstract
Multilineage and single-lineage hemopoietic precursors were studied in 102 bone marrow transplant recipients and their respective donors to determine their contribution to clinical outcome as measured by time to engraftment and survival. The patient population was heterogenous with respect to diagnosis and disease status. They included individuals with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), aplastic anemia, and a few other hematopoietic malignancies. The frequency of various clonogenic precursors in the normal donor population varied considerably. The data yielded a symmetrical distribution. In contrast, most bone marrow transplant recipients presented with significantly reduced numbers of clonogenic cells before transplantation, resulting in skewed distribution profiles. Serial studies of recipients demonstrated a significantly lower than normal level of clonogenic precursors even 3 and 4 years after transplantation. The median values and distribution profiles approximated those observed before transplantation but did not return to measurements obtained for normal donors. Patients with ALL deviated from this pattern. The median values and distribution profiles of clonogenic precursors before transplantation approximated the pattern of normal donors. The frequency of clonogenic progenitors after transplantation, however, remained significantly lower than that of their respective donor or pretransplant values. Cell cycle studies performed after normalization of peripheral blood hematopoietic parameters demonstrated for most recipients that a higher than normal proportion of multipotent cells was in S-phase (P = .011). By univariate and multivariate approaches, clonogenic precursors and clinical parameters were assessed for their contributions to clinical outcome as measured by time to engraftment and survival time. The number of nucleated cells in the transplant inoculum contributed to survival independent of other risk factors. Patients with a higher cell load had a higher probability of surviving than did patients with a lower cell concentration in the transplant inoculum (P = .042). The frequency of clonogenic precursors in the transplant inoculum altered neither survival nor time to engraftment. The time to engraftment was significantly influenced by the frequency of clonogenic megakaryocyte precursors (CFU-M) observed in recipients prior to transplantation (P = .003). Patients with high values engrafted faster than did patients with a low frequency of CFU-M. This was independent of both diagnosis and disease status of the patients at time of transplantation.
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- 1987
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23. Chromosome-mediated transfer of the malignant phenotype by human acute myelogenous leukemic cells
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Minden, MD, Gusella, JF, and Housman, D
- Abstract
Acute myelogenous leukemia (AML) is a malignancy of the myeloid cells of the bone marrow. Recently, a number of groups have demonstrated that it is possible to study the malignant phenotype at the level of DNA through gene transfer experiments. We have used such an approach to determine whether it is possible to transfer the malignant phenotype of anchorage independence from human AML cells to anchorage-dependent rodent cells, using chromosomes as the source of genetic information. We found that chromosomes isolated from leukemic cell lines were capable of transferring the malignant phenotype of anchorage independence, whereas chromosomes derived from the lymphocytes of normal individuals were not active in this assay. Using Southern blot analysis of the DNA from transferants, we were able to show that the transfer of anchorage independence correlated with the presence of human DNA in the transferants. The pattern of human DNA in the transferants derived from different transfection experiments is compared.
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- 1984
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24. The structure of the T cell antigen receptor genes in normal and malignant T cells
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Minden, MD and Mak, TW
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In this review the genomic structure and the RNA transcripts of the alpha and beta chain of the T cell antigen receptor have been discussed. Studies of the structure of TcR beta in hematologic malignancies have revealed rearrangement in almost all of the T cell malignancies and a small proportion of non-T cell malignancies. In addition, clonal involvement of T cells in diseases such as Hodgkin's disease, angioimmunoblastic lymphadenopathy, and chronic T cell lymphocytosis have been observed. The study of the structure of the TcR beta gene is thus a useful tool for identifying clonal expansions of cells and in conjunction with studies of the immunoglobulin gene structure, and cell surface markers a useful tool for identifying cell lineage. At the present time the evaluation of the structure of the alpha chain genes has not been as fruitful. However, chromosome translocations involving the TcR alpha chain genes have been recognized and, in one case, this rearrangement has been in association with a known oncogene. With the isolation of more probes to the alpha chain region it should be possible to test its utility in identifying clonal populations and cell lineage. The recent isolation of the gamma gene of the T cell will also permit such studies. Preliminary results of studies carried out with a probe to the gamma chain gene of the T cell have paralleled results obtained with the TcR beta probe (unpublished observation).
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- 1986
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25. Effects of recombinant GM-CSF on the blast cells of acute myeloblastic leukemia
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Hoang, T, Nara, N, Wong, G, Clark, S, Minden, MD, and McCulloch, EA
- Abstract
The effects of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) were compared to those of media conditioned by the continuous bladder carcinoma line, HTB9 (HTB9-CM), using three criteria. First, both GM-CSF and HTB9-CM stimulated blast colony formation in methylcellulose cultures, patient-to-patient variations were seen in the dose-response curves, and GM-CSF was effective, but less so that HTB9-CM. Second, GM-CSF also enhanced growth of blast progenitors in suspension culture, indicating its capacity to support self-renewal. GM-CSF was as effective as HTB9-CM in the production of adherent cells during the growth of blast cells in suspension, a finding that is interpreted to mean that GM-CSF also supports postdeterministic events in blast differentiation. Finally, colonies growing in the presence of GM-CSF were not phenotypically different than those stimulated by HTB9-CM.
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- 1986
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26. Production of growth factors by malignant lymphoma cell lines
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Tweeddale, M, Jamal, N, Nguyen, A, Wang, XH, Minden, MD, and Messner, HA
- Abstract
Fourteen Epstein-Barr virus (EBV)-negative cell lines were raised from bone marrow (BM), peripheral blood (PB), or lymph node samples of patients with intermediate- or high-grade malignant lymphoma. The cell lines were propagated in liquid suspension culture. They contain clonogenic progenitors capable of forming lymphoma colonies in semi- solid culture medium. Cells of these lines were used to examine the growth factor requirements of their clonogenic progenitors and to assess their ability to produce their own growth factors. Two of the cell lines (OCI-Ly9 and OCI-Ly13.1) required addition of exogenous factors for colony growth. These factors were routinely provided by media conditioned by phytohemagglutinin-stimulated leukocytes (PHA- LCM). Three lines formed some and nine lines gave rise to optimal numbers of colonies without addition of growth factors. Eight of these factor-independent lines were able to function as feeder cells and promoted colony formation by both factor-dependent lines. Cell lines that displayed feeder cell function released activities into supernatants able to replace their cellular source. Some of these endogenously produced growth-promoting activities could be replaced by known hematopoietic growth factors. Both factor-dependent cell lines were cultured with recombinant IL-1 alpha, IL-2, IL-3, IL-6, and GM colony-stimulating factor (CSF) and semipurified B-cell growth factor (BCGF) interleukin-4 (IL-4). A heterogeneous response pattern was observed. Both lines formed colonies with IL-4. The colonies were comparable in frequency and size with colonies observed with (PHA-LCM). OCI-Ly9 responded to IL-6 but showed no growth with IL-2. In contrast, the TAC-positive line OCI-Ly13.1 gave rise to colonies with IL-2 while remaining unresponsive to IL-6. A moderate number of colonies was observed when cells of this line were cultured with GM-CSF. Colony formation of both lines was uninfluenced by IL1 alpha or IL-3.
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- 1989
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27. A possible autocrine role for interleukin-6 in two lymphoma cell lines
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Yee, C, Biondi, A, Wang, XH, Iscove, NN, de Sousa, J, Aarden, LA, Wong, GG, Clark, SC, Messner, HA, and Minden, MD
- Abstract
Interleukin-6 (IL-6) is a growth factor with diverse biologic activity. Originally described as a T-cell product that enhances immunoglobulin (Ig) secretion in antigen-stimulated B cells, it also affects the growth of T cells, plasmacytomas, hybridomas, and hematopoietic stem cells. We report the expression and secretion of IL-6 by two lymphoma cell lines, OCI-LY3 and OCI-LY12. Addition of recombinant IL-6 stimulated their growth, whereas addition of polyclonal anti- recombinant IL-6 (anti-rIL-6) had a marked inhibitory effect on proliferation. These results suggest an autocrine role for IL-6 in the growth of these lymphoma cells in culture.
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- 1989
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28. T-cell receptor delta gene rearrangement in childhood T-cell acute lymphoblastic leukemia
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Biondi, A, Champagne, E, Rossi, V, Giudici, G, Cantu-Rajnoldi, A, Masera, G, Mantovani, A, Mak, TW, and Minden, MD
- Abstract
During the development of functional T lymphocytes, a variety of genes involved in antigen recognition undergo somatic rearrangement. These include the alpha, beta, and gamma chain genes. Recently a fourth rearranging gene, the delta chain gene, embedded in the alpha chain locus, has been described. We have determined the structure of the beta, gamma, and delta chain genes in 15 cases of T-cell acute lymphoblastic leukemia (T-ALL) representing stage I (CD7+, CD1-, CD3-) and stage II (CD7+, CD1+, CD3-) of intrathymic T-cell development. The alpha-delta locus was rearranged in 14 of the 15 cases. In three cases the delta constant region was deleted on both chromosomes, suggesting biallelic V-J alpha rearrangement. A limited pattern of rearrangement of the delta locus was observed in the remaining 11 cases. When the alpha-delta region was rearranged, there was rearrangement of the beta and gamma TcR in all cases except two; in these cases the beta chain was in the germline configuration. These findings support the hypothesis that delta chain gene rearrangement is an early event in T- cell development, possibly contemporary to gamma gene rearrangement, and that the delta locus has a limited repertoire.
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- 1989
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29. Structure and expression of genes of GM-CSF and G-CSF in blast cells from patients with acute myeloblastic leukemia
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Cheng, GY, Kelleher, CA, Miyauchi, J, Wang, C, Wong, G, Clark, SC, McCulloch, EA, and Minden, MD
- Abstract
The hematopoietic growth factors granulocyte/macrophage colony- stimulating factor (GM-CSF) and G-CSF, available as recombinant products, stimulate the growth in culture of blasts from patients with acute myeloblastic leukemia (AML). We used cDNA probes for each gene to study the genomic organization in blast cells of 22 patients and expression in the blast cells of 18 patients. Alteration in the structure of G-CSF (two instances) and GM-CSF (two instances) was found. In two patients in whom it was possible to study DNA from bone marrow obtained at remission, the new bands detected in the leukemic cells were not found. Fifteen of 18 patients showed no RNA expression of either growth factor. Both patients with GM-CSF abnormalities as seen by Southern analysis expressed an abnormally large GM-CSF message but no G-CSF messages. One patient with an abnormal Southern pattern with G-CSF expressed normal-sized G-CSF and GM-CSF messages. The biologic significance of these findings remains to be determined. Nonetheless, the abnormal Southern patterns may prove to be useful clonal markers in the study of AML.
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- 1988
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30. The effects of three recombinant growth factors, IL-3, GM-CSF, and G- CSF, on the blast cells of acute myeloblastic leukemia maintained in short-term suspension culture
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Miyauchi, J, Kelleher, CA, Yang, YC, Wong, GG, Clark, SC, Minden, MD, Minkin, S, and McCulloch, EA
- Abstract
The blast stem cells of acute myeloblastic leukemia (AML) respond in cell culture to growth factors by both self-renewal and terminal divisions. Both of these functions have been shown to be stimulated by the recombinant growth factors granulocyte-macrophage colony- stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). In this paper, recombinant gibbon interleukin-3 (IL-3), homologous to human IL-3, was tested on blast cells and compared with the effects of GM-CSF, G-CSF, and medium conditioned by the bladder cell line 5637 (5637-CM). We found that IL-3 was an effective stimulator of blast renewal and terminal divisions. However, great patient-to-patient variation was found. A graphic method of presenting complex comparisons between growth factors is also included.
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- 1987
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31. The presence of clonogenic cells in high-grade malignant lymphoma: a prognostic factor
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Tweeddale, ME, Lim, B, Jamal, N, Robinson, J, Zalcberg, J, Lockwood, G, Minden, MD, and Messner, HA
- Abstract
A culture system has been developed that promotes growth of clonogenic lymphoma cells of some patients with intermediate and high-grade malignant lymphoma. The formation of colonies in bone marrow, lymph nodes, and peripheral blood samples is best supported by human plasma. Colony formation of some patients was dependent upon growth factors, which in this study were added in the form of medium conditioned by phytohemagglutinin (PHA)-stimulated leukocytes (PHA-LCM). Some gave rise to lymphoma colonies without PHA-LCM but improved their frequency with PHA-LCM; others were completely independent of PHA-LCM. Colonies grown in primary cultures were routinely recloned and propagated as Epstein-Barr virus (EBV)-negative cell lines with stable B cell phenotype. The cell lines showed the same immunoglobulin rearrangement pattern as that observed in the primary lymphoma sample. In addition, a significant clinical correlation was observed between culture data and clinical outcome. Survival of patients who formed lymphoma colonies at any time during their clinical course was significantly shorter than survival of patients who did not give rise to colonies (P = 0.0009). The same observation was made when the survival assessment was performed for the subset of patients studied at diagnosis (P = 0.0014).
- Published
- 1987
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32. Synergism between recombinant growth factors, GM-CSF and G-CSF, acting on the blast cells of acute myeloblastic leukemia [published erratum appears in Blood 1987 Jul;70(1):339]
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Kelleher, C, Miyauchi, J, Wong, G, Clark, S, Minden, MD, and McCulloch, EA
- Abstract
The genes for the hemopoietic growth factors, GM colony-stimulating factor (CSF) and G-CSF have been cloned, and recombinant material is available for both. We tested these recombinant factors for their effects on the blast cells of acute myeloblastic leukemia (AML). Culture methods are available that support both colony formation by AML blasts and the growth of blast stem cells in suspension. Recombinant GM- CSF is active in both culture systems, although to a varying degree. We found that recombinant G-CSF was also effective; however, the two recombinant factors showed striking synergism for the stimulation of blast growth of cells from five of eight AML patients. In these cases, the combination was equivalent to the stimulating activity of supernatants from the continuous cell line 5637. This conditioned medium (HTB9-CM) is considered the standard for blast growth. Blasts from one of the patients grew without added factor. In another instance, recombinant GM-CSF alone was almost as effective as HTB9-CM. In the third case, both recombinant factors were active, but synergism was not observed and their combined effect was not equivalent to that of HTB9-CM. Both GM-CSF and G-CSF were active on normal bone marrow granulopoietic progenitors, but synergism was not observed. We conclude that the marked heterogeneity observed when AML blasts are examined by other criteria is also observed when their response to growth factors is evaluated.
- Published
- 1987
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33. Proliferative state of blast cell progenitors in acute myeloblastic leukemia (AML)
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Minden, MD, Till, JE, and McCulloch, EA
- Abstract
Peripheral blood from patients with acute myeloblastic leukemia (AML) contains cells capable of giving rise to colonies in culture when stimulated by media conditioned by leukocytes (LCM) in the presence of phytohemagglutinin (PHA). Two types of colonies are recognized with high frequency: The first grows in the presence of low concentrations of PHA LCM, have a blast-like morphology, and are numerically correlated with morphologically identified blast cells. The second requires either high PHA LCM concentrations or PHA alone with or without 2-mercaptoethanol and consists of cells capable of forming rossettes with sheep erythrocytes and resembles. T-lymphocyte colonies from normal blood. Precursors of blast cell colonies from 15 leukemic patients were tested for cycle state, using either the 3H-thymidine or hydroxyurea techniques. All were found to have a high proportion of cells in the S phase of the cycle. In contrast, T lymphocyte precursors from three normal individual were quiescent. The data are consistent with the maintenance of the leukemic blast cell populations by the proliferative activity of a small subpopulation of blasts.
- Published
- 1978
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34. Self-renewal in culture of proliferative blast progenitor cells in acute myeloblastic leukemia
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Buick, RN, Minden, MD, and McCulloch, EA
- Abstract
We have proposed that colonies of cells with blastlike morphology growing in culture are derived from a blast subpopulation with high proliferative potential. To test whether or not these blast progenitors have the capacity for self-renewal, blast colonies grown from the peripheral blood of the 21 patients with acute myeloblastic leukemia were replated; secondary colonies were observed in 17 instances, and these were similar to primary colonies in size, morphology, and culture requirements. Great patient-to-patient variation was observed in the frequency of secondary colonies, but low secondary plating efficiency was significantly correlated with successful remission induction. We conclude that the blast progenitors detected in the assay have at least limited self-renewal capacity and that this capacity may, along with other risk factors, contribute to clinical outcome.
- Published
- 1979
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35. Separation of blast cell and T-lymphocyte progenitors in the blood of patients with acute myeloblastic leukemia
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Minden, MD, Buick, RN, and McCulloch, EA
- Abstract
The peripheral blood of acute myeloblastic leukemia (AML) patients often contains large numbers of two distinct cell populations, both capable of forming colonies in culture under similar conditions. The first population consists of the precursors of blast cells and has specificity for AML; the second population consists of T-lymphocyte precursors, also found in normal blood. The two progenitor populations can be separated by exploiting the capacity of T-lymphocyte (but not blasts) progenitors to form rosettes with sheep erythrocytes (E rosettes). After E-rosette formation, T-lymphocyte precursors can be removed by centrifugation on Ficoll-Hypaque. Such separation has a number of consequences: (1) Blast progenitors can be detected where unseparated mononuclear preparations have yielded either no colonies or only T-lymphocyte colonies (20 of 21 patients). (2) The stimulator requirements of the blast progenitors change, indicating that cell-cell interactions may take place between blast and T-lymphocyte progenitors. (3) It is feasible to characterize blast and T-lymphocyte precursors independently, even though they may coexist in peripheral blood. This may be important if progenitor properties are attributes contributing to the variance in outcome in AML.
- Published
- 1979
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36. The structure of the T cell gamma chain gene in lymphoproliferative disorders and lymphoma cell lines [published erratum appears in Blood 1987 Jan;69(1):368]
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Griesser, H, primary, Feller, A, additional, Lennert, K, additional, Tweedale, M, additional, Messner, HA, additional, Zalcberg, J, additional, Minden, MD, additional, and Mak, TW, additional
- Published
- 1986
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37. Health care crisis in Gaza.
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Schimmer AD, Malkin D, Zackenhaus E, Kagal A, Klip A, Rotin D, Minden MD, Teitel J, Schimmer, Aaron D, Malkin, David, Zackenhaus, Eldad, Kagal, Allan, Klip, Amira, Rotin, Daniela, Minden, Mark D, and Teitel, Jerome
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- 2009
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38. Phosphoproteomics predict response to midostaurin plus chemotherapy in independent cohorts of FLT3-mutated acute myeloid leukaemia.
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Borek WE, Nobre L, Pedicona SF, Campbell AE, Christopher JA, Nawaz N, Perkins DN, Moreno-Cardoso P, Kelsall J, Ferguson HR, Patel B, Gallipoli P, Arruda A, Ambinder AJ, Thompson A, Williamson A, Ghiaur G, Minden MD, Gribben JG, Britton DJ, Cutillas PR, and Dokal AD
- Abstract
Background: Acute myeloid leukaemia (AML) is a bone marrow malignancy with poor prognosis. One of several treatments for AML is midostaurin combined with intensive chemotherapy (MIC), currently approved for FLT3 mutation-positive (FLT3-MP) AML. However, many patients carrying FLT3 mutations are refractory or experience an early relapse following MIC treatment, and might benefit more from receiving a different treatment. Development of a stratification method that outperforms FLT3 mutational status in predicting MIC response would thus benefit a large number of patients., Methods: We employed mass spectrometry phosphoproteomics to analyse 71 diagnosis samples of 47 patients with FLT3-MP AML who subsequently received MIC. We then used machine learning to identify biomarkers of response to MIC, and validated the resulting predictive model in two independent validation cohorts (n = 20)., Findings: We identified three distinct phosphoproteomic AML subtypes amongst long-term survivors. The subtypes showed similar duration of MIC response, but different modulation of AML-implicated pathways, and exhibited distinct, highly-predictive biomarkers of MIC response. Using these biomarkers, we built a phosphoproteomics-based predictive model of MIC response, which we called MPhos. When applied to two retrospective real-world patient test cohorts (n = 20), MPhos predicted MIC response with 83% sensitivity and 100% specificity (log-rank p < 7∗10
-5 , HR = 0.005 [95% CI: 0-0.31])., Interpretation: In validation, MPhos outperformed the currently-used FLT3-based stratification method. Our findings have the potential to transform clinical decision-making, and highlight the important role that phosphoproteomics is destined to play in precision oncology., Funding: This work was funded by Innovate UK grants (application numbers: 22217 and 10054602) and by Kinomica Ltd., Competing Interests: Declaration of interests WEB—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences, named on a Kinomica patent; LN—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; SFP—is an employee at Kinomica, owns Kinomica share options; AEC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; NN—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; JAC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; DNP—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; PMC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; JK—is an employee at Kinomica, owns Kinomica share options; HRF—no conflict of interest; BP—no conflict of interest; PG—no conflict of interest; AA—no conflict of interest; AJA—received a honorarium for speaking engagements from Astellas; AT—received consultant fees from Kinomica for the role of Programme Director; AW—owns Kinomica share options, funded attendance and travel to conferences; GG—no conflict of interest; MDM—no conflict of interest; JGG—Kinomica co-founder, owns Kinomica share options; DJB—co-founder of Kinomica, owns Kinomica share options, named on Kinomica patents, Kinomica funded attendance and travel to conferences, received honoraria from Kinomica in a consulting role; PRC—co-founder and director of Kinomica, owns Kinomica share options, named on Kinomica patents, Kinomica funded attendance and travel to conferences, received honoraria from Kinomica in a consulting role; ADD—is an employee at Kinomica (CTO), named on Kinomica patents, Kinomica funded attendance and travel to conferences owns Kinomica share options., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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39. Phase I/II study of the clinical activity and safety of GSK3326595 in patients with myeloid neoplasms.
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Watts J, Minden MD, Bachiashvili K, Brunner AM, Abedin S, Crossman T, Zajac M, Moroz V, Egger JL, Tarkar A, Kremer BE, Barbash O, and Borthakur G
- Abstract
Background: GSK3326595 is a potent, selective, reversible protein arginine methyltransferase 5 (PRMT5) inhibitor under investigation for treatment of myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). In preclinical models of AML, PRMT5 inhibition decreased proliferation and increased cell death, supporting additional clinical research in myeloid neoplasms., Objectives: To determine the clinical activity, safety, tolerability, dosing, additional measures of clinical activity, pharmacokinetics, and pharmacodynamics of GSK3326595., Design: In part 1 of this open-label, multicenter, multipart, phase I/II study, adults with relapsed/refractory myeloid neoplasms (e.g., MDS, CMML, and AML) received monotherapy with 400 or 300 mg oral GSK3326595 once daily. Study termination occurred prior to part 2 enrollment., Methods: Clinical activity was determined by the clinical benefit rate (CBR; proportion of patients achieving complete remission (CR), complete marrow remission (mCR), partial remission, stable disease (SD) >8 weeks, or hematologic improvement). Adverse events (AEs) were assessed by incidence and severity. Exploratory examination of spliceosome mutations was performed to determine the relationship between genomic profiles and clinical response to GSK3326595., Results: Thirty patients with a median age of 73.5 years (range, 47-90) were enrolled; 13 (43%) and 17 (57%) received 400 and 300 mg of GSK3326595, respectively. Five (17%) patients met CBR criteria: 4 (13%) with SD >8 weeks and 1 (3%) achieving mCR. Of five patients with clinical benefit: three had SRSF2 mutation, one U2AF1, and one was splicing factor wild-type. Frequent GSK3326595-related AEs were decreased platelet count (27%), dysgeusia (23%), fatigue (20%), and nausea (20%). GSK3326595 had rapid absorption, with a T
max of approximately 2 h and a terminal half-life of 4-6 h., Conclusion: GSK3326595 monotherapy had limited clinical activity in heavily pretreated patients despite robust target engagement. The safety profile was broadly consistent with other published PRMT5 inhibitor studies., Trial Registration: ClinicalTrials.gov: NCT03614728., (© The Author(s), 2024.)- Published
- 2024
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40. Assessing Competencies, Needs, and Satisfaction With the Transition From Pediatric to Adult Health Care in Rheumatology: Development and Validation of the Transition-KompAZ.
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Haney H, Klotsche J, Niewerth M, Hansmann S, Erbis G, Reiser C, Saur SJ, Hoff P, Seipelt E, Maier A, Schalm S, Tatsis S, Foeldvari I, Kötter I, and Minden K
- Abstract
J Rheumatol 2024; doi: 10.3899/jrheum.2024-0097 There were incorrect footnotes in Table 2. All instances of footnote "a" in the Possible Score Range column should be an asterisk. The correct footnote should be, "Only participants with ≤ 1 missing or * additional answer category (ie, "does not currently apply to me") per domain are included for the sum score of the corresponding scale." We apologize for this error. This correction applies only to the August 15 2024 First Release. The correct table appears in the print and online issues.
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- 2024
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41. Evolution from an antecedent chronic myeloid malignancy does not impact survival outcomes in NPM1-mutated AML.
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Smith E, Atenafu EG, Bankar A, Chan S, Davidson M, Gupta V, Minden MD, Richard-Carpentier G, Schimmer A, Schuh AC, Sibai H, Yee K, and Maze D
- Abstract
Nucleophosmin-1 (NPM1)-mutated AML is a molecularly defined subtype typically associated with favorable treatment response and prognosis; however, its prognostic significance in AML evolving from an antecedent chronic myeloid malignancy is unknown. This study's primary objective was to determine the impact of mutated NPM1 on the prognosis of AML evolving from an antecedent chronic myeloid malignancy. We conducted a retrospective chart review including patients with NPM1-mutated de novo and sAML. sAML was defined as those with a preceding chronic-phase myeloid malignancy before diagnosis of AML. Of 575 NPM1-mutated patients eligible for inclusion in our study, 51 (8.9%) patients were considered to have sAML. The median time from diagnosis of NPM1-mutated chronic myeloid malignancy to sAML evolution was 3.6 months (0.5-79.3 months). No significant differences in leukemia-free (2-year LKFS 52.0% vs. 51.2%, p = .9922) or overall survival (2-year OS 56.3% vs. 49.4%, p = .4246) were observed between patients with NPM1-mutated de novo versus sAML. Our study suggests that evolution from a preceding myeloid malignancy is not a significant predictor of poor prognosis in the setting of an NPM1 mutation. Our study demonstrated a short time to progression to sAML in most patients, which further supports the consideration of NPM1 as an AML-defining mutation., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)
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- 2024
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42. School Well-Being and Academic Performance of Children With Juvenile Idiopathic Arthritis: A National Register-Based Study.
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Pedersen MJ, Høst C, Hansen SN, Klotsche J, Minden K, Deleuran BW, and Bech BH
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- Humans, Male, Female, Denmark epidemiology, Adolescent, Cross-Sectional Studies, Child, Surveys and Questionnaires, Quality of Life, Social Class, Arthritis, Juvenile psychology, Registries, Academic Performance, Schools
- Abstract
Objective: We aimed to investigate how school well-being (SWB) and academic performance of children with juvenile idiopathic arthritis (JIA) compare to their peers on a national level using the Danish national registers. Further, we investigated the potential influence of socioeconomic status (SES)., Methods: A population-wide, register-based, cross-sectional study was performed. We compared the results of children with and without JIA in the Danish National Well-Being Questionnaire (DNWQ), the National Danish School Testing (NDST), and their ninth grade (aged approximately 16 yrs) final school marks in Danish and mathematics. The results were analyzed using adjusted ordinal logistic regression (SWB) and linear regression (tests and marks)., Results: In separate cohorts, we included a total of 505,340 children answering the DNWQ, 812,461 children with NDST results, and the ninth-grade final marks of 581,804 children. Of these children, 1042, 1541, and 1410, respectively, fulfilled the criteria of JIA. Children with JIA reported SWB comparable to their peers, except for the question "Do you perform well in school?" (odds ratio 0.89, 95% CI 0.81-0.99). In the NDST, the children with JIA in general did just as well as their peers. We found no differences in the ninth-grade final marks in either Danish or mathematics. Stratifying the analyses on SES showed no significant differences in the associations., Conclusion: Overall, children with JIA report SWB comparable to that of children without JIA and perform equally well in school as children without JIA., (Copyright © 2024 by the Journal of Rheumatology.)
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- 2024
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43. Outcomes and adverse events in older acute lymphoblastic Leukemia patients treated with a pediatric-inspired protocol with Pegylated or native Asparaginase.
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Perusini MA, Andrews C, Atenafu EG, Gupta V, Maze D, Schuh AC, Yee KW, Bankar A, Davidson MB, Richard-Carpentier G, Chan SM, Sibai J, Schimmer AD, Minden MD, and Sibai H
- Subjects
- Humans, Aged, Retrospective Studies, Antineoplastic Combined Chemotherapy Protocols adverse effects, Polyethylene Glycols adverse effects, Asparaginase adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
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This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment.
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- 2024
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44. Double-negative T cells utilize a TNFα-JAK1-ICAM-1 cytotoxic axis against acute myeloid leukemia.
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Tin E, Lee JB, Khatri I, Na Y, Minden MD, and Zhang L
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- Humans, Cytotoxicity, Immunologic, Signal Transduction, Cell Line, Tumor, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets immunology, Leukemia, Myeloid, Acute metabolism, Intercellular Adhesion Molecule-1 metabolism, Tumor Necrosis Factor-alpha metabolism, Janus Kinase 1 metabolism
- Abstract
Abstract: Allogeneic double-negative T cells (DNTs) are a rare T-cell subset that effectively target acute myeloid leukemia (AML) without inducing graft-versus-host disease in an allogeneic setting. A phase 1 clinical trial demonstrated the feasibility, safety, and potential efficacy of allogeneic DNT therapy among patients with relapsed AML. However, the molecular mechanisms of DNT-mediated cytotoxicity against AML remain elusive. Thus, we used a flow cytometry-based high throughput screening to compare the surface molecule expression profile on DNTs during their interaction with DNT-susceptible or -resistant AML cells and identified a tumor necrosis factor α (TNFα)-dependent cytotoxic pathway in DNT-AML interaction. TNFα secreted by DNTs, upon encountering susceptible AML targets, sensitized AML cells to DNT-mediated killing, including those otherwise resistant to DNTs. Mechanistically, TNFα upregulated ICAM-1 on AML cells through a noncanonical JAK1-dependent pathway. DNTs then engaged with AML cells more effectively through an ICAM-1 receptor, lymphocyte function-associated antigen 1, leading to enhanced killing. These results reveal a TNFα-JAK1-ICAM-1 axis in DNT-mediated cytotoxicity against AML to improve therapeutic efficacy., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2024
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45. Pseudolaric Acid B Targets CD147 to Selectively Kill Acute Myeloid Leukemia Cells.
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Zou S, Parfenova E, Vrdoljak N, Minden MD, and Spagnuolo PA
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- Humans, Cell Line, Tumor, Cell Survival drug effects, Basigin metabolism, Basigin genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Cell Proliferation drug effects, Apoptosis drug effects, Diterpenes pharmacology
- Abstract
Acute myeloid leukemia (AML) is an aggressive blood cancer. With low survival rates, new drug targets are needed to improve treatment regimens and patient outcomes. Pseudolaric acid B (PAB) is a plant-derived bioactive compound predicted to interact with cluster of differentiation 147 (CD147/BSG). CD147 is a transmembrane glycoprotein overexpressed in various malignancies with suggested roles in regulating cancer cell survival, proliferation, invasion, and apoptosis. However, the detailed function of PAB in AML remains unknown. In this study, AML cell lines and patient-derived cells were used to show that PAB selectively targeted AML (IC50: 1.59 ± 0.47 µM). Moreover, proliferation assays, flow cytometry, and immunoblotting confirmed that PAB targeting of CD147 resulted in AML cell apoptosis. Indeed, the genetic silencing of CD147 significantly suppressed AML cell growth and attenuated PAB activity. Overall, PAB imparts anti-AML activity through transmembrane glycoprotein CD147.
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- 2024
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46. Genomic Characterization of Partial Tandem Duplication Involving the KMT2A Gene in Adult Acute Myeloid Leukemia.
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Seto A, Downs G, King O, Salehi-Rad S, Baptista A, Chin K, Grenier S, Nwachukwu B, Tierens A, Minden MD, Smith AC, and Capo-Chichi JM
- Abstract
Background: Gene rearrangements affecting KMT2A are frequent in acute myeloid leukemia (AML) and are often associated with a poor prognosis. KMT2A gene fusions are often detected by chromosome banding analysis and confirmed by fluorescence in situ hybridization. However, small intragenic insertions, termed KMT2A partial tandem duplication (KMT2A-PTD), are particularly challenging to detect using standard molecular and cytogenetic approaches., Methods: We have validated the use of a custom hybrid-capture-based next-generation sequencing (NGS) panel for comprehensive profiling of AML patients seen at our institution. This NGS panel targets the entire consensus coding DNA sequence of KMT2A . To deduce the presence of a KMT2A-PTD, we used the relative ratio of KMT2A exons coverage. We sought to corroborate the KMT2A-PTD NGS results using (1) multiplex-ligation probe amplification (MLPA) and (2) optical genome mapping (OGM)., Results: We analyzed 932 AML cases and identified 41 individuals harboring a KMT2A-PTD. MLPA, NGS, and OGM confirmed the presence of a KMT2A-PTD in 22 of the cases analyzed where orthogonal testing was possible. The two false-positive KMT2A-PTD calls by NGS could be explained by the presence of cryptic structural variants impacting KMT2A and interfering with KMT2A-PTD analysis. OGM revealed the nature of these previously undetected gene rearrangements in KMT2A , while MLPA yielded inconclusive results. MLPA analysis for KMT2A-PTD is limited to exon 4, whereas NGS and OGM resolved KMT2A-PTD sizes and copy number levels., Conclusions: KMT2A-PTDs are complex gene rearrangements that cannot be fully ascertained using a single genomic platform. MLPA, NGS panels, and OGM are complementary technologies applied in standard-of-care testing for AML patients. MLPA and NGS panels are designed for targeted copy number analysis; however, our results showed that integration of concurrent genomic alterations is needed for accurate KMT2A-PTD identification. Unbalanced chromosomal rearrangements overlapping with KMT2A can interfere with the diagnostic sensitivity and specificity of copy-number-based KMT2A-PTD detection methodologies.
- Published
- 2024
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47. Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy.
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Hagen JT, Montgomery MM, Aruleba RT, Chrest BR, Green TD, Kassai M, Zeczycki TN, Schmidt CA, Bhowmick D, Tan SF, Feith DJ, Chalfant CE, Loughran TP Jr, Liles D, Minden MD, Schimmer AD, Cabot MC, Mclung JM, and Fisher-Wellman KH
- Abstract
Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of this, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well as the endogenous F
1 -ATPase inhibitor ATP5IF1 . In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F1 -ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as a cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy., Competing Interests: Conflicts of Interest ADS has received research funding from Takeda Pharmaceuticals and BMS, and consulting fees/honorarium from Takeda, Astra Zeneca, BMS and Novartis. ADS is named on a patent application for the use of DNT cells to treat AML. ADS is a member of the Medical and Scientific Advisory Board of the Leukemia and Lymphoma Society of Canada and the Therapy Acceleration Program for the Leukemia and Lymphoma Society. TPL has received Scientific Advisory Board membership, consultancy fees, honoraria, and/or stock options from Keystone Nano, Flagship Labs 86, Dren Bio, Recludix Pharma, Kymera Therapeutics, and Prime Genomics. DJF has received research funding, honoraria, and/or stock options from AstraZeneca, Dren Bio, Recludix Pharma, and Kymera Therapeutics.- Published
- 2024
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48. A real-world analysis of clinical outcomes in AML with myelodysplasia-related changes: a comparison of ICC and WHO-HAEM5 criteria.
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Zhou Q, Zhao D, Zarif M, Davidson MB, Minden MD, Tierens A, Yeung YWT, Wei C, and Chang H
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- Humans, Retrospective Studies, Consensus, World Health Organization, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes drug therapy, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute drug therapy
- Abstract
Abstract: The proposed fifth edition of the World Health Organization classification of hematolymphoid tumors (WHO-HAEM5) and International Consensus Classification (ICC) provide different definitions of acute myeloid leukemia with myelodysplasia-related genetics (AML-MR). We conducted a retrospective study which included a cohort of 432 patients, with 354 patients fulfilling WHO-HAEM5 criteria for WHO-AML-MR or 276 patients fulfilling ICC criteria for ICC-AML-MR by gene mutation or cytogenetics (ICC-AML-MR-M/CG). The clinicopathological features were largely similar, irrespective of the classification used, except for higher rates of complex karyotype, monosomy 17, TP53 mutations, and fewer RUNX1 mutations in the WHO-AML-MR group. TP53 mutations were associated with distinct clinicopathological features and dismal outcomes (hazard ratio [HR], 2.98; P < .001). ICC-AML-MR-M/CG group had superior outcome compared with the WHO-AML-MR group (HR, 0.80, P = .032), largely in part due to defining TP53 mutated AML as a standalone entity. In the intensively-treated group, WHO-AML-MR had significantly worse outcomes than AML by differentiation (HR, 1.97; P = .024). Based on ICC criteria, ICC-AML-MR-M/CG had more inferior outcomes compared to AML not otherwise specified (HR, 2.11; P = .048 and HR, 2.55; P = .028; respectively). Furthermore, changing the order of genetic abnormalities defining AML-MR (ie, by gene mutations or cytogenetics) did not significantly affect clinical outcomes. ICC-AML-MR-M/CG showed similar outcomes regardless of the order of assignment. We propose to harmonize the 2 classifications by excluding TP53 mutations from WHO-HAEM5 defined AML-MR group and combining AML-MR defined by gene mutations and cytogenetics to form a unified group., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
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49. Asparaginase completion among adults including older patients with acute lymphoblastic leukemia treated with a modified DFCI protocol.
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Perusini MA, Andrews C, Eshetu AG, Gupta V, Maze D, Yee KWL, Bankar A, Davidson MB, Richard-Carpentier G, Chan SM, Schimmer AD, Sibai J, Alharbi S, Lucero JA, Linn SM, Minden MD, Schuh AC, and Sibai H
- Subjects
- Adult, Humans, Asparaginase therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Antineoplastic Agents therapeutic use
- Published
- 2024
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50. Outcomes of intensive and nonintensive blast-reduction strategies in accelerated and blast-phase MPN.
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Davidson MB, Kennedy JA, Capo-Chichi JM, Shi Y, Xu W, Cheung V, Arruda A, Bankar A, Richard-Carpentier G, Chan S, Maze D, Minden MD, Schimmer AD, Schuh AC, Sibai H, Yee K, Tierens A, Viswabandya A, and Gupta V
- Subjects
- Humans, Treatment Outcome, Retrospective Studies, Cytarabine therapeutic use, Daunorubicin, Myeloproliferative Disorders genetics
- Abstract
Abstract: Transformation of BCR::ABL1-negative myeloproliferative neoplasms (MPN) to an accelerated or blast phase is associated with poor outcomes. The efficacy of acute myeloid leukemia (AML)-type intensive and nonintensive hypomethylating agent-based regimens is not well studied. We therefore performed a retrospective analysis of patients with MPN-AP/BP (N = 138) treated with intensive (N = 81) and nonintensive (N = 57) blast-reduction strategies. We used clinically relatable response criteria developed at the Princess Margaret Cancer Centre. The overall best response, comprising complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and reversion to chronic phase MPN (cMPN), in the intensive and nonintensive groups was 77% (62 of 81) and 39% (21 of 54), respectively. Similar overall best response rates were observed in patients receiving induction with daunorubicin combined with cytarabine arabinoside (daunorubicin + ara-C) (74% [23 of 31]) or FLAG-IDA/NOVE-HiDAC (78% [39 of 50], P = .78). However, patients receiving daunorubicin + ara-C more often required second inductions (29% [9 of 31] vs 4% [2 of 50], P = .002). Most responses in the entire cohort were reversions to cMPN (55 of 83 [66%]). CR and CRi comprised 30% (25 of 83) and 4% (3 of 83) of responses, respectively. Mutations in TP53 (overall response [OR] 8.2 [95% confidence interval [CI] 2.01, 37.1], P = .004) and RAS pathway (OR 5.1 [95%CI 1.2, 23.7], P = .03) were associated with inferior treatment response for intensively treated patients, and poorer performance status (Eastern Cooperative Oncology Group) was associated with inferior treatment response in both intensively (OR 10.4 [95% CI 2.0, 78.5], P = .009) and nonintensively treated groups (OR 12 [95% CI 2.04, 230.3], P = .02). In patients with paired samples before and after therapy (N = 26), there was a significant residual mutation burden remaining irrespective of response to blast-reduction therapy., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
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