7 results on '"Nowakowski G"'
Search Results
2. Histone deacetylase inhibitors interrupt HSP90•RASGRP1 and HSP90•CRAF interactions to upregulate BIM and circumvent drug resistance in lymphoma cells.
- Author
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Ding H, Peterson KL, Correia C, Koh B, Schneider PA, Nowakowski GS, and Kaufmann SH
- Subjects
- Animals, Cells, Cultured, Drug Resistance, Neoplasm, Genes, bcl-2, Humans, Lymphoma, B-Cell pathology, Mice, Up-Regulation, Bcl-2-Like Protein 11 genetics, DNA-Binding Proteins physiology, Guanine Nucleotide Exchange Factors physiology, HSP90 Heat-Shock Proteins physiology, Histone Deacetylase Inhibitors pharmacology, Lymphoma, B-Cell drug therapy, Proto-Oncogene Proteins c-raf physiology
- Abstract
Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here, we show that trichostatin A, romidepsin and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen-activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo. Importantly, these pro-apoptotic effects are mimicked by RASGRP1 small interfering RNA (siRNA) or HSP90 inhibition and reversed by overexpression of constitutively active MEK1 or siRNA-mediated downregulation of BIM. Collectively, these observations not only identify a new HSP90 client protein, RASGRP1, but also delineate a complete signaling pathway from HSP90 acetylation through RASGRP1 and CRAF degradation to BIM upregulation that contributes to selective cytotoxicity of HDAC inhibitors in lymphoid malignancies.
- Published
- 2017
- Full Text
- View/download PDF
3. Denileukin diftitox in combination with rituximab for previously untreated follicular B-cell non-Hodgkin's lymphoma.
- Author
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Ansell SM, Tang H, Kurtin PJ, Koenig PA, Nowakowski GS, Nikcevich DA, Nelson GD, Yang Z, Grote DM, Ziesmer SC, Silberstein PT, Erlichman C, and Witzig TE
- Subjects
- Adult, Aged, Antibodies, Monoclonal, Murine-Derived administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Diphtheria Toxin administration & dosage, Female, Humans, Interleukin-2 administration & dosage, Interleukin-2 Receptor alpha Subunit immunology, Lymphoma, B-Cell immunology, Lymphoma, Follicular immunology, Male, Middle Aged, Recombinant Fusion Proteins administration & dosage, Rituximab, T-Lymphocytes immunology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, B-Cell drug therapy, Lymphoma, Follicular drug therapy
- Abstract
Follicular lymphoma exhibits intratumoral infiltration by non-malignant T lymphocytes, including CD4+CD25+ regulatory T (T(reg)) cells. We combined denileukin diftitox with rituximab in previously untreated, advanced-stage follicular lymphoma patients anticipating that denileukin diftitox would deplete CD25+ T(reg) cells while rituximab would deplete malignant B cells. Patients received rituximab 375 mg/m(2) weekly for 4 weeks and denileukin diftitox 18 mcg/kg/day for 5 days every 3 weeks for 4 cycles; neither agent was given as maintenance therapy. Between August 2008 and March 2010, 24 patients were enrolled. One patient died before treatment was given and was not included in the analysis. Eleven of 23 patients (48%; 95% confidence interval (CI): 27-69%) responded; 2 (9%) had complete responses and 9 (39%) had partial responses. The progression-free rate at 2 years was 55% (95%CI: 37-82%). Thirteen patients (57%) experienced grade ≥3 adverse events and one patient (4%) died. In correlative studies, soluble CD25 and the number of CD25+ T cells decreased after treatment; however, there was a compensatory increase in IL-15 and IP-10. We conclude that although the addition of denileukin diftitox to rituximab decreased the number of CD25+ T cells, denileukin diftitox contributed to the toxicity of the combination without an improvement in response rate or time to progression.
- Published
- 2012
- Full Text
- View/download PDF
4. Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study.
- Author
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Nowakowski GS, LaPlant B, Habermann TM, Rivera CE, Macon WR, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Ansell SM, Klebig RR, Reeder CB, and Witzig TE
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Murine-Derived administration & dosage, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Female, Follow-Up Studies, Humans, Lenalidomide, Lymphoma, Follicular mortality, Lymphoma, Follicular pathology, Lymphoma, Large B-Cell, Diffuse mortality, Lymphoma, Large B-Cell, Diffuse pathology, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Prednisone administration & dosage, Rituximab, Survival Rate, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Treatment Outcome, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, Follicular drug therapy, Lymphoma, Large B-Cell, Diffuse drug therapy
- Abstract
Lenalidomide was shown to have significant single-agent activity in relapsed aggressive non-Hodgkin's lymphoma (NHL). We conducted a phase I trial to establish the maximum tolerated dose of lenalidomide that could be combined with R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone). Eligible patients were adults with newly diagnosed, untreated CD20 positive diffuse large cell or follicular grade III NHL. Patients received oral lenalidomide on days 1-10 with standard dose R-CHOP every 21 days. All patients received pegfilgrastim on day 2 of the cycle and aspirin prophylaxis. The lenalidomide dose levels tested were 15, 20 and 25 mg. A total of 24 patients were enrolled. The median age was 65 (35-82) years and 54% were over 60 years. Three patients received 15 mg, 3 received 20 mg and 18 received 25 mg of lenalidomide. No dose limiting toxicity was found, and 25 mg on days 1-10 is the recommended dose for phase II. The incidence of grade IV neutropenia and thrombocytopenia was 67% and 21%, respectively. Febrile neutropenia was rare (4%) and there were no toxic deaths. The overall response rate was 100% with a complete response rate of 77%. Lenalidomide at the dose of 25 mg/day administered on days 1 to 10 of 21-day cycle can be safely combined with R-CHOP in the initial chemotherapy of aggressive B-cell lymphoma.
- Published
- 2011
- Full Text
- View/download PDF
5. The absolute monocyte and lymphocyte prognostic score predicts survival and identifies high-risk patients in diffuse large-B-cell lymphoma.
- Author
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Wilcox RA, Ristow K, Habermann TM, Inwards DJ, Micallef IN, Johnston PB, Colgan JP, Nowakowski GS, Ansell SM, Witzig TE, Markovic SN, and Porrata L
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Lymphoma, Large B-Cell, Diffuse drug therapy, Male, Middle Aged, Neoplasm Staging, Prognosis, Retrospective Studies, Risk Factors, Survival Rate, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphocytes pathology, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse mortality, Monocytes pathology
- Abstract
Despite the use of modern immunochemotherapy regimens, almost 50% of patients with diffuse large-B-cell lymphoma will relapse. Current prognostic models, including the International Prognostic Index, incorporate patient and tumor characteristics. In contrast, recent observations show that variables related to host adaptive immunity and the tumor microenvironment are significant prognostic variables in non-Hodgkin lymphoma. Therefore, we retrospectively examined the absolute monocyte and lymphocyte counts as prognostic variables in a cohort of 366 diffuse large-B-cell lymphoma patients who were treated between 1993 and 2007 and followed at a single institution. The absolute monocyte and lymphocyte counts in univariate analysis predicted progression-free and overall survival when analyzed as continuous and dichotomized variables. On multivariate analysis performed with factors included in the IPI, the absolute monocyte and lymphocyte counts remained independent predictors of progression-free and overall survival. Therefore, the absolute monocyte and lymphocyte counts were combined to generate a prognostic score that identified patients with an especially poor overall survival. This prognostic score was independent of the IPI and added to its ability to identify high-risk patients.
- Published
- 2011
- Full Text
- View/download PDF
6. Lymphopenia assessed during routine follow-up after immunochemotherapy (R-CHOP) is a risk factor for predicting relapse in patients with diffuse large B-cell lymphoma.
- Author
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Porrata LF, Rsitow K, Inwards DJ, Ansell SM, Micallef IN, Johnston PB, Habermann TM, Witzig TE, Colgan JP, Nowakowski GS, Thompson CA, and Markovic SN
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Murine-Derived, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Female, Follow-Up Studies, Humans, Lymphocyte Count, Lymphoma, Large B-Cell, Diffuse immunology, Lymphoma, Large B-Cell, Diffuse pathology, Lymphopenia drug therapy, Lymphopenia pathology, Male, Middle Aged, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local pathology, Prednisone administration & dosage, Prognosis, Risk Factors, Rituximab, Survival Rate, Vincristine administration & dosage, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphopenia chemically induced, Neoplasm Recurrence, Local diagnosis
- Abstract
A specific predictor during routine follow-up to ascertain risk for relapse after standard chemotherapy in non-Hodgkin's lymphoma (NHL) has not been identified. Thus, we studied absolute lymphocyte count (ALC) as a marker of poststandard chemotherapy (rituximab, cyclophosphamide, adriamycin, vincristine and prednisone (R-CHOP)) NHL relapse in patients with diffuse large B-cell lymphoma (DLBCL). ALC was obtained at the time of confirmed relapse and at last follow-up. From 2000 until 2006, 149 consecutive DLBCL patients, originally diagnosed, treated with R-CHOP and followed up at Mayo Clinic, Rochester, were included in this study. Patients at last follow-up without relapse (N=112) had a higher ALC compared with those with relapsed lymphoma ((N=37) median ALC x 10(9)/l of 1.43 (range: 0.33-4.0) versus 0.67 (range: 0.18-1.98), P<0.0001, respectively). ALC at the time of confirmed relapse was a strong predictor for relapse with an area under the curve =0.91 (P<0.0001). An ALC <0.96 x 10(9)/l at the time of confirmed relapse had a positive predictive value of 72% and a positive likelihood ratio of 7.4 to predict relapse after R-CHOP in DLBCL. Patients with an ALC>or=0.96 x 10(9)/l (N=103) had a cumulative incidence of relapse of 6 versus 79% with an ALC <0.96 x 10(9)/l (N=46) (P<0.0001). This study suggests that lymphopenia measured by ALC can be used as a marker to assess risk of DLBCL relapse during routine follow-up after standard chemotherapy.
- Published
- 2010
- Full Text
- View/download PDF
7. Chronic lymphoproliferative disorder of natural killer cells: a distinct entity with subtypes correlating with normal natural killer cell subsets.
- Author
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Morice WG, Jevremovic D, Olteanu H, Roden A, Nowakowski G, Kroft S, Hanson CA, and Kurtin PJ
- Subjects
- CD56 Antigen metabolism, Cells, Cultured, Female, Flow Cytometry, Humans, Immunophenotyping, Killer Cells, Natural metabolism, Lymphoproliferative Disorders classification, Lymphoproliferative Disorders genetics, Middle Aged, NK Cell Lectin-Like Receptor Subfamily B metabolism, Receptors, KIR metabolism, Killer Cells, Natural pathology, Lymphoproliferative Disorders pathology
- Published
- 2010
- Full Text
- View/download PDF
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