We have recently reported the identification of a new recessive mutation on murine chromosome 18 ... more We have recently reported the identification of a new recessive mutation on murine chromosome 18 that results in tail kinks and deformity in the lower extremities of mice. Preliminary examination of the bones of these mice showed that there are abnormalities present that resembled chronic recurrent multifocal osteomyelitis. Accordingly, this new mutation was named "CMO." In this report, we describe the histology of bones in CMO mice, as well as the capacity of the bone marrow cells from these animals to form osteoclasts (OCLs). In addition, we tested conditioned media from non-adherent marrow cells and total marrow cells from CMO mice for their capacity to induce OCL formation in normal murine marrow cultures. These studies demonstrated that the bone disease in these animals is inflammatory in nature, and a soluble factor(s) that is not IL-1alpha, IL-6 or TNF-alpha is released by marrow cells from CMO animals and enhances OCL formation in normal murine marrow cultures.
Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammati... more Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contributes to MM-related anemia. Searching for hepcidin-inducing cytokines in MM, we quantified the stimulation of hepcidin promoter-luciferase activity in HuH7 cells by MM sera. MM sera activated the hepcidin promoter significantly more than did normal sera. We then examined the role of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6), the major transcriptional regulators of hepcidin. Mutations in both BMP-responsive elements abrogated the activation dramatically, while mutations in the IL-6-responsive signal transducer and activator of transcription 3-binding site (STAT3-BS) had only a minor effect. Cotreatment with anti-BMP-2/4 or noggin-Fc blocked the promoter induction with al...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2014
This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tole... more This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma). Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic t...
We have recently reported the identification of a new recessive mutation on murine chromosome 18 ... more We have recently reported the identification of a new recessive mutation on murine chromosome 18 that results in tail kinks and deformity in the lower extremities of mice. Preliminary examination of the bones of these mice showed that there are abnormalities present that resembled chronic recurrent multifocal osteomyelitis. Accordingly, this new mutation was named "CMO." In this report, we describe the histology of bones in CMO mice, as well as the capacity of the bone marrow cells from these animals to form osteoclasts (OCLs). In addition, we tested conditioned media from non-adherent marrow cells and total marrow cells from CMO mice for their capacity to induce OCL formation in normal murine marrow cultures. These studies demonstrated that the bone disease in these animals is inflammatory in nature, and a soluble factor(s) that is not IL-1alpha, IL-6 or TNF-alpha is released by marrow cells from CMO animals and enhances OCL formation in normal murine marrow cultures.
Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammati... more Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contributes to MM-related anemia. Searching for hepcidin-inducing cytokines in MM, we quantified the stimulation of hepcidin promoter-luciferase activity in HuH7 cells by MM sera. MM sera activated the hepcidin promoter significantly more than did normal sera. We then examined the role of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6), the major transcriptional regulators of hepcidin. Mutations in both BMP-responsive elements abrogated the activation dramatically, while mutations in the IL-6-responsive signal transducer and activator of transcription 3-binding site (STAT3-BS) had only a minor effect. Cotreatment with anti-BMP-2/4 or noggin-Fc blocked the promoter induction with al...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2014
This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tole... more This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma). Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic t...
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