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Biomedical subjects

Kenneth Anderson

Publications and source records attributed to Kenneth Anderson.

At least 19 recordsLinked to original sources
PubMed2006

Quantifying serum antibody in bird fanciers' hypersensitivity pneumonitis.

BACKGROUND: Detecting serum antibody against inhaled antigens is an important diagnostic adjunct for hypersensitivity pneumonitis (HP). We sought to validate a quantitative fluorimetric assay testing serum from bird fanciers. METHODS: Antibody activity was assessed in bird fanciers and control subjects using various avian antigens and serological methods, and the titer was compared with symptoms of HP. RESULTS: IgG antibody against pigeon serum antigens, quantified by fluorimetry, provided a good discriminator of disease. Levels below 10 mg/L were insignificant, and increasing titers were associated with disease. The assay was unaffected by total IgG, autoantibodies and antibody to dietary hen's egg antigens. Antigens from pigeon serum seem sufficient to recognize immune sensitivity to most common pet avian species. Decreasing antibody titers confirmed antigen avoidance. CONCLUSION: Increasing antibody titer reflected the likelihood of HP, and decreasing titers confirmed antigen avoidance. Quantifying antibody was rapid and the increased sensitivity will improve the rate of false-negative reporting and obviate the need for invasive diagnostic procedures. Automated fluorimetry provides a method for the international standardization of HP serology thereby improving quality control and improving its suitability as a diagnostic adjunct.

Animals↗
PubMed2006

Beyond single-agent bortezomib: combination regimens in relapsed multiple myeloma.

PURPOSE OF REVIEW: Bortezomib-based combinations are being investigated in relapsed or refractory multiple myeloma with the aim of improving outcomes. This review presents recent data from clinical trials of these combinations and discusses their implications. RECENT FINDINGS: Preclinical findings indicating additive or synergistic activity of bortezomib plus conventional and novel agents for multiple myeloma appear to be supported by clinical studies of bortezomib-based combinations. Bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates. Encouraging responses to bortezomib and its combinations are also seen in elderly patients, patients with adverse prognostic factors such as refractory disease and increased beta2-microglobulin, patients with cytogenetic abnormalities such as chromosome 13 deletion, advanced bone disease, extramedullary involvement, and patients with renal impairment, including patients with renal failure requiring dialysis. Toxicities are predictable and manageable and comparable to those seen with bortezomib monotherapy. SUMMARY: Bortezomib-based combinations show promising activity in relapsed or refractory multiple myeloma, including reversal of chemoresistance to previously used agents. As high complete and overall response rates translate into longer survival, bortezomib-based combinations appear likely to have a significant impact on the multiple myeloma treatment algorithm and on the course of the disease itself.

Antineoplastic Agents↗
PubMed2006

FQPD, a novel immunomodulatory drug, has significant in vitro activity in multiple myeloma.

Multiple myeloma (MM) is a plasma cell malignancy that claims thousands of lives each year and has considerable morbidity. The disease remains incurable despite recent advances in the understanding of the disease biology and the introduction of more effective drugs is needed. This study evaluated the anti-MM activity of 3-(7-fluoro-4H-quinazolin-3-yl)-piperidine-2,6-dione, hydrochloride (FQPD), a novel immunomodulatory drug. FQPD inhibited the proliferation of multiple MM cell lines, including those resistant to conventional treatments, such as dexamethasone. It induced apoptosis in MM cell lines, as well as freshly isolated patient MM cells, without cytotoxicity on normal human lymphocytes. Moreover, it induced apoptosis in MM cells adherent to bone marrow (BM) stromal cells or in the presence of cytokines, such as interleukin-6 and vascular endothelial growth factor, confirming its ability to overcome the protective effects of the BM milieu. Apoptosis in the MM cells was mediated via poly-ADP ribose polymerase cleavage as well as cleavage of caspase 8 and caspase 9. Our studies therefore demonstrated in vitro anti-MM activity of FQPD and provide the rationale for its in vivo evaluation in animal models and derived clinical trials.

6-Ketoprostaglandin F1 alpha↗
PubMed2006

Nerve growth factor in serum and lymphocyte culture in pigeon fanciers' acute hypersensitivity pneumonitis.

BACKGROUND: Nerve growth factor (NGF) is a neurotrophic cytokine with immunomodulatory activity. NGF contributes to neurogenic inflammation and has been described in asthma and idiopathic pulmonary fibrosis. OBJECTIVES: To identify and quantify NGF in serum and peripheral blood lymphocyte cultures from pigeon fanciers, and to investigate an association with the immune response to inhaled avian antigens, and with symptoms of acute hypersensitivity pneumonitis (HP). METHODS: NGF was quantified and compared with serum IgG antibody against inhaled avian antigens, with serum C-reactive protein (CRP), and with KL-6, a marker of lung interstitial inflammation. These were measured using enzyme-linked immunoassay. Levels were compared with symptom history in 55 pigeon fanciers (26 subjects with acute HP but symptom-free at the time of testing) and 15 subjects with no avian exposure. RESULTS: Pigeon fanciers had higher-than-normal serum IgG antibody, CRP, and KL-6 levels (p < 0.01 each). These measures were unrelated to HP symptom category; instead, in all pigeon fanciers, the concentrations of CRP and KL-6 correlated with each other and with the antibody titers (p < 0.01 each). Serum NGF levels were normal; however, NGF production by mitogen-activated lymphocytes was higher than normal, and correlated with IgG antibody titer (p < 0.05) and with serum CRP (p < 0.05). CONCLUSIONS: Serum NGF was normal in pigeon fanciers; however, their blood lymphocytes ex vivo synthesized increased NGF in concentrations that correlated with the titer of serum IgG antibody to inhaled avian antigens. These also correlated with CRP and KL-6 levels, suggesting that antigen exposure in seropositive subjects is associated with subclinical inflammation involving coordinated synthesis of neurotrophin and immune mediators.

Adult↗
PubMed2005

Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma.

BACKGROUND: Bortezomib, a first-in-class proteasome inhibitor, is active with manageable toxicities in relapsed and/or refractory myeloma. METHODS: Bortezomib 1.0 or 1.3 mg/m2 was administered Days 1, 4, 8, and 11 every 21 days for up to 8 cycles to patients with relapsed and/or refractory myeloma participating in two Phase II trials. Dexamethasone could be added because of progressive disease after 2 cycles or stable disease after 4 cycles. Continuation of or retreatment with bortezomib was offered to patients who, in the investigator's opinion, would benefit from extended treatment. RESULTS: Sixty-three patients with relapsed/refractory myeloma treated in this extension trial received a median of 7 additional cycles of therapy, for a total of 14 cycles (range, 7-32) over a median duration of therapy of 45.1 weeks in the parent and extension studies. Seventy-eight percent of patients completed this study at the same or higher bortezomib dose than they started on during this study, and the treatment schedule of twice-weekly administration remained unchanged in 89%. Overall, 75% of patients received dexamethasone in combination with bortezomib for a median of 5 cycles starting either in the parent or extension study. The safety profile was similar between the extension and parent trials, with no evidence of new cumulative toxicity. The most commonly reported Grade 3/4 toxicities were thrombocytopenia (29%), with a consistent pattern of recovery during the rest period of each cycle, diarrhea (11%), anemia (11%), and neutropenia (10%). Neuropathy was reported less frequently. CONCLUSIONS: Retreatment with or continuation of bortezomib +/- dexamethasone beyond 6 months was safe, and toxicities were manageable, in patients with relapsed and/or refractory myeloma.

Adult↗
PubMed2005

Fusion of dendritic cells with multiple myeloma cells results in maturation and enhanced antigen presentation.

Dendritic cells (DCs) are potent antigen-presenting cells that are uniquely capable of inducing primary immune responses. Although tumour cells may directly inhibit DC maturation, exposure to tumour products may also result in their activation. Fusions of cancer cells and DCs are being explored as cancer vaccines. The effect of tumour cell fusion on DC maturation and their functional characteristics has not been defined. In the present study, immature and mature DC generated from human CD34+ and peripheral blood precursors were fused to multiple myeloma cells in the presence of polyethylene glycol. Fusion of both immature and mature DCs with tumour cells resulted in an activated phenotype. In this regard, fusion cells expressed interleukin-12, a cytokine essential for the induction of T-helper cell type 1 immunity. In contrast to immature DCs, fusion cells also strongly expressed CC-chemokine receptor R7, which is responsible for DC migration to draining lymph nodes. Fusions generated with both immature and mature DCs also potently stimulated T-cell expression of gamma-interferon and cytotoxic T lymphocyte killing of tumour targets. These findings demonstrate that tumour cell fusion induces DC maturation and the development of an activated phenotype necessary for their effectiveness as cancer vaccines.

Antigen Presentation↗
PubMed2005

Trunk muscle activity increases with unstable squat movements.

The objective of this study was to determine differences in electromyographic (EMG) activity of the soleus (SOL), vastus lateralis (VL), biceps femoris (BF), abdominal stabilizers (AS), upper lumbar erector spinae (ULES), and lumbo-sacral erector spinae (LSES) muscles while performing squats of varied stability and resistance. Stability was altered by doing the squat movement on a Smith machine, a free squat, and while standing on two balance discs. Fourteen male subjects performed the movements. Activities of the SOL, AS, ULES, and LSES were highest during the unstable squat and lowest with the Smith machine protocol (p < 0.05). Increased EMG activity of these muscles may be attributed to their postural and stabilization role. Furthermore, EMG activity was higher during concentric contractions compared to eccentric contractions. Performing squats on unstable surfaces may permit a training adaptation of the trunk muscles responsible for supporting the spinal column (i.e., erector spinae) as well as the muscles most responsible for maintaining posture (i.e., SOL).

Abdominal Muscles↗
PubMed2005

The impact of instability resistance training on balance and stability.

The most predominant literature regarding balance has emphasised the physiological mechanisms controlling stability. Topics range from extrinsic factors (environment) to intrinsic factors (i.e. muscle coordination, vestibular response). Balance is achieved through an interaction of central anticipatory and reflexive actions as well as the active and passive restraints imposed by the muscular system. However, less research has attempted to document the effects of balance on performance measures (i.e. force, power). Furthermore, short- and long-term adaptations to unstable environments need more substantial research. While force and other performance measures can be adversely affected by a lack of balance, the transferability of instability training to activities of daily living and sport is not precisely known. The applicability of instability and resistance training using unstable platforms or implements may have strong relevance in a rehabilitative or athletic setting. Therefore, a comprehensive review of the literature in this area may possibly be of benefit to practitioners who deal with the general population, athletes or persons debilitated by balance and/or stability disabilities.

Adaptation, Physiological↗
PubMed2005

Emerging trends in the clinical use of bortezomib in multiple myeloma.

Consolidation with high-dose therapy followed by single or double autologous stem cell transplantation has improved response and survival of patients with multiple myeloma (MM), but the disease remains incurable. The emergence of novel agents offer potentially significant advances in the treatment of MM. Bortezomib, a selective inhibitor of the proteasome, has proven to be safe and effective in patients with relapsed and/or refractory MM as monotherapy in phase II/III clinical trials and has produced promising activity in combination regimens with cytotoxic agents. Bortezomib-based combination regimens have also exhibited clinical benefits with manageable toxicities and may ultimately lead to improvement in the duration of response and survival of patients in the first-line setting. High complete and near-complete response rates after 2-4 cycles of bortezomib-based induction therapy may improve outcome in autologous stem cell transplantation recipients. Bortezomib also appears to overcome the adverse prognostic impact of high b2-microglobulin levels and chromosome 13 deletion, as these patients at high risk have shown responses and improved survival with bortezomib therapy. Of interest, patients whose disease previously responded to bortezomib appear to retain sensitivity to the drug, and bortezomib is being explored in maintenance regimens. The use of bortezomib in MM therapy, including ongoing randomized phase III trials, is reviewed herein.

Antineoplastic Agents↗
PubMed2004

Strategies to improve the outcome of stem cell transplantation in multiple myeloma.

Multiple myeloma (MM) is an incurable hematological malignancy with an average survival of 3 years with conventional therapy. Allogeneic hematopoietic cell transplantation (allo-HCT) may cure some patients, but has been associated with a very high transplantation-related mortality (TRM) of over 40%.(1) In contrast to allo-HCT, autologous hematopoietic cell transplantation (AHCT) has been much safer, with a TRM <3% in the 1990s. Therefore, in the last 15 years AHCT has become a common procedure for MM patients. The widespread use of AHCT has been associated with a median survival of 55-72 months,(2,3,4,5,6) and two large randomized trials have shown that AHCT is superior to conventional chemotherapy for the treatment of MM.(3,7) Approaches to improve the outcome of stem cell transplantation for MM patients include consideration of patient status, efficacy and toxicity of induction therapy, source of hematopoietic rescue, conditioning regimens, and maintenance therapy. Recent attempts to improve outcome include tandem AHCT, AHCT followed by RIC (reduced intensity conditioning) allo-HCT, and allo-HCT with T-cell depletion and subsequent donor-lymphocyte infusions (DLI), while novel therapies and improved supportive care may improve the overall survival (OS) of all MM patients with or without transplantation.

Hematopoietic Stem Cell Transplantation↗
PubMed2004

Proteasome inhibition in hematologic malignancies.

Hematologic malignancies, including multiple myeloma (MM), will account for more than 100,000 new cases of cancer and over 57,000 deaths in the United States in 2003. Treatment of MM is a serious challenge, because despite a variety of available therapies, median survival is short. A new therapeutic area focuses on inhibiting the activity of the proteasome, a 26S protease complex involved in cell cycle regulation, cell adhesion, inflammation, and protein turnover. The novel proteasome inhibitor, bortezomib (Velcade), was recently approved for use in patients with refractory and relapsed MM and to date is the only proteasome inhibitor to have entered clinical trials. Bortezomib has demonstrated activity with manageable toxicity in a variety of hematologic malignancies in addition to MM, including leukemia and non-Hodgkin's lymphoma. This article reviews clinical information on bortezomib in hematologic malignancies both as monotherapy and in combination with dexamethasone. Preliminary reports of bortezomib in combination with Doxil (pegylated liposomal doxorubicin), melphalan, and thalidomide are discussed, and current trials are described. Available data suggest that bortezomib will be useful in the treatment of a variety of hematologic malignancies.

Asthenia↗
PubMed2004

Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity.

OBJECTIVES: To determine the progression-free survival at 12 weeks, to evaluate the toxic effects, and to analyze the biological activity of thalidomide in patients with relapsed multiple myeloma (MM) after high-dose chemotherapy and stem cell transplantation. PATIENTS AND METHODS: From 1999 to 2001, we performed a multicenter prospective phase 2 study in patients with MM that relapsed after high-dose chemotherapy and stem cell transplantation to evaluate the efficacy of oral thalidomide, with dose escalation from 200 to 600 mg/d over 12 weeks and a subsequent maintenance phase of 200 mg/d for up to 1 year. Outcome was correlated with serum and plasma levels of vascular endothelial growth factor and serum levels of tumor necrosis factor alpha, soluble intercellular adhesion molecule 1, interferon gamma, interleukin (IL) 2, and IL-6 during treatment. RESULTS: Thirty patients were treated (19 men and 11 women; median age, 58 years). The median number of prior therapies was 5, and the median duration from diagnosis of MM to study enrollment was 4.3 years. The 12-week progression-free survival rate was 67% (95% confidence interval [CI], 48%-86%). The observed response rate (partial response plus minor response) was 43% (95% CI, 28%-60%) with a median duration of 6 months. Attributable toxicities included constipation, fatigue, rash, and neuropathy, which was dose limiting in 8 patients (27%). Dose escalation from 200 to 600 mg/d was achieved in 50% of patients. Although responses were observed with lower doses, possibly eliminating the need to escalate the dose, responses were also seen in patients who completed the dose escalation. Some patients had disease progression while receiving the maintenance dose of 200 mg/d. Analysis of biomarker assays did not identify any biomarker associated with greater response, but a significant increase in levels of soluble intercellular adhesion molecule 1, IL-2, and interferon gamma was seen with thalidomide therapy. CONCLUSION: The optimal thalidomide dose varies, and adverse effects can be dose limiting. The dose of thalidomide therapy should be based on the individual patient to ensure that it is well tolerated and that a response is achieved.

Disease Progression↗
PubMed2004

Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid.

The synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its chemical derivatives induce differentiation and apoptosis of human leukemia cells. The precise mechanisms responsible for the effects of CDDO, however, remain unclear. In the present study, we examined the effects of CDDO and its C-28 imidazolide ester (CDDO-Im) on apoptosis of multiple myeloma (MM) cells. The results show that both CDDO and CDDO-Im are potent inducers of MM cell apoptosis and that CDDO-Im is more active than CDDO. CDDO-Im treatment was associated with (a) depletion of glutathione, (b) increases in reactive oxygen species, (c) a reduction of the Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE) inhibitory protein, (d) activation of caspase-8, and (e) a decrease of the mitochondrial transmembrane potential. The reducing agents, N-acetyl-L-cysteine, DTT, and catalase inhibited each of these CDDO-Im-induced proapoptotic signals. Inhibition of caspase-8 with z-IETD-fmk also abrogated CDDO-Im-induced decreases of the mitochondrial transmembrane potential and inhibited apoptosis. These results demonstrate that CDDO-Im disrupts intracellular redox balance and thereby activates the extrinsic caspase-8-dependent apoptotic pathway. We further show that CDDO-Im induces apoptosis of primary MM cells at submicromolar concentrations and that MM cells are more sensitive to this agent than normal bone marrow mononuclear cells. These results suggest that CDDO compounds have potential as new agents for the treatment of MM.

Antioxidants↗
PubMed2003

Biologic sequelae of c-Jun NH(2)-terminal kinase (JNK) activation in multiple myeloma cell lines.

Although c-Jun NH(2)-terminal kinase (JNK) is activated by treatment with therapeutic agents, the biologic sequelae of inhibiting constitutive activation of JNK has not yet been clarified. In this study, we examine the biologic effect of JNK inhibition in multiple myeloma (MM) cell lines. JNK-specific inhibitor SP600125 induces growth inhibition via induction of G1 or G2/M arrest in U266 and MM.1S multiple myeloma cell lines, respectively. Neither exogenous IL-6 nor insulin-like growth factor-1 (IGF-1) overcome SP600125-induced growth inhibition, and IL-6 enhances SP600125-induced G2/M phase in MM.1S cells. Induction of growth arrest is mediated by upregulation of p27(Kip1), without alteration of p53 and JNK protein expression. Importantly, SP600125 inhibits growth of MM cells adherent to bone marrow stromal cells (BMSCs). SP600125 induces NF-kappaB activation in a dose-dependent fashion, associated with phosphorylation of IkappaB kinase alpha (IKKalpha) and degradation of IkappaBalpha. In contrast, SP600125 does not affect phosphorylation of STAT3, Akt, and/or ERK. IKK-specific inhibitor PS-1145 inhibits SP600125-induced NF-kappaB activation and blocks the protective effect of SP600125 against apoptosis. Our data therefore demonstrate for the first time that inhibiting JNK activity induces growth arrest and activates NF-kappaB in MM cells.

Anthracenes↗
PubMed2003

A workshop on the marrow microenvironment and hematological malignancy.

The Division of Cancer Biology of the National Cancer Institute hosted a workshop on hematological malignancies and the marrow microenvironment in Rockville, Maryland in the fall of 2002. There were 22 invited participants from the United States, Canada, and Europe, and the workshop was organized into disease-specific sessions. The sessions were designed to explore the basic science and therapeutic applications related to the stromal and nonstromal components of the marrow in malignant hematological diseases.

Animals↗
PubMed2003

Treatment recommendations in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.

This presentation represents consensus recommendations for the treatment of patients with Waldenstrom's macroglobulinemia (WM), which were prepared in conjunction with the second International Workshop held in Athens, Greece during September 2002. The faculty adopted the following statements for the management of patients with Waldenstrom's macroglobulinemia: (1) Alkylating agents, nucleoside analogues, and rituximab are reasonable choices for first line therapy of WM. (2) Both cladribine and fludarabine are reasonable choices for the therapy of WM. (3) Combinations of alkylating agents, nucleoside analogues, or rituximab should at this time be encouraged in the context of a clinical trial. (4) In WM, rituximab can cause a sudden rise in serum IgM and viscosity levels in certain patients, which may lead to complications, therefore close monitoring of these parameters and symptoms of hyperviscosity is recommended for WM patients undergoing rituximab therapy. (5) For relapsed disease, it is reasonable to use an alternate first line agent or re-use of the same agent; however, since autologous stem cell transplantation may have a role in treating patients with relapsed disease it is recommended that for patients in whom autologous transplantation is seriously being considered, exposure to alkylator or nucleoside analogue drugs should be limited. (6) Combination chemotherapy for patients who can tolerate myelotoxic therapy, thalidomide alone or with dexamethasone, can reasonably be considered to have relapsed. (7) Autologous stem cell transplantation may be considered for patients with refractory or relapsing disease. (8) Allogeneic transplantation should only be undertaken in the context of a clinical trial. (9) Plasmapheresis should be considered as interim therapy until definitive therapy can be initiated. (10) Rituximab should be considered for patients with IgM-related neuropathies. (11) Corticosteroids may be useful in the treatment of symptomatic mixed cryoglobulinemia. (12) Splenectomy is rarely indicated but has been used to manage painful splenomegaly and hypersplenism.

Amyloidosis↗