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Anthony D Ho

Publications and source records attributed to Anthony D Ho.

At least 55 records · Page 3Linked to original sources
PubMed2004

Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity.

The balance of arginine metabolism via nitric oxide synthase (NOS) or arginase is an important determinant of the inflammatory response of murine macrophages and dendritic cells. Here we analyzed the expression of the isoform arginase I in human myeloid cells. Using healthy donors and patients with arginase I deficiency, we found that in human leukocytes arginase I is constitutively expressed only in granulocytes and is not modulated by a variety of proinflammatory and anti-inflammatory stimuli in vitro. We demonstrate that arginase I is localized in azurophil granules of neutrophils and constitutes a novel antimicrobial effector pathway, likely through arginine depletion in the phagolysosome. Our findings demonstrate important differences between murine and human leukocytes with respect to regulation and function of arginine metabolism via arginase.

Animals↗
PubMed2004

Effect of tetravalent bispecific CD19xCD3 recombinant antibody construct and CD28 costimulation on lysis of malignant B cells from patients with chronic lymphocytic leukemia by autologous T cells.

To develop an effective antitumor immunotherapy for B-lineage non-Hodgkin's lymphoma, we constructed a tetravalent tandem diabody (tanDb) specific for both human CD19 (B-cell marker) and CD3 (T-cell antigen). Here, we report the effective killing of malignant primary B cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) by autologous T cells induced by tanDb at very low E:T ratios. Mononuclear cells from patients with B-CLL were cultured with bispecific antibody fragments in either the presence or absence of monospecific anti-CD28 antibody. Use of tetravalent tanDbs caused almost quantitative elimination of malignant B cells from the blood samples of 19 patients and some cytotoxic activity in 3 of 23 analyzed cases. In contrast, the structurally similar but bivalent diabody and single-chain diabody demonstrated nearly no antitumor activity in an autologous system. tanDb-induced activation and proliferation of T cells occurred only in the presence of CD19+ target cells. Expression of the B7-1 (CD80) and B7-2 (CD86) molecules on the surface of leukemia cells made unnecessary the additional CD28-costimulation of T cells. When only a few tanDb molecules were present, the effect of CD28 costimulation on T-cell activation was more pronounced. Depending on the patient sample, we observed a 10- to 1,000-fold decrease of the half-maximal concentrations of tanDb for cell lysis. Upon CD28 crosslinking by agonistic MAb, specific tumor cell lysis was found at tanDb concentrations as low as 0.5 pM. These data demonstrate that the tetravalent CD19xCD3 tanDb might be a promising tool for the immunotherapy of human B-cell leukemias and lymphomas.

Aged↗
PubMed2004

Tuning the volume of the immune response: strength and persistence of stimulation determine migration and cytokine secretion of dendritic cells.

Migration to lymph nodes and secretion of cytokines are critical functions of mature dendritic cells (DCs); however, these 2 functions are not necessarily linked. This is the first report showing that quantitative differences in identical signaling pathways determine DC migration and cytokine secretion. Using different polymerized forms of CD40 ligand, we demonstrate that the strength and persistence of CD40 signaling can induce either function. Induction of monocyte-derived DC (MoDC) migration required a weak and transient CD40 signal, whereas strong and persistent CD40 signaling blocked migration and biased toward cytokine secretion. In contrast to MoDCs, CD40 activation of CD1c+ peripheral blood DCs (PBDCs) induced a nonpersistent, intracellular signaling profile resulting in migratory-type DCs unable to secrete interleukin-12p70 (IL-12p70). Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38K activation synergistically mediated cytokine secretion, whereas migration was enhanced by p38K activation but reduced by persistent ERK1/2 activity. This model of signal strength and persistence also applied when stimulating DCs with intact microbes. Thus, a novel concept emerges in which the type of immune response induced by DCs is tuned by the strength and persistence of DC activating signals.

CD40 Antigens↗
PubMed2004

Molecular evidence for stem cell function of the slow-dividing fraction among human hematopoietic progenitor cells by genome-wide analysis.

The molecular mechanisms that regulate asymmetric divisions of hematopoietic progenitor cells (HPCs) are not yet understood. The slow-dividing fraction (SDF) of HPCs is associated with primitive function and self-renewal, whereas the fast-dividing fraction (FDF) predominantly proceeds to differentiation. CD34+/CD38- cells of human umbilical cord blood were separated into the SDF and FDF. Genomewide gene expression analysis of these populations was determined using the newly developed Human Transcriptome Microarray containing 51 145 cDNA clones of the Unigene Set-RZPD3. In addition, gene expression profiles of CD34+/CD38- cells were compared with those of CD34+/CD38+ cells. Among the genes showing the highest expression levels in the SDF were the following: CD133, ERG, cyclin G2, MDR1, osteopontin, CLQR1, IFI16, JAK3, FZD6, and HOXA9, a pattern compatible with their primitive function and self-renewal capacity. Furthermore, morphologic differences between the SDF and FDF were determined. Cells in the SDF have more membrane protrusions and CD133 is located on these lamellipodia. The majority of cells in the SDF are rhodamine-123dull. These results provide molecular evidence that the SDF is associated with primitive function and serves as basis for a detailed understanding of asymmetric division of stem cells.

ADP-ribosyl Cyclase↗
PubMed2004

Gene expression patterns in acute myeloid leukemia correlate with centrosome aberrations and numerical chromosome changes.

Centrosomes, which mediate accurate chromosome segregation during mitosis, undergo duplication precisely once per cell division at the G1/S boundary. Recently, we described centrosome aberrations as a possible cause of aneuploidy in acute myeloid leukemia (AML) and found a correlation of the percentage of cells carrying abnormal centrosomes to their cytogenetic risk profile. To elucidate the molecular events responsible for the development of centrosome aberrations in AML, tumor RNA of 29 AML samples was hybridized to cDNA microarrays. The microarrays comprised some 2800 different genes with relevance to hematopoiesis, tumorigenesis and mitosis and included a set of 359 centrosome-associated genes. We identified two gene expression signatures, which allowed an accurate classification according to the extent of centrosome aberrations and the ploidy status in 28 of 29 patients each. Specifically, 18 genes were present in both signatures, including genes that code for cell cycle regulatory proteins (cyclin A2, cyclin D3, cyclin H, CDK6, p18INK4c, p21Cip1, PAK1) and centrosome-associated proteins (pericentrin, alpha2-tubulin, NUMA1, TUBGCP2, PRKAR2A). In conclusion, the high expression of centrosome-associated genes matches the description of centrosome aberrations in several tumor types. Moreover, in AML the identification of G1/S-phase stimulatory genes suggests that one mechanism of aneuploidy induction might be the deregulation of centrosome replication at the G1/S boundary.

Aneuploidy↗
PubMed2004

Prophylactic treatment of known ifosfamide-induced encephalopathy for chemotherapy with high-dose ifosfamide?

We report about a case of advanced Ewing sarcoma in a 30-year-old woman. Initial treatment was started according to the Euro-Ewing 99 protocol. During the initial therapy, an ifosfamide-induced encephalopathy occurred as status epilepticus. Because of cerebral toxicity, the following chemotherapies went without ifosfamide. During final radiotherapy multiple lung metastasis were diagnosed. After two cycles of chemotherapy with cyclophosphamide and topotecan (no response), left thoracotomy, and palliative pneumectomy, the patient was transferred to our ward for further treatment. Undergoing two cycles of chemotherapy with ifosfamide 4 g/m(2) intravenously for 3 consecutive days followed by high-dose chemotherapy (HDCT) according to the ICE-regimen (ifosfamide 2 g/m(2), carboplatin 200 mg/m(2), and etoposide 2 x 100 mg/m(2) intravenously for 6 consecutive days), and peripheral blood stem cell transplantation (PBSCT), complete remission was achieved. Under preventive therapy with methylene blue, thiamin, and glucose 5% infusions, no encephalopathy occurred.

Adult↗
PubMed2004

Secondary follicular lymphoma of the bone, transformed into large cell lymphoma, in a patient with chronic lymphocytic leukaemia: an uncommon manifestation of Richter's syndrome.

Patients with chronic lymphocytic leukemia (CLL) are at a significantly increased risk of developing a second malignant neoplasm in the course of their disease. The occurrence of large cell lymphoma [Richter's syndrome (RS)] has been described in approximately 3-5% of CLL patients. Other types of secondary lymphoid malignancies are extremely rare. Here we describe a patient, heavily pretreated, with long history of CLL who developed a secondary follicular lymphoma, transformed into a diffuse large cell lymphoma (LCL), with isolated manifestation in the bone, a very rare manifestation of RS. CLL and LCL cells were of distinct clonal origin, as documented by DNA sequencing of the CDR3 regions. Twelve months after the completion of chemo- and local radiotherapy, the patient is still in remission.

Aged↗
PubMed2004

High-dose melphalan with autologous stem cell transplantation after VAD induction chemotherapy for treatment of amyloid light chain amyloidosis: a single centre prospective phase II study.

Amyloid light chain (AL) amyloidosis is the result of a clonal plasma cell expansion, in which monoclonal light chains transform to amyloid deposit in various tissues and can lead to organ dysfunction and organ failure. The median survival of patients with AL amyloidosis without therapy is 10-14 months. With high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), haematological and clinical remission rates of up to 50% of treated patients have been reported from phase II studies. HDM followed by ASCT appears to prolong survival in patients, if haematological remission can be reached. In this phase II study, we evaluated vincristine, adriamycin and dexamethasone (VAD) as induction chemotherapy prior to stem cell mobilization and HDM with ASCT. The regimen was, in general, feasible in patients with AL amyloidosis, but VAD chemotherapy had a considerable World Health Organization (WHO) grade III-IV toxicity (25%) and mortality (7%) rate. VAD pretreatment did not interfere with stem cell mobilization and HDM with ASCT was possible in 86% of patients. The overall treatment efficacy was comparable with reported results of HDM and ASCT without preceding chemotherapy. We could not show an additional benefit of VAD induction in terms of increasing haematological response rate; however the 13% mortality rate after HDM and ASCT in our series was lower than the previous report.

Adult↗
PubMed2004

Significant thrombocytopenia associated with the addition of rituximab to a combination of fludarabine and cyclophosphamide in the treatment of relapsed follicular lymphoma.

Fludarabine in combination with cyclophosphamide is an effective treatment for newly diagnosed as well as relapsed follicular lymphoma. The anti-CD20 antibody rituximab has been employed successfully for the same indications. No such data were available on a combined use of these agents. Therefore, we conducted a phase II study to evaluate the safety and efficacy of a combination of rituximab (375 mg/m2), fludarabine (4 x 25 mg/m2) and cyclophosphamide (1 x 750 mg/m2), for the treatment of relapsed follicular lymphoma. An unexpected, severe hematologic toxicity with significant, prolonged thrombocytopenias WHO grade III/IV in 6 (35%) of 17 patients treated in total occurred, leading to early termination of the trial. Cytologic and serologic analyses point toward a direct toxic effect. Older patients (mean age 64.7 vs. 56.5 yr) were significantly (P = 0.02) more likely to suffer from this toxicity, whereas no other clinical or hematologic parameter differed statistically between the patients suffering from thrombocytopenia and those who did not. The addition of rituximab to fludarabine/cyclophosphamide employed at doses given above in relapsed follicular lymphoma may have led to this increase in thrombocytopenias. Therefore, caution should be exercised when combining these drugs for the treatment of patients with relapsed follicular lymphoma, especially when treating older patients.

Adult↗
PubMed2004

Evaluation of mineralized collagen and alpha-tricalcium phosphate as scaffolds for tissue engineering of bone using human mesenchymal stem cells.

Owing to their plasticity and high proliferation capacity in vitro, mesenchymal stem cells (MSC) isolated from human bone marrow are promising candidates for use in tissue engineering approaches for the repair or replacement of mesenchymal tissues such as bone, cartilage or tendon. In keeping with the tissue engineering concept, these cells are cultivated on three-dimensional (3D) scaffolds to replace 3D tissue defects. Among the scaffolds tested for tissue engineering of bone, those containing phosphorus and calcium, as natural bone does, are the most promising candidates for this purpose. In this study, MSC from five patients were isolated from bone marrow. After in vitro expansion, cells were cultivated and differentiated towards the osteogenic lineage on mineralized collagen sponges and alpha-tricalcium phosphate (alpha-TCP). To analyze how appropriate these scaffolds would be for tissue engineering purposes, we established an in vitro characterization system to describe seeding efficiency, cell distribution and proliferation behavior on each scaffold. Real-time reverse transcriptase polymerase chain reaction quantification of important genes involved in osteogenic differentiation [e.g. bone sialoprotein (BSP), bone morphogenic protein 2, alkaline phosphatase and osteocalcin] was used to monitor the differentiation process of cells seeded on mineralized collagen and alpha-TCP. Using this in vitro characterization, we were able to demonstrate effective 3D growth of MSC on both scaffolds investigated. Improved osteogenic differentiation was observed on the scaffolds as compared to control monolayers. Of the two matrices, mineralized collagen was superior to alpha-TCP with regard to seeding efficacy (98 vs. 67%, p = 0.0003), increase in osteogenic marker genes (BSP expression on day 24, Pcollagen vs. TCP = 0.046) and 3D cell alignment (cell infiltration up to 500 vs. 200 microm). In conclusion, our data suggest that mineralized collagen is a promising candidate for use as a scaffold in tissue engineering of bone.

Adult↗
PubMed2004

Role of histone deacetylase inhibitors in the treatment of cancer (Review).

Acetylation and deacetylation of nucleosomal histones play an important role in the modulation of chromatin structure, chromatin function and in the regulation of gene expression. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two opposing classes of enzymes, which tightly control the equilibrium of histone acetylation. An imbalance in the equilibrium of histone acetylation has been associated with carcinogenesis and cancer progression. So far, a number of structurally distinct classes of compounds have been identified as HDAC inhibitors including the short-chain fatty acids, hydroxamates, cyclic tetrapeptides and benzamides. These compounds lead to an accumulation of acetylated histone proteins both in tumor cells and in normal tissues. HDAC inhibitors are able to activate differentiation, to arrest the cell cycle in G1 and/or G2, and to induce apoptosis in transformed or cancer cells. Attention is currently being drawn to molecular mechanisms involving histone deacetylases. An induction of p21(WAF/CIP1) and a suppression of angiogenic stimulating factors have been observed in tumor cells following exposure to HDAC inhibitors. In xenograft models, several HDAC inhibitors have demonstrated antitumor activity with only few side effects. Several clinical trials showed that HDAC inhibitors in well tolerated doses have significant antitumoral activities. A combination of HDAC inhibitors with differentiation-inducing agents and cytotoxic drugs is an innovative therapeutic strategy that carries the potential for significant improvements in the treatment of cancer.

Animals↗
PubMed2003

[Stem cells in hematology and oncology].

100 years ago, hematopoietic stem cells were postulated as blood lymphocyte-like cells. Within the last 20 years, the frequency of autologous and allogeneic transplantation of hematopoietic stem cells has increased. Hematopoietic growth factors allow the stem cells' mobilization from the bone marrow into the peripheral blood. Quantification of these hematopoietic stem cells by means of flow cytometry can be achieved within hours. A minimum quantity of 2.0 x 10(6) CD34-positive blood stem cells per kg body weight allows hematopoietic reconstitution within 14 days after infusion of the transplant. High-dose therapy followed by the transplantation of autologous blood stem cell transplantation is an established therapy for relapsed high-grade lymphoma and multiple myeloma. Especially in cases of subgroups of acute myeloid leukemia, myelodysplastic syndrome and myeloproliferative syndromes, myeloablative high-dose therapy followed by the transplantation of allogeneic stem cells leads to a better prognosis. Reduced conditioning before an allogeneic transplantation decreases early lethality. The combination of myeloablative high dose therapy followed by autologous hematopoietic stem cell transplantation and allogeneic stem cell transplantation will lead to maximum tumor reduction and development of a graft-versus-leukemia reaction with reduced toxicity. Hematopoietic stem cell transplantation is to be carried out in studies.

Acute Disease↗
PubMed2003

Development of leukocytoclastic vasculitis in a patient with multiple myeloma during treatment with thalidomide.

Thalidomide, an agent with antiangiogenic and immunomodulatory properties, is therapeutically effective in multiple myeloma, leprosy, and autoimmune diseases. The most common clinical toxicities of thalidomide are constipation, neuropathy, fatigue, sedation, rash, tremor, and edema. We here describe for the first time a patient who developed leukocytoclastic vasculitis during therapy with thalidomide. Of the 260 patients treated with thalidomide in our institution, this is the first patient who developed autoimmune disease. We conclude that patients with malignant disorders who are treated with thalidomide should be carefully monitored for the development of autoimmune disorders. Whether autoimmune phenomena also occur during treatment with new drugs such as PS-341 or potent immunomodulatory agents remains to be evaluated.

Adjuvants, Immunologic↗
PubMed2003

Lack of evidence for inhibition of angiogenesis as a central mechanism of the antiarthritic effect of methotrexate.

OBJECTIVES: The aim of this study was to investigate whether methotrexate (MTX) has an antiangiogenic effect and whether this property plays a role in the control of rheumatoid arthritis (RA). METHODS: A human placenta angiogenesis assay was used to examine the antiangiogenic effects of MTX in vitro. In addition, DBA/1 mice were used to compare the antiarthritic effect of MTX in collagen-induced arthritis (CIA) and its antiangiogenic effect in a murine in vivo matrigel model for angiogenesis. RESULTS: The spreading of microvessels from placental vessel fragments was not significantly inhibited by MTX. Treatment with MTX reduced significantly the incidence of CIA in DBA/1 mice in a dose-dependent manner. However, treatment with the same doses of MTX did not significantly reduce vessel growth in subcutaneous depots of bFGF-enriched matrigel. CONCLUSION: These data support the hypothesis that inhibition of angiogenesis does not significantly contribute to the antiarthritic effect of MTX seen in patients and animal models for RA. Therefore, the combination of MTX with antiangiogenic drugs appears to be a rational strategy in the treatment of RA.

Angiogenesis Inhibitors↗
PubMed2003

Centrosomal aberrations in primary invasive breast cancer are associated with nodal status and hormone receptor expression.

Our purpose was to assess the presence of centrosomal aberrations as measured by immunohistochemistry in primary invasive breast cancer and their association with established and proposed prognostic factors. Tissue sections of 103 primary invasive breast cancers were examined using centrosome-specific antibodies to pericentrin and gamma-tubulin. At least 3 different tumor regions per case were examined to determine maximum centrosomal aberration levels, which represent the proportion of cells with abnormal centrosomes in the region with the highest percentage of cells with centrosomal aberrations. The chi(2) test was performed to evaluate the association of maximum centrosomal aberration levels with patient age; tumor size; nodal status; nuclear grade; hormone receptor and Her2/neu expression; proportion of Ki67-, p53- and Bcl-2-positive tumor cells; DNA index; S-phase fraction; and proliferation index. With pericentrin immunohistochemistry, maximum centrosomal aberration levels >35% were detectable in 92 of the 103 breast carcinomas (89%). We found a highly significant correlation of maximum centrosomal aberration levels above 35% with axillary nodal tumor involvement (p < 0.0001) and the absence of hormone receptors (p < 0.0001). In addition, there was a borderline significant relationship with age <50 years (p = 0.050) and Her2/neu overexpression (p = 0.050). Among node-negative patients, maximum centrosomal aberration levels >35% were also associated with an increased DNA index (p = 0.006). In a subset of patients, additional staining of centrosomes with a monoclonal anti-gamma-tubulin antibody essentially confirmed these results. In primary invasive breast cancer, centrosomal aberrations are associated with those factors predicting a more aggressive course of disease. This might indicate a fundamental role of centrosomal dysfunction in disease evolution, possibly as a result of chromosome missegregation during mitosis.

Adult↗
PubMed2003

[Stem cell transplantation in primary systemic vasculitis].

BACKGROUND: Many patients with various autoimmune diseases fail to respond to conventional immunosuppressive therapy and develop irreversible organ damage. In some cases the complications might be fatal. Furthermore, prolonged immunosuppression with cyclophosphamide or corticosteroids often leads to long-term side effects, cumulative organ damage, and development of secondary malignancies. THERAPY: Thus, short-term, high-dose immunosuppressive therapy with autologous stem cell transplantation might be an alternative for otherwise refractory patients. This concept has been used mainly in patients with scleroderma, systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. PATIENTS: Patients with primary systemic vasculitis (PSV) seem to be suitable candidates for high-dose chemotherapy (HDCT). Although complete, long-term remissions are possible with standard immunosuppressive therapy, there is a subgroup of patients who cannot be cured by standard therapy. They need long-term immunosuppression and eventually die due to progression of the disease or cumulative therapy-related toxicity. In large series, the 5-year mortality rate was > 20%. The severity of vasculitis rather than the distinction between subgroups should determine whether HDCT might be a life-saving treatment. RESULTS AND CONCLUSION: Careful patient selection with the help of scoring systems and determination of the optimal time in the course of disease are now the major goals in the approach to HDCT. First reports as well as our own single-center experience in HDCT with a limited number of patients with severe PSV have shown that long-term remissions are possible even in patients refractory to conventional immunosuppression.

Adrenal Cortex Hormones↗