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Ulrike Heider

Publications and source records attributed to Ulrike Heider.

At least 19 recordsLinked to original sources
PubMed2006

Circulating proteasome levels are an independent prognostic factor for survival in multiple myeloma.

The proteasome is a proteolytic complex for intracellular degradation of ubiquitinated proteins which are involved in cell-cycle regulation and apoptosis. A constitutively increased proteasome activity has been found in myeloma cells. We studied circulating proteasome levels and their prognostic significance in sera of 50 control subjects, 20 persons with monoclonal gammopathies of undetermined significance (MGUS), and 141 previously untreated patients with multiple myeloma (MM) by an anti-20S proteasome enzyme-linked immunoabsorbent assay (ELISA). Serum proteasome concentrations were significantly elevated in MM compared with controls (P < .001), in MM versus MGUS (P = .03), and in active (n = 101) versus smoldering (n = 40) MM (P < .001). In patients with active MM, there was a significant (P < .001) decrease from pretreatment to post-treatment proteasome concentrations in responders to chemotherapy, but not in nonresponders. Circulating proteasome levels were identified as a prognostic factor for overall survival in the univariate (P < .001 log-rank test) and in the multivariate (hazard ratio, 4.38) survival analysis in patients with active MM. We demonstrate for the first time that increased serum proteasome concentrations correlate with advanced disease and are an independent prognostic factor in MM.

Female↗
PubMed2006

Angiogenesis in multiple myeloma.

Multiple myeloma (MM) was the first haematological malignancy in which a prognostic relevance of bone marrow microvessel density (MVD) was shown. Myeloma-induced angiogenesis involves either the direct production of angiogenic molecules by myeloma cells or their induction in bone marrow stromal cells or endothelial cells (EC). Recent data demonstrate an increased angiogenic potential and a paracrine stimulatory effect of bone marrow EC on plasma cells (PC) in MM. Soluble angiogenic factors are elevated in bone marrow (BM) and in peripheral blood samples from myeloma patients. Furthermore, correlation with disease stage and prognosis was shown for serum levels of the angiogenic factors basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF). In this review we summarize recent data which give strong evidence for an increased angiogenic activity in bone marrow microenvironment and support the hypothesis that angiogenesis is not only an epiphenomenon of tumour growth but may also promote PC growth in MM.

Angiogenic Proteins↗
PubMed2006

Bone markers in multiple myeloma.

Bone disease, a hallmark of multiple myeloma occurs in the majority of the patients, is associated with bone pain, fractures, hypercalcemia and has major impacts on quality of life. Myeloma is characterized by a unique form of bone disease with osteolytic bone destruction that is not followed by reactive bone formation, resulting in extensive lytic lesions. This review will focus on the pathophysiology of osteoclast activation and osteoblast inhibition in multiple myeloma and on biochemical markers of bone turnover. Since osteolytic lesions do not rapidly heal in myeloma, X-rays cannot reflect the activity of bone disease during antimyeloma treatment. Activity in bone turnover does not parallel changes in monoclonal protein levels. Thus, there is a need for biochemical markers reflecting disease activity in bone. The utility, prognostic implications and limitations of classical and novel markers of bone remodeling (e.g. ICTP, NTx, TRACP-5b, osteoprotegerin, sRANKL) will be discussed in this overview.

Biomarkers↗
PubMed2006

Differential display of genes expressed in the filarial nematode Litomosoides sigmodontis reveals a putative phosphate permease up-regulated after depletion of Wolbachia endobacteria.

Mutualist symbiotic Wolbachia endobacteria are found in most filarial nematodes. Wolbachia are essential for embryogenesis and for larval development into adults, and thus represent a new target for anti-filarial drug development. Tetracycline antibiotics deplete Wolbachia in animal model filaria Litomosoides sigmodontis and Brugia pahangi, as well as in the human parasites Brugia malayi, Onchocerca volvulus and Wuchereria bancrofti. Very little is known about the molecular details of the symbiotic interaction between Wolbachia and filarial nematodes. Nematode genes that respond to anti-Wolbachia antibiotic treatment may play important roles in the symbiosis. Differential display PCR was used to detect several candidate genes that are up-regulated after 3, 6, 15, 30 and 36 days of tetracycline treatment. One of these genes, Ls-ppe-1, was similar to a family of phosphate permeases, and had putative orthologues in O. volvulus and B. malayi. Ls-ppe-1 steady-state mRNA levels were elevated by day 3-6 of treatment, and remained elevated through to 70 days post-treatment. In Caenorhabditis elegans, the knockdown of a homologous phosphate permease results in embryonic lethality, with the production of degenerating embryos, a phenotype also seen in filarial nematodes after depletion of Wolbachia with tetracycline. The potential role of Ls-ppe-1 in the nematode-bacterial symbiosis is discussed.

Adaptation, Physiological↗
PubMed2006

RNAi mediated silencing of actin expression in adult Litomosoides sigmodontis is specific, persistent and results in a phenotype.

In this report, the actin gene from the rodent filaria Litomosoides sigmodontis was successfully knocked down by RNA interference (RNAi). By establishing controls for measuring off-target RNAi effects we showed that lower concentrations of double stranded RNA (dsRNA) are more effective than those previously reported. While all tested concentrations reduced Ls-act transcription, the concentration that consistently reduced Ls-act expression to <10% of the controls was 3.5 microM, a 10-fold lower concentration than that used previously for Brugia malayi. The knockdown of Ls-act was specific as Ls-hsp60 and Ls-gst2 showed no reduction in transcription. Soaking of nematodes with dsRNA coding for the Caenorhabditis elegans yolk receptor (Ce-rme-2), which has no orthologues in filaria, did not affect Ls-act transcription, further demonstrating that the reduction in Ls-act was specific and not due to toxicity of dsRNA or off-target effects. After transferring the nematodes to dsRNA-free medium, the inhibition of Ls-act persisted for at least 72 h, the length of the observation time. Additionally, two phenotypes were seen with Ls-act RNAi. First, adults observed 48 and 72 h after the start of the experiment showed paralysis, as demonstrated by being stretched out and having slower movements. Second, the release of microfilariae was significantly inhibited after soaking with dsRNA. Thus, the use of lower dsRNA concentrations and proper controls for off-target effects make RNAi a viable method to study the function of filarial genes.

Actins↗
PubMed2006

Peroxisome proliferator-activated receptor-gamma ligands inhibit proliferation and induce apoptosis in mantle cell lymphoma.

Peroxisome proliferator-activated receptor-gamma, a nuclear receptor and transcription factor, and its natural and synthetic ligands have become a focus of novel approaches to induction of apoptosis in solid tumors and hematologic malignancies, including malignant B-lineage cells. The effect on mantle cell lymphoma, a subtype with dismal prognosis, has not yet been analyzed. We investigated the effect of 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), pioglitazone (PGZ) or rosiglitazone (RGZ) on human mantle cell lymphoma cell lines (GRANTA-519, Hbl-2 and JeKo-1). Mantle cell lymphoma cell lines exhibited a high expression of Peroxisome proliferator-activated receptor-gamma protein in Western blot analysis. MTT assays revealed anti-proliferative effects induced by both 15d-PGJ2, the natural activator of Peroxisome proliferator-activated receptor-gamma, and PGZ and RGZ, synthetic Peroxisome proliferator-activated receptor-gamma ligands, in a dose-dependent manner. At a dose of 50 micromol/l, 15d-PGJ2 induced growth inhibition in all cell lines. The anti-proliferative effect of PGZ and RGZ was slightly lower. Induction of apoptosis was indicated by annexin V staining. At a dose of 50 micromol/l, 15d-PGJ2 led to apoptosis in all cell lines (87-99%) after 48 h of incubation. Again, the apoptotic effect with thiazolidinediones was slightly lower at the same dose level. This is the first study evaluating Peroxisome proliferator-activated receptor-gamma expression and its therapeutic implications in human mantle cell lymphoma cells. Thiazolidinediones comprise anti-lymphoma activity in vitro and should be further explored for the treatment of mantle cell lymphoma.

Annexin A5↗
PubMed2006

Histone deacetylase inhibitors reduce VEGF production and induce growth suppression and apoptosis in human mantle cell lymphoma.

OBJECTIVES: Mantle cell lymphoma (MCL) is an incurable disease with an aggressive course and novel treatment strategies are urgently needed. The purpose of this study was to evaluate the effects of histone deacetylase (HDAC) inhibitors, a new group of antiproliferative agents, on human MCL cells. METHODS: Three MCL cell lines (JeKo-1, Hbl-2 and Granta-519) were exposed to different concentrations of the HDAC inhibitors sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) for 8-72 h. Their effects on cell viability, apoptosis induction and cell cycle proliferation were studied. Moreover, the influence of SAHA on the expression of cyclin D1, the cell cycle regulators p21 and p27 and the production of vascular endothelial growth factor (VEGF) were analyzed. RESULTS: The HDAC inhibitors induced accumulation of acetylated histones in MCL cells. MTT assays and Annexin-V staining showed that they potently inhibited viability in a dose-dependent manner and induced apoptosis in all cell lines tested. Cell cycle analysis indicated that their exposure to SAHA or NaB decreased the proportion of cells in S phase and increased the proportion of cells in the G0/G1 and/or G2/M phases. Incubation with the two HDAC inhibitors resulted in downregulation of cyclin D1. SAHA lead to an upregulation of p21 in all cell lines and an upregulation of p27 in JeKo-1 and Granta-519 cells, while expression of p27 in Hbl-2 was not altered. In addition, SAHA inhibited the production of the angiogenic cytokine VEGF. Treatment with NaB increased the expression of p21 in JeKo-1 and Hbl-2 cells, while in Granta 519 cells no effect was noted. The expression of p27 remained constant in all three cell lines after exposure to NaB. CONCLUSION: Based on these findings, we provide evidence that HDAC inhibitors have antiproliferative effects in MCL and may represent a promising therapeutic approach.

Apoptosis↗
PubMed2006

Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment.

OBJECTIVES: Myeloma bone disease is a result of excessive osteoclast activation and impaired osteoblast function. Recent in vitro studies suggested that proteasome inhibitors might increase osteoblast function. METHODS: We analyzed serum markers of osteoblast activity in 25 patients with multiple myeloma receiving bortezomib alone or in combination with dexamethasone. As control, serum samples from 58 consecutive myeloma patients receiving a therapy different than bortezomib (i.e. adriamycin/dexamethasone, melphalan/prednisone or thalidomide) were evaluated. The serum concentrations of bone-specific alkaline phosphatase (BAP) and osteocalcin were quantified before initiation of treatment and after 3 months. RESULTS: In patients treated with bortezomib, mean serum levels of osteocalcin significantly increased from 6.3 to 10.8 microg/L (P = 0.024), while mean BAP levels increased from 19.7 to 30.2 U/L (P < 0.0005). Of interest, the increase in BAP was significant both in responders and non-responders. In contrast, the control group did not show a statistically significant change in BAP (24.8 U/L vs. 23.3 U/L) and osteocalcin (6.8 microg/L vs. 6.5 microg/L) before and after the treatment. CONCLUSION: These data show that treatment with bortezomib leads to enhanced markers of osteoblast activity in patients with myeloma. The comparison with the control group suggests that the effect on osteoblasts is unique to the proteasome inhibitor.

Adult↗
PubMed2006

The effects of the histone deacetylase inhibitor valproic acid on cell cycle, growth suppression and apoptosis in multiple myeloma.

The aim of this study was to evaluate the effects of valproic acid (VPA), as a histone deacetylase inhibitor, on myeloma cell lines and on sorted human bone marrow multiple myeloma cells. VPA induced accumulation of acetylated histones, potently inhibited proliferation in a dose-dependent manner and induced apoptosis in all myeloma cell lines tested as well as in sorted primary multiple myeloma cells. Cell cycle analysis indicated an arrest in G0/1 phase in response to VPA. Accumulation of p21 and reduced levels of cyclin D1 were detected. The production of vascular endothelial growth factor was significantly inhibited by VPA. These results provide the framework for clinical trials.

Apoptosis↗
PubMed2005

Novel aspects of osteoclast activation and osteoblast inhibition in myeloma bone disease.

Increased bone resorption is a major characteristic of multiple myeloma and is caused by osteoclast activation and osteoblast inhibition (uncoupling). Myeloma cells alter the local regulation of bone metabolism by increasing the receptor activator of NF-kappaB ligand (RANKL) and decreasing osteoprotegerin expression within the bone marrow microenvironment, thereby stimulating the central pathway for osteoclast formation and activation. In addition, they produce the chemokines MIP-1alpha, MIP-1beta, and SDF-1alpha, which also increase osteoclast activity. On the other hand, myeloma cells suppress osteoblast function by the secretion of osteoblast inhibiting factors, e.g., the Wnt inhibitors DKK-1 and sFRP-2. Moreover, they inhibit differentiation of osteoblast precursors and induce apoptosis in osteoblasts. The resulting bone destruction releases several cytokines, which in turn promote myeloma cell growth. Therefore, the inhibition of bone resorption could stop this vicious circle and not only decrease myeloma bone disease, but also the tumor progression.

Animals↗
PubMed2005

Proteasome inhibitors abrogate osteoclast differentiation and osteoclast function.

Cancer-induced bone disease results in bone destruction, pathological fractures, and pain. We hypothesized that the inhibition of the proteasome-ubiquitin system in osteoclasts could abolish the receptor activator of NF-kappaB ligand (RANKL) mediated osteoclast differentiation and function, since RANKL-mediated downstream signaling plays a crucial role in osteoclast life cycle. In this study, we examined the effects of the proteasome inhibitors MG-132 and MG-262 on RANKL-induced osteoclast differentiation and function. Osteoclast precursors from peripheral blood mononuclear cells were cultured in the presence of RANKL and M-CSF. Osteoclasts were identified as multi-nucleated TRAP-positive cells. Osteoclast function was quantified with the extent of dentine resorption and TRAP activity in culture supernatants. For the evaluation of the effects of proteasome inhibitors towards osteoclastogenesis, sub-apoptotic concentrations of MG-132 and MG-262 were used. Effects on NF-kappaB were obtained in treated and untreated osteoclasts. MG-132 and MG-262 inhibit both osteoclast differentiation and osteoclast function. 0.01 microM MG-132 induced a 3.2-fold (P = 0.004) and 0.001 microM MG-262 a 3.3-fold (P = 0.004) reduction of osteoclast differentiation, respectively. The resorption capacity was decreased 2.6- and 11.1-fold (P = 0.003) by treatment with 0.01 and 0.1 microM MG-132, and 14.2- and 16.6-fold (P = 0.003) by 0.001 and 0.01 microM MG-262, respectively. This decrease correlated with the extent of NF-kappaB binding capacity. In conclusion, this study shows for the first time that proteasome inhibitors act on osteoclast development and function at low concentrations and should be considered as potential drugs for the treatment of cancer-induced osteolytic bone disease.

Bone Resorption↗
PubMed2004

Expression of receptor activator of NF-kappaB ligand (RANKL) mRNA in human multiple myeloma cells.

PURPOSE: Increased bone resorption is a hallmark of multiple myeloma and a result of excessive osteoclast activation. Recently, the receptor activator of NF-kappaB ligand (RANKL) was found to be the critical factor for osteoclastogenesis. Studies showed that myeloma cells induce RANKL expression in bone marrow stromal cells, but it remained a controversy whether myeloma cells directly express RANKL. METHODS: Therefore, we analyzed the expression of RANKL mRNA in freshly isolated CD138 positive plasma cells from patients with multiple myeloma and osteolytic bone lesions, using three different primer pairs against human RANKL. RESULTS: RANKL mRNA could be detected in bone marrow plasma cells from myeloma patients with osteolytic myeloma bone disease. CONCLUSIONS: These findings show that myeloma cells directly express RANKL and indicate that specific blockade of RANKL may be an effective treatment for myeloma bone disease.

Bone Marrow↗
PubMed2004

Treatment of refractory chronic lymphocytic leukemia with Campath-1H in combination with lamivudine in chronic hepatitis B infection.

Campath-1H, a monoclonal antibody against human CD52, is used for the therapy of refractory or relapsed chronic lymphocytic leukemia (CLL). Treatment with campath is associated with an increased incidence of infections and also fatal reactivation of viral infections. Reactivation of hepatitis B virus (HBV) in HBsAg-positive patients is a well-documented complication of cytotoxic or immunosuppressive therapy and has also been observed after treatment with rituximab. To date, there are no reports on campath treatment in HBsAg carriers. Here, we present the case of a patient with heavily pretreated CLL who was HBsAg-positive with a high virus load (>2 billion copies/mL). He required treatment because of progressive CLL with massive bone marrow infiltration, severe anemia and thrombocytopenia. Campath was initiated and lamivudine, an inhibitor of reverse transcriptase, was simultaneously given to prevent HBV proliferation. During the treatment, no deterioration of liver parameters was observed, and the virus load decreased. After therapy with campath, hemoglobin and platelet counts increased markedly. This report shows that lamivudine is highly effective in inhibiting HBV proliferation and can be used to prevent HBV flare-up during campath treatment in patients tested positive for HBs antigen.

Aged↗
PubMed2004

Ligands of peroxisome proliferator-activated receptor gamma induce apoptosis in multiple myeloma.

The activation of proliferator-activated receptor gamma (PPAR-gamma) by its natural and synthetic ligands induces apoptosis in several tumor cell lines, including malignant B-lineage cells. We investigated whether treatment with pioglitazone (PGZ), rosiglitazone (RGZ) or 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) inhibited tumor cell growth in five human multiple myeloma cell lines (LP-1, U-266, RPMI-8226-S, OPM-2 and IM-9) and human bone marrow myeloma cells expressing PPAR-gamma protein. MTT assays revealed growth arrest induced by the natural activator of PPAR-gamma 15d-PGJ2 and a lower antiproliferative effect with thiazolidinediones (PGZ and RGZ) in a dose-dependent manner. Induction of apoptosis was indicated by Annexin-V staining. At a dose of 50 microM, 15d-PGJ2 led to a high rate of apoptosis in all cell lines (60-92%). Furthermore, induction of apoptosis in sorted bone marrow plasma cells from myeloma patients was detected. Thiazolidinediones comprise anti-myeloma activity in vitro and should be explored further for the treatment of multiple myeloma.

Apoptosis↗
PubMed2003

Serum levels of carboxy-terminal telopeptide of type-I collagen are elevated in patients with multiple myeloma showing skeletal manifestations in magnetic resonance imaging but lacking lytic bone lesions in conventional radiography.

PURPOSE: Skeletal involvement is a hallmark of multiple myeloma. Increased bone resorption can even be present in patients lacking osteolyses in conventional radiography. Magnetic resonance imaging (MRI) of the spine was established as a more sensitive technique to depict bone abnormalities. Type-I collagen degradation product carboxyterminal telopeptide of type-I collagen (ICTP) was introduced as a novel biochemical parameter reflecting the bone resorption activity in myeloma. The aim of this study was to evaluate whether increased ICTP serum levels predict abnormal MRI patterns in myeloma patients. EXPERIMENTAL DESIGN: MRI of the spine was performed in 32 untreated patients with multiple myeloma, who had no skeletal abnormalities in conventional radiographies. Simultaneously, ICTP was measured in serum by a competitive radioimmunoassay at corresponding time points. RESULTS: Serum ICTP was significantly (P = 0.002) elevated in patients with abnormal bone MRI compared with those patients with normal MRI findings. The sensitivity of ICTP for depiction of MRI abnormalities was 79%; the positive and negative predictive values were 85 and 84%, respectively. Compared with ICTP, the parameters of disease activity, beta2-microglobulin and C-reactive protein, had a much lower sensitivity for abnormal MRI (29 and 64%, respectively). CONCLUSIONS: In myeloma patients without osteolytic lesions in conventional radiography, abnormal skeletal MRI is accompanied by an increase in serum levels of ICTP. Our data show that ICTP can be used as an inexpensive parameter to identify myeloma patients with normal skeletal survey who have a high probability of skeletal involvement and deserve more accurate diagnostic evaluation using MRI.

Aged↗
PubMed2003

Proteasome inhibitors induce growth inhibition and apoptosis in myeloma cell lines and in human bone marrow myeloma cells irrespective of chromosome 13 deletion.

PURPOSE: In this study, we investigated the effects of cell-permeable proteasome inhibitors MG-132, MG-262, PSI, and lactacystin on multiple myeloma cell lines OPM-2, U266, RPMI 8226-S, freshly isolated plasma cells with or without deletion of chromosome 13 from patients with multiple myeloma and plasma cell leukemia, and CD34+ human hematopoietic stem cells. The effects of proteasome inhibitors on cell cycle progression, cell growth, and apoptosis were determined. METHODS: MTT-assay was used to examine the cytotoxicity, and annexin-V staining to quantify apoptosis. Cell cycle analyses were performed using 7-ADD and Ki-67 staining by flow cytometry. RESULTS: PSI was the most potent proteasome inhibitor among those tested with a half maximal cytotoxicity (IC(50)) of 5.7 nM, followed by MG-262, MG-132, and lactacystin. Growth inhibition occurred irrespective of chromosome 13 status. Cell cycle arrest occurred in a dose- and time-dependent manner. Low, subapoptotic dosages led to a partial loss of Ki-67 antigen, whereas apoptotic dosages led to reduced Ki-67 levels. Apoptosis was partially dependent on activation of caspase-3, since Ac-DEVD-cho, a caspase-3 inhibitor, could reduce apoptosis significantly. The cytotoxicity of the four proteasome inhibitors tested was significantly lower in human hematopoietic stem cells than in myeloma cells. CONCLUSIONS: Our results show that proteasome inhibitors induce time- and dose-dependent cell cycle alterations, growth inhibition, and apoptosis in human myeloma cells irrespective of chromosome 13 deletion.

Antigens, CD34↗
PubMed2003

Bone marrow angiogenesis and its correlation with other disease characteristics in multiple myeloma in stage I versus stage II-III.

PURPOSE: We studied bone marrow angiogenesis in different stages of multiple myeloma according to the Durie and Salmon classification and its correlations with other disease characteristics. METHODS: Sixty-five immunohistochemical CD34-stained, paraffin-embedded bone marrow biopsies of multiple myeloma patients and 12 controls were studied. The mean number of microvessels per area in each sample was determined as the microvessel density (MVD). In addition, plasma cell infiltration of the bone marrow, serum beta2-microglobulin, immunoglobulin levels, C-reactive protein, and serum calcium concentration were measured in 22 patients with stage I multiple myeloma and in 43 patients in stage II-III. RESULTS: In myeloma patients, the bone marrow MVD was significantly higher than in controls (P<0.001). In 43 patients with stage II-III multiple myeloma, MVD was significantly higher than in 22 patients with stage I (median MVD 46 and 21 vessels/mm(2), respectively, P=0.005). Additionally, in stage II-III the bone marrow MVD correlated positively with the bone marrow plasma cell infiltration (r=0.55, P<0.001) and the serum beta2-microglobulin level (r=0.53, P<0.001), while in stage I patients no correlation could be found. CONCLUSIONS: Angiogenesis is significantly increased in stage II-III myeloma in comparison to stage I. In stages II-III, bone marrow angiogenesis is correlated with plasma cell infiltration and serum beta2-microglobulin levels.

Adult↗