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Christian Jakob

Publications and source records attributed to Christian Jakob.

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

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

Bortezomib-induced tumor lysis syndrome in multiple myeloma.

Tumor lysis syndrome (TLS) is exceedingly rare in multiple myeloma because of the relatively slow proliferation and response of the malignant cells. Bortezomib is a novel agent that inhibits proteasome and has shown activity against multiple myeloma. We report 8 episodes of TLS seen in 7 patients with bortezomib therapy, with or without dexamethasone, among 496 patients treated on 3 phase II multicenter studies. Biochemical abnormalities resolved with supportive therapy in 6 patients (including hemodialysis in 2) but proved fatal in 1. Clinicians should be alert for TLS in patients with myeloma with significant disease burden treated with bortezomib because of the potential for rapid onset of cell lysis with this agent.

Antineoplastic Agents↗
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↗
PubMed2006

Volume-reduced platelet concentrates.

Volume-reduced platelet concentrates (PCs) can be a useful option for transfusing a high number of platelets in the smallest possible plasma volume, especially in neonatal and other pediatric patients. In addition to decreasing the risk of circulatory overload, volume-reduced PCs contain less plasma, which may reduce the likelihood of adverse plasma-related transfusion reactions. Volume reduction can be achieved either during collection and processing of apheresis PCs (primary volume reduction) or, subsequently, by recentrifugation of stored PCs (secondary volume reduction). There is no standard method for preparing volume-reduced PCs. Although in vitro data suggest impaired platelet function with some methods of volume-reducing PCs, in vivo studies show acceptable hemostatic function, posttransfusion recovery, and platelet count increments for both primary and secondary volume-reduced PCs. This review presents an overview of recent studies on functional characteristics of different types of volume-reduced PCs.

Blood Platelets↗
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: an emerging target for cancer therapy.

Proteasome inhibitors represent novel anti-cancer drugs which interact with the proteasome-ubiquitin pathway. The 26S proteasome is a multicatalytic threonine protease with three distinct catalytic activities. It is responsible for intracellular protein turnover in eukaryotic cells, including the processing and degradation of short- and some long-living proteins required for regulation of various cellular functions. Subsequently, the inhibition of the proteasomal function results in stabilization and accumulation of its substrates, which notably include cyclins, cyclin-dependent kinase inhibitors, transcriptional factors, tumor suppressor proteins and proto-oncogenes. This results in confounding signals in the cell inducing cell cycle arrest and activation of apoptotic programs. Acting on transcriptional factor NF-kappaB, which is upregulated in some tumors undergoing chemotherapy or irradiation and downregulated by proteasome inhibition, a significant chemosensitization and consequently synergistic effects concerning the anti-tumor activity could be achieved. Bortezomib is the first proteasome inhibitor that has entered clinical trials. In multiple myeloma, both the US Food and Drug Administration and European Medicine Evaluation Agency granted approval for the use of bortezomib (Velcade) for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. At present, other trials examine the activity in a variety of solid tumors and hematological malignancies. This paper reviews preclinical and clinical results.

Animals↗
PubMed2005

A randomized crossover comparison of the size 2 1/2 laryngeal mask airway ProSeal versus laryngeal mask airway-Classic in pediatric patients.

The laryngeal mask airway (LMA)-ProSeal (P-LMA) forms a more effective seal than the LMA-Classic (C-LMA) and facilitates gastric tube (g-tube) placement in adults. The first pediatric sizes of P-LMA recently became available. In 30 anesthetized, nonparalyzed children, aged 7.7 +/- 2 yr and weighing 27 (20-35) kg, we inserted the size (1/2) P-LMA and C-LMA in random order. Ease of insertion, quality of initial airway, fiberoptic position, airway leak pressure, and maximum tidal volume were determined. G-tube placement was assessed for the P-LMA. Ease of insertion was similar for both devices. The quality of the initial airway was better for the P-LMA (P = 0.01). Airway leak pressure in neutral head position (22.6 versus 18.5 mbar; P = 0.003), maximum flexion (37 versus 26.3 mbar; P < 0.001), maximum extension (15.2 versus 13 mbar; P = 0.045), and maximum tidal volume (1088 versus 949 mL; P = 0.002) were significantly better for the P-LMA. Air entry into the stomach occurred with the C-LMA but not with the P-LMA (P = 0.014). G-tube placement was possible in all patients. The reliability of g-tube placement and the significantly increased airway leak pressure found in this investigation might have important implications for use of the size (1/2) P-LMA for positive pressure ventilation in children.

Anesthesia, General↗
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↗