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Peng Liu - One of the best experts on this subject based on the ideXlab platform.
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2 20 the biological role of bag3 in human Chronic Lymphatic Leukemia
Clinical Lymphoma Myeloma & Leukemia, 2011Co-Authors: Huayuan Zhu, Peng LiuAbstract:Abstract 4589 Objective: BAG3, a member of BAG family, is shown to sustain cell survival and underlies resistance to chemotherapy in human cancer cells, through down-modulation of apoptosis. It can also enhance cell adhesion and migration to promote tumoral invasion. However, the role of BAG3 in human Chronic Lymphatic Leukemia (CLL) remains unclear. Our study aims to discover the roles of BAG3 in the apoptosis and migration of primary CLL cells. Method: In our study, Peripheral blood mononuclear cells were freshly isolated from 18 previously untreated patients. The primary CLL cells were cultured for 6 hours, following, three siRNA (siRNA-1, siRNA-2 and siRNA-3) targeting with different regions of BAG3 mRNA and one non-targeting siRNA were transfected into CLL cells by using Lipofectamine 2000. 6 samples were collected for checking the transfection efficiency by real-time PCR and western blot after 24 or 48 hours. The other 6 samples were exposured with or without fludarabine 12 hours later after tansfection; with another 24 or 48 hours, both cells were harvested, stained with annexin V/PI,and then apoptosis were analyzed using a FACSCalibur flow cytometer.on the other hand, transwell assay were performed in another 6 samples 12 hours after tansfection. to analysis cell migration, the cells were collected and counted 24 hours later. Result: By using the siRNA technique, we successfully down-regulated the expression of BAG3 by 3 different siRNAs. BAG3 mRNA was decreased □‘6 folds (p < 0.05). In order to analyze the effect of BAG3 on CLL cell apoptosis, we used flow cytometry to measure cell apoptosis. Here, the apoptosis rates of CLL cells were increased □‘2 folds after 24 hours transfection by siRNA-2 and siRNA-3 (p < 0.05), and □‘2.5 folds after 48 hours transfection by BAG3 siRNA-1, siRNA-2 and siRNA-3 (p < 0.05). These indicate that BAG3 makes an anti-apoptotic, and knocking-down of it increases the cell apoptosis. To assess the role of BAG3 in the migration of CLL, we used transwell assay to measure cell migration. We found that the migration of CLL cells was decreased 28% by BAG3 siRNA-1 treatment (p < 0.05), 47% by siRNA-2 (p < 0.01) and 50% by siRNA-3 (p < 0.01), respectively. These data showed that BAG3 enhances the CLL migration, and down-regulation of it can inhibit cell migration. Furthermore, fludarabine and BAG3 siRNA were co-treated with CLL cells, to check whether knocking-down of BAG3 can reverse the CLL cells’ resistance against fludarabine. However, the apoptosis rates are not different between co-treated cells and fludarabine-treated cells, which indicated knocking-down of BAG3 may not reverse the fludarabine resistance, though it can promote cell apoptosis and inhibit cell migration. Conclusion : Based on these observations, we conclude that BAG3 may be a potential therapeutic target of human CLL, and inhibition of BAG3 expression can induce cell apoptosis and inhibit cell migration. Disclosures: No relevant conflicts of interest to declare.
Joachim L Schultze - One of the best experts on this subject based on the ideXlab platform.
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increased frequency of ctla4 tgfβ cd4 cd25 t cells in peripheral blood of patients with Chronic Lymphatic Leukemia and multiple myeloma
Cancer Cell International, 2004Co-Authors: Marc Beyer, M Kochanek, M Von Bergweltbaildon, Alexey Popov, J Wolf, Joachim L SchultzeAbstract:A globally suppressed T cell function has been described for cancer patients including patients with Chronic Lymphatic Leukemia (CLL) or multiple myeloma (MM). This has been mainly associated with inhibitory factors released by the tumor cells, while the role of recently characterized regulatory immune cells is not understood. Several different regulatory T cells such as CD4+ CD25+ T cells (Treg), TGFβ producing TH3 or IL-10 producing TR1 cells have been described in murine models, and Treg cells have also been implicated in the control of graft versus host disease after allogeneic transplantation in humans. In contrast, little is known about frequencies and function of regulatory cells in Leukemias and lymphomas. To address this issue we have analyzed 82 peripheral blood samples from 24 CLL patients, 18 MM patients and 26 healthy individuals. By assessing CD4+ CD25+ T cells we established a strongly significant increase of this subpopulation in both CLL (13 ± 7% mean ± SD, p < 0.01) and MM (13 ± 9%, p < 0.01) when compared to healthy individuals (3.5 ± 1.5%). While CDC4+ CD25+ T cells could also comprise previously activated T cells, the expression of CTLA4 has been associated with Treg cells. In fact, 80± 14% respectively 67± 26% of CD4+ CD25+ T cells in CLL resp. MM were also CTLA4+, while only 30 ± 22% were found to be positive in healthy individuals strongly suggesting that these cells are mainly Treg cells. In contrast, using the BDCA-4 specific antibody for Neuropilin-1, we were unable to detect this molecule recently described on murine Treg cells on any of our samples. Interestingly, a significant proportion of CD4+ CD25+ T cells in CLL 28 ± 13% and MM 22 ± 12% also expressed intracellular TGFβ, which was only found in 6 ± 4% of these T cells in healthy individuals. Whether TGFβ production reflects a particular activation status of Treg cells or whether these cells are a defined subpopulation requires further investigation. By analyzing co-expression of CCR7 and CD45RA we established that the fraction of CD4+ CD25+ T cells was particularly increased in the naive and the central memory pool in peripheral blood of CLL and MM patients. Next we assessed T cell activation as a function of Treg cells. As expected, there was already a significantly decreased proliferative response of CD4+ T cells in many CLL patients even when CD25+ cells were depleted. These findings are most likely explained by Chronic exposure to inhibitory cytokines as well as Treg cells. However, even under these conditions, coculture experiments of CD4+ CD25and CD4+ CD25+ Treg cells supported the inhibitory role of Treg cells in CLL. We therefore propose that immunotherapy in any malignancy including CLL and MM characterized by an increase of regulatory factors and cells will significantly benefit from strategies inhibiting immune repression. from Association for Immunotherapy of Cancer: Cancer Immunotherapy – 2nd Annual Meeting Mainz, Germany, 6–7 May 2004
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minimal residual disease detection after myeloablative chemotherapy in Chronic Lymphatic Leukemia
Journal of Molecular Medicine, 1999Co-Authors: Joachim L Schultze, John W Donovan, John G GribbenAbstract:Detection of clonal tumor cells in Leukemias and lymphomas by PCR in minimal residual disease (MRD) has been shown to be a valuable parameter for identifying patients who may require further treatment. Here we introduce the studies underway in our own and other institutions addressing the value of PCR technology in detecting residual CLL cells either in the autologous stem cell product or after induction of MRD in patients after autologous or allogeneic stem cell transplant. The PCR technology used for these questions and the results are discussed.
Huayuan Zhu - One of the best experts on this subject based on the ideXlab platform.
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2 20 the biological role of bag3 in human Chronic Lymphatic Leukemia
Clinical Lymphoma Myeloma & Leukemia, 2011Co-Authors: Huayuan Zhu, Peng LiuAbstract:Abstract 4589 Objective: BAG3, a member of BAG family, is shown to sustain cell survival and underlies resistance to chemotherapy in human cancer cells, through down-modulation of apoptosis. It can also enhance cell adhesion and migration to promote tumoral invasion. However, the role of BAG3 in human Chronic Lymphatic Leukemia (CLL) remains unclear. Our study aims to discover the roles of BAG3 in the apoptosis and migration of primary CLL cells. Method: In our study, Peripheral blood mononuclear cells were freshly isolated from 18 previously untreated patients. The primary CLL cells were cultured for 6 hours, following, three siRNA (siRNA-1, siRNA-2 and siRNA-3) targeting with different regions of BAG3 mRNA and one non-targeting siRNA were transfected into CLL cells by using Lipofectamine 2000. 6 samples were collected for checking the transfection efficiency by real-time PCR and western blot after 24 or 48 hours. The other 6 samples were exposured with or without fludarabine 12 hours later after tansfection; with another 24 or 48 hours, both cells were harvested, stained with annexin V/PI,and then apoptosis were analyzed using a FACSCalibur flow cytometer.on the other hand, transwell assay were performed in another 6 samples 12 hours after tansfection. to analysis cell migration, the cells were collected and counted 24 hours later. Result: By using the siRNA technique, we successfully down-regulated the expression of BAG3 by 3 different siRNAs. BAG3 mRNA was decreased □‘6 folds (p < 0.05). In order to analyze the effect of BAG3 on CLL cell apoptosis, we used flow cytometry to measure cell apoptosis. Here, the apoptosis rates of CLL cells were increased □‘2 folds after 24 hours transfection by siRNA-2 and siRNA-3 (p < 0.05), and □‘2.5 folds after 48 hours transfection by BAG3 siRNA-1, siRNA-2 and siRNA-3 (p < 0.05). These indicate that BAG3 makes an anti-apoptotic, and knocking-down of it increases the cell apoptosis. To assess the role of BAG3 in the migration of CLL, we used transwell assay to measure cell migration. We found that the migration of CLL cells was decreased 28% by BAG3 siRNA-1 treatment (p < 0.05), 47% by siRNA-2 (p < 0.01) and 50% by siRNA-3 (p < 0.01), respectively. These data showed that BAG3 enhances the CLL migration, and down-regulation of it can inhibit cell migration. Furthermore, fludarabine and BAG3 siRNA were co-treated with CLL cells, to check whether knocking-down of BAG3 can reverse the CLL cells’ resistance against fludarabine. However, the apoptosis rates are not different between co-treated cells and fludarabine-treated cells, which indicated knocking-down of BAG3 may not reverse the fludarabine resistance, though it can promote cell apoptosis and inhibit cell migration. Conclusion : Based on these observations, we conclude that BAG3 may be a potential therapeutic target of human CLL, and inhibition of BAG3 expression can induce cell apoptosis and inhibit cell migration. Disclosures: No relevant conflicts of interest to declare.
Alexander Klarer - One of the best experts on this subject based on the ideXlab platform.
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herpes simplex type 1 pneumonitis and acute respiratory distress syndrome in a patient with Chronic Lymphatic Leukemia a case report
Journal of Medical Case Reports, 2017Co-Authors: Miriam Luginbuehl, Alexander Imhof, Alexander KlarerAbstract:Pulmonary pathogenicity of herpes simplex virus type 1 in patients in intensive care without classic immunosuppression as well as the necessity of antiviral treatment in the case of herpes simplex virus detection in respiratory specimens in these patients is controversial. We present a case of acute respiratory distress syndrome in a patient with stable Chronic Lymphatic Leukemia not requiring treatment, in whom we diagnosed herpes simplex virus type 1 bronchopneumonitis based on herpes simplex virus type 1 detection in bronchoalveolar lavage fluid and clinical response to antiviral treatment. A 72-year-old white man presented with symptoms of lower respiratory tract infection. His medical history was significant for Chronic Lymphatic Leukemia, which had been stable without treatment, arterial hypertension, multiple squamous cell carcinomas of the scalp, and alcohol overuse. Community-acquired pneumonia was suspected and appropriate broad-spectrum antibacterial treatment was initiated. Within a few hours, rapid respiratory deterioration led to cardiac arrest. He was successfully resuscitated, but developed acute respiratory distress syndrome. Furthermore, he remained febrile and inflammation markers remained elevated despite antibacterial treatment. Polymerase chain reaction from bronchoalveolar lavage fluid and viral culture from tracheobronchial secretions tested positive for herpes simplex virus type 1. We initiated antiviral treatment with acyclovir. Concomitantly we further escalated the antibacterial treatment, although no bacterial pathogen had been isolated at any point. Defervescence occurred rapidly and his C-reactive protein and leukocyte levels decreased. He was successfully weaned from mechanical ventilation, transferred to the ward, and eventually discharged to home. Herpes simplex virus should be considered a cause for lower respiratory tract infection in critically ill patients, especially in the setting of an underlying disease.
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Herpes simplex type 1 pneumonitis and acute respiratory distress syndrome in a patient with Chronic Lymphatic Leukemia: a case report
'Springer Science and Business Media LLC', 2017Co-Authors: Miriam Luginbuehl, Alexander Imhof, Alexander KlarerAbstract:Abstract Background Pulmonary pathogenicity of herpes simplex virus type 1 in patients in intensive care without classic immunosuppression as well as the necessity of antiviral treatment in the case of herpes simplex virus detection in respiratory specimens in these patients is controversial. We present a case of acute respiratory distress syndrome in a patient with stable Chronic Lymphatic Leukemia not requiring treatment, in whom we diagnosed herpes simplex virus type 1 bronchopneumonitis based on herpes simplex virus type 1 detection in bronchoalveolar lavage fluid and clinical response to antiviral treatment. Case presentation A 72-year-old white man presented with symptoms of lower respiratory tract infection. His medical history was significant for Chronic Lymphatic Leukemia, which had been stable without treatment, arterial hypertension, multiple squamous cell carcinomas of the scalp, and alcohol overuse. Community-acquired pneumonia was suspected and appropriate broad-spectrum antibacterial treatment was initiated. Within a few hours, rapid respiratory deterioration led to cardiac arrest. He was successfully resuscitated, but developed acute respiratory distress syndrome. Furthermore, he remained febrile and inflammation markers remained elevated despite antibacterial treatment. Polymerase chain reaction from bronchoalveolar lavage fluid and viral culture from tracheobronchial secretions tested positive for herpes simplex virus type 1. We initiated antiviral treatment with acyclovir. Concomitantly we further escalated the antibacterial treatment, although no bacterial pathogen had been isolated at any point. Defervescence occurred rapidly and his C-reactive protein and leukocyte levels decreased. He was successfully weaned from mechanical ventilation, transferred to the ward, and eventually discharged to home. Conclusions Herpes simplex virus should be considered a cause for lower respiratory tract infection in critically ill patients, especially in the setting of an underlying disease
Guenther Stockhammer - One of the best experts on this subject based on the ideXlab platform.
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progressive multifocal leukoencephalopathy complicating untreated Chronic Lymphatic Leukemia case report and review of the literature
Journal of Clinical Virology, 2014Co-Authors: Franziska Di Pauli, Thomas Berger, Alois Walder, Hans Maier, Paul Rhomberg, Christian Uprimny, Michael Steurer, Guenther StockhammerAbstract:A 58-year old female with a four-year history of previously untreated CLL at Binet stage A complained about word finding problems, impaired vision, and gait unsteadiness. Concerning her CLL she was asymptomatic and had never required any specific treatment. Her neurological examination disclosed cognitive alterations, homonyme hemianopia to the right, aphasia, and mild right-sided hemiparesis. Cerebral MRI showed a hyperintense lesion on T2 weighted images without contrast enhancement. CSF examination revealed normal findings, including CSF protein, cell count, cytology and PCR-analysis was negative for the presence of JC virus DNA. On follow-up MRI, performed 2 weeks later, the T2 lesion was further enlarging. Subsequent stereotactic brain biopsy was diagnostic for PML revealing abnormal oligodendrocytes staining positive against antibodies specific for simian vacuolating virus 40. In addition, repeated CSF analyses for JC-Virus DNA in the course of the disease became positive. After confirmation of diagnosis treatment with mirtazapine (30 mg/d) and mefloquine (250 mg/d) was initiated. Rapid clinical progression correlated to further worsening on MRI. Therefore this treatment was terminated after 16 days and the regime was changed to a five-day courses of cytarabine (2 mg/kg/d) combined with intrathecal administration of liposomal cytarabine (50 mg). Due to further clinical progression with global aphasia, blindness and severe right-sided hemiparesia, medication was stopped. The Patient died three and a half months after onset of symptoms.