Cyclooxygenase-2 (COX-2) is an inducible enzyme and serves as a source of paracrine prostaglandin E2 (PGE2) formation in many tissues. In glomerular immune injury COX-2 formation is up-regulated in association with increased mesangial cell growth. To examine whether COX-2 exerts growth modulating effects on glomerular cells, we established two separate COX-2-overexpressing mesangial cell lines (COX-2؉) and assessed their proliferative response to the potent mesangial cell growth-promoting factor, platelet-derived growth factor (PDGF). PDGF increased proliferation in mocktransfected cells. In contrast, PDGF did not induce proliferation in COX-2؉ cells. Our results also showed that the tumor suppressor protein p53 and the cyclindependent kinase inhibitors p21 cip-1 and p27 kip-1 were up-regulated in COX-2؉ cells de novo as well as under PDGF-stimulated conditions. To study whether COX-2 products are required for these effects, COX-2؉ cells were treated with indomethacin (1 g/ml) or NS-398 (3 M). Unexpectedly, both COX inhibitors had no significant effect on cell proliferation, not on the protein levels of p53, p21 cip-1 , or p27 kip-1 . To evaluate the role of p21 cip-1 and p27 kip-1 , COX-2 was overexpressed in mesangial cells derived from p21 cip-1 (p21؊/؊ COX-2؉) and p27 kip-1 (p27؊/؊ COX-2؉) null mice. In contrast to the wild type COX-2؉ cells, p21؊/؊ COX-2؉ and p27؊/؊ COX-2؉ cells proliferated in response to PDGF. These data suggest that COX-2 inhibits mesangial cell proliferation by a novel mechanism that is independent of prostaglandin synthesis, but involves p53, p21 cip-1 , and p27 kip-1 .
Chemokines play a pivotal role in the regulation of inflammatory cell infiltration in glomerular immune injury. To characterize mechanisms relevant for the regulation of chemokine expression in vivo, the LPS-mediated model of renal inflammation in rats was used in which we have previously demonstrated that the chemokine RANTES/CCL5 is expressed and secreted in glomeruli. Glomerular RANTES/CCL5 expression in this model correlated with an increased glomerular binding activity of the transcription factors AP-1, C/EBP, and NF-κB. To gain further insight into the functional roles of these transcription factors in the regulation of glomerular RANTES/CCL5 expression, we cloned the rat RANTES/CCL5 promoter and established the model of in vivo LPS tolerance. In tolerant rats, LPS-induced glomerular RANTES/CCL5 expression and activation of the transcription factors AP-1 and C/EBP were significantly reduced using both consensus and rat RANTES/CCL5-specific oligonucleotides. Reduced glomerular NF-κB binding activity after LPS injection could be demonstrated in tolerant rats only when using rat RANTES/CCL5-specific oligonucleotides. Reduced binding activity to this RANTES/CCL5-specific NF-κB binding site in the context of broad NF-κB activation might be due to changes in transcription factor interactions or chromatin remodeling processes.
Background: During the last 15 years there has been a substantial improvement in treatment options for patients with multiple myeloma. For patients younger than 65 years high dose chemotherapy with melphalan and autologous stem cell transplantation is still regarded as the standard therapy. This very effective treatment regimen is now widely used for more than 20 years. However, the therapy of elderly patients (> 70 years) with HDT-ASCT has only been a reserved option for a selected group of patients with a lower biological age. Therefore, for these patients only few studies have analyzed the role of HDT-ASCT regarding overall survival (OS), progression free survival (PFS) and risk assessment-which is our study subject. In addition we want to compare HDT-ASCT with the current standard of treatment for older patients like the continuous lenalidomide and dexamethasone regime (Rd) or bortezomib based regimes. Method: We retrospectively analyzed 62 elderly patients with a median age at ASCT of 71.3 years with multiple myeloma who underwent HDT-ASCT treatment at the Asklepios Hospital Altona in Hamburg, Germany between 2004 and 2013 (3 previously treated with HDT-ASCT and 59 previously untreated). Overall these patients received 86 ASCT. Primary scopes of interest were OS, PFS and treatment related mortality (TRM). Secondary outcome variables were melphalan-dosage, chronic renal failure (Durie Salmon stage A/B), tandem-therapy, ISS-Score, as well as best response after therapy. OS was calculated from beginning of therapy until death of any cause. PFS was calculated from beginning of therapy until progression. Results: The median OS was 60.8 months. TRM was 0%. Median PFS was 33.3 months (n=40). The following factors were significant regarding OS: 1. Chronic renal failure (39 vs. 65.6 months; p=0.03). 2. Higher ISS-Score (ISS III: 33.7 vs. ISS I/II: 76.7 months; p= 0.013). The following factors showed a non statistically significant trend regarding OS: 1. High melphalan dosage, at least once 200mg/m² melphalan, during HDCT-ASCT (70.3 vs. 53 months; p=0.1). 2. Response after therapy (complete remission (CR) / very good partial remission (VGPR): 74.6 vs. partial remission / minimal remission / stable disease: 59.4 months; p= 0.088). 3. Tandem therapy (single transplantation: 60.6 vs. tandem transplantation: 96.3 months; p= 0.127). Conclusion: With a median OS of more than 5 years and a TRM of 0% high dose chemotherapy with melphalan is a valid treatment option for selected elderly patients with multiple myeloma aged > 70 years. The median OS and PFS (60.8 months; 33.3 months) in our patient group was higher than published data with lenalidomide or bortezomib based treatments (e.g. Rd), which has a median OS of 58.9 months and a of PFS 26 month (Facon et al. 2015, Clinical Lymphoma Myeloma and Leukemia, Vol: 15, p: e134). At relapse fewer patients are eligible for HDT-ASCT than de novo patients, therefore HDT-ASCT should be used as first line therapy for suitable patients. Adverse effects of long time glucocorticoid, bortezomib and lenalidomide treatment also have a negative impact on the quality of life for myeloma patients and can lead to irreversible medical consequences. Of note, the treatment duration with high dose melphalan is shorter and has a lower cost than other treatment options for multiple myeloma, which can lead to long treatment free intervals and therefore improve the quality of life for patients. Disclosures: No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.
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