Secretion-mediated STAT3 activation promotes self-renewal of glioma stem-like cells during hypoxia.

High-grade gliomas (HGGs) include the most common and the most aggressive primary brain tumor of adults and children. Despite multimodality treatment, most high-grade gliomas eventually recur and are ultimately incurable. Several studies suggest that the initiation, progression, and recurrence of gliomas are driven, at least partly, by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew. We have identified a hypoxia-induced pathway that utilizes the Hypoxia Inducible Factor 1α (HIF-1α) transcription factor and the JAK1/2-STAT3 (Janus Kinase 1/2 - Signal Transducer and Activator of Transcription 3) axis to enhance the self-renewal of glioma stem-like cells. Hypoxia is a commonly found pathologic feature of HGGs. Under hypoxic conditions, HIF-1α levels are greatly increased in glioma stem-like cells. Increased HIF-1α activates the JAK1/2-STAT3 axis and enhances tumor stem-like cell self-renewal. Our data further demonstrate the importance of Vascular Endothelial Growth Factor (VEGF) secretion for this pathway of hypoxia-mediated self-renewal. Brefeldin A and EHT-1864, agents that significantly inhibit VEGF secretion, decreased stem cell self-renewal, inhibited tumor growth, and increased the survival of mice allografted with S100ß-v-erbB/p53-/- glioma stem-like cells. These agents also inhibit the expression of a hypoxia gene expression signature that is associated with decreased survival of HGG patients. These findings suggest that targeting the secretion of extracellular, autocrine/paracrine mediators of glioma stem-like cell self-renewal could potentially contribute to the treatment of HGGs.

Extended follow-up of the CYCLOFA-LUNE trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide or on cyclosporine A.

Objective To evaluate the extended follow-up of the CYCLOFA-LUNE trial, a randomized prospective trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide (CPH) or cyclosporine A (CyA). Patients and methods Data for kidney function and adverse events were collected by a cross-sectional survey for 38 of 40 patients initially randomized in the CYCLOFA-LUNE trial. Results The median follow-up time was 7.7 years (range 5.0-10.3). Rates of renal impairment and end-stage renal disease, adverse events (death, cardiovascular event, tumor, premature menopause) did not differ between the CPH and CyA group, nor did mean serum creatinine, 24 h proteinuria and SLICC damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. Conclusion An immunosuppressive regimen based on CyA achieved similar clinical results to that based on CPH in the very long term.

Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study.

Intravenous cyclophosphamide is considered to be the standard of care for the treatment of proliferative lupus nephritis. However, its use is limited by potentially severe toxic effects. Cyclosporine A has been suggested to be an efficient and safe treatment alternative to cyclophosphamide. Forty patients with clinically active proliferative lupus nephritis were randomly assigned to one of two sequential induction and maintenance treatment regimens based either on cyclophosphamide or Cyclosporine A. The primary outcomes were remission (defined as normal urinary sediment, proteinuria <0.3 g/24 h, and stable s-creatinine) and response to therapy (defined as stable s-creatinine, 50% reduction in proteinuria, and either normalization of urinary sediment or significant improvement in C3) at the end of induction and maintenance phase. Secondary outcomes were incidence of adverse events, and relapse-free survival. At the end of the induction phase, 24% of the 21 patients treated by cyclophosphamide achieved remission, and 52% achieved response, as compared with 26% and 43%, respectively of the 19 patients treated by the Cyclosporine A. At the end of the maintenance phase, 14% of patients in cyclophosphamide group, and 37% in Cyclosporine A group had remission, and 38% and 58% respectively response. Treatment with Cyclosporine A was associated with transient increase in blood pressure and reversible decrease in glomerular filtration rate. There was no significant difference in median relapse-free survival. In conclusion, Cyclosporine A was as effective as cyclophosphamide in the trial of sequential induction and maintenance treatment in patients with proliferative lupus nephritis and preserved renal function.(ClinicalTrials.gov identifier: NCT00976300)

Osteopontin, a novel substrate for matrix metalloproteinase-3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin).

Osteopontin (OPN) is a secreted phosphoprotein shown to function in wound healing, inflammation, and tumor progression. Expression of OPN is often co-localized with members of the matrix metalloproteinase (MMP) family. We report that OPN is a novel substrate for two MMPs, MMP-3 (stromelysin-1) and MMP-7 (matrilysin). Three cleavage sites were identified for MMP-3 in human OPN, and two of those sites were also cleaved by MMP-7. These include hydrolysis of the human Gly166-Leu167, Ala201-Tyr202 (MMP-3 only), and Asp210-Leu211 peptide bonds. Only the N-terminal Gly-Leu cleavage site is conserved in rat OPN (Gly151-Leu152). These sites are distinct from previously reported cleavage sites in OPN for the proteases thrombin or enterokinase. We found evidence for the predicted MMP cleavage fragments of OPN in vitro in tumor cell lines, and in vivo in remodeling tissues such as the postpartum uterus, where OPN and MMPs are co-expressed. Furthermore, cleavage of OPN by MMP-3 or MMP-7 potentiated the function of OPN as an adhesive and migratory stimulus in vitro through cell surface integrins. We predict that interaction of MMPs with OPN at tumor and wound healing sites in vivo may be a mechanism of regulation of OPN bioactivity.

[Vasoactive factors in chronic glomerulonephritis]. / Vazoaktivní pusobky u chronické glomerulonefritidy.

BACKGROUND: The kidney damage in chronic glomerulonephritis develops not only as a result of causal immunopathological evens, but also due to chronic adaptation changes. The study was aimed at identification of active agents, which can serve as markers of proceeding adaptation changes and to determine, if these changes may be determined in patients undergoing the stage of remission of chronic glomerulonephritis. METHODS AND RESULTS: The authors determined renin activity, concentration of atrium natriuretic peptide and endothelin in plasma and elimination of some prostanoids in urine in 33 patients with chronic stabilized glomerulonephritis with normal glomerular filtration and with normal blood pressure and in 21 healthy subjects. Seventeen patients without proteinuria did not receive therapy, 16 patients with minute proteinuria received 100 mg of acetylosalicylic acid daily. In the untreated patients without proteinuria, the elimination of thromboxane in urine was significantly higher than in both other groups. The plasma level of atrium natriuretic peptide in all 33 patients was significantly lower than in the healthy persons. CONCLUSIONS: Based on this study the authors believe that adaptation changes proceed even in patients with chronic glomerulonephritis in clinical remission. The increased production of renal thromboxane, which can be successfully blocked by acetylosalicylic acid may be the marker of glomerular changes. A decreased level of atrium natriuretic peptide could reflect tubulointerstitial changes.

[Microalbuminuria in patients with glomerulonephritis in remission]. / Mikroalbuminurie u nemocných s glomerulonefritdou v remisi.

The authors focused their attention on residual changes in patients with glomerulonephritis who have a zero or only "physiological" proteinuria (under 0.15 g/24 hours), normal or slightly elevated s-creatinine and who do not suffer from hypertension. In these patients microalbuminuria in urine per 24 hours was assessed. Patients with albuminuria under 20 micrograms/min were included in the group with normal albuminuria (13 patients) and patients with albuminuria of more than 20 micrograms/min in the microalbuminuric group (11 patients). The two groups did not differ significantly as to age, sex, duration of the disease, maximum levels of proteinuria and s-creatinine values at the onset of the disease. S-creatinine and blood pressure values at the time of investigation were also comparable. The groups differed, however, significantly as to the period of "absolute" remission which the authors defined as the period during which proteinuria did not exceed the "physiological" limit. This period was in the normoalbuminuric group significantly longer--on average 5.1 years--while in the microalbuminuric group it was 2.1 years (difference at the 1% level of significance).

[Successful completion of pregnancy in a dialyzed patient]. / Uspesne ukoncené tehotenství u dialyzované pacientky.

The authors describe the first case of a successful pregnancy in the Czech Republic in a patient treated by continuous ambulatory peritoneal dialysis. The 22-year-old patient became pregnant ten months after the onset of treatment by peritoneal dialysis. During pregnancy deterioration of arterial hypertension occurred, deterioration of anaemia and from the 29th week onwards cholestasis gravidarum developed. The development of the foetus was within normal limits. Because of suspected preeclampsia the pregnancy was terminated during the 35th week by Caesarean section. The patient was delivered of a healthy eutrophic boy without any congenital abnormalities.