Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer.

Many prostate cancers relapse after initial chemotherapy treatment. Combining molecular and chemotherapy together with encapsulation of drugs in nanocarriers provides effective drug delivery and toxicity reduction. We developed core shell lipid-polymer hybrid nanoparticles (CSLPHNPs) with poly (lactic-co-glycolic acid) (PLGA) core and lipid layer containing docetaxel and clinically used inhibitor of sphingosine kinase 1 (SK1) FTY720 (fingolimod).

Combination of RAD001 (everolimus) and docetaxel reduces prostate and breast cancer cell VEGF production and tumour vascularisation independently of sphingosine-kinase-1.

Resistance to docetaxel is a key problem in current prostate and breast cancer management. We have recently discovered a new molecular mechanism of prostate cancer docetaxel chemoresistance mediated by the mammalian target of rapamycin (mTOR)/sphingosine-kinase-1 (SK1) pathway. Here we investigated the influence of this pathway on vascular endothelial growth factor (VEGF) production and tumour vascularisation in hormone resistant prostate and breast cancer models.

Everolimus (RAD001) sensitizes prostate cancer cells to docetaxel by down-regulation of HIF-1α and sphingosine kinase 1.

Resistance to docetaxel is a key problem in current prostate cancer management. Sphingosine kinase 1 (SK1) and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways have been implicated in prostate cancer chemoresistance. Here we investigated whether their combined targeting may re-sensitize prostate cancer cells to docetaxel.

High cut-off dialysis in chronic haemodialysis patients.

Background: Haemodialysis patients suffer from chronic systemic inflammation and high incidence of cardiovascular disease. One cause for this may be the failure of diseased kidneys to eliminate immune mediators. Current haemodialysis treatment achieves insufficient elimination of proteins in the molecular weight range 15-45 kD.

Therapeutic potential of targeting SK1 in human cancers.

Sphingosine kinase 1 (SK1) is a lipid enzyme with oncogenic properties that converts the proapoptotic lipids ceramide and sphingosine into the antiapoptotic lipid sphingosine-1-phosphate and activates the signal transduction pathways that lead to cell proliferation, migration, the activation of the inflammatory response, and the impairment of apoptosis. There is compelling evidence that SK1 activation contributes to cancer progression leading to increased oncogenic transformation, tumor growth, resistance to therapies, tumor neovascularization, and metastatic spread. High levels of SK1 expression or activity have been associated with a poor prognosis in several human cancers.

Randomized controlled pilot study of 2 weeks' treatment with high cutoff membrane for hemodialysis patients with elevated C-reactive protein.

Chronic inflammation in hemodialysis (HD) patients is associated with cardiovascular complications and mortality. Circulating immune active proteins in the molecular range 15-45 kD that cannot be efficiently cleared by high-flux (HF) dialysis may be causally involved. We intended to test the feasibility of using a high cutoff (HCO) dialyzer in chronic HD patients and its influence on inflammation and monocyte activation.

Therapeutic potential of targeting sphingosine kinase 1 in prostate cancer.

Sphingosine kinase 1 (SK1) is a lipid enzyme with oncogenic properties that converts the proapoptotic lipid sphingosine into the antiapoptotic lipid sphingosine-1-phosphate, which activates the signal transduction pathways that lead to cell proliferation, migration, activation of the inflammatory response and impairment of apoptosis. Compelling evidence suggests that SK1 activation contributes to cancer progression leading to increased oncogenic transformation, tumor growth, resistance to therapies, tumor neovascularization and metastatic spread. High levels of SK1 expression or activity have been associated with poor prognosis in several cancers, including those of the prostate.

FTY720 (fingolimod) sensitizes prostate cancer cells to radiotherapy by inhibition of sphingosine kinase-1.

Radiotherapy is widely used as a radical treatment for prostate cancer, but curative treatments are elusive for poorly differentiated tumors where survival is just 15% at 15 years. Dose escalation improves local response rates but is limited by tolerance in normal tissues. A sphingosine analogue, FTY720 (fingolimod), a drug currently in phase III studies for treatment of multiple sclerosis, has been found to be a potent apoptosis inducer in prostate cancer cells.

Biomarkers as a tool for management of immunosuppression in transplant patients.

Therapeutic drug monitoring is a well-established approach in transplantation medicine to guide immunosuppressive therapy. However, it cannot always predict the effects of immunosuppressive drugs on immune cells, because it does not reflect any aspect of an individual patient's immune system. Pharmacodynamic monitoring is a more recent strategy to provide information about the biologic effect of a specific drug or drug combination on the individual transplant patient.

Polyoma BK virus-associated nephropathy in kidney-transplant patients: Effects of leflunomide on T-cell functions and disease outcome.

Background: In kidney-transplant recipients, leflunomide has been shown to be efficient for treating polyomavirus BK virus-associated-nephropathy (PVAN). However, it is unknown whether the beneficial effect of leflunomide is related to it having a lower immunosuppressive effect than mycophenolate mofetil (MMF), or to its anti-viral activity. The aim of this study was to assess i) T-cell functions before and after conversion from MMF to leflunomide in kidney-transplant patients with PVAN, and ii) effects of leflunomide on PVAN outcome.

Pharmacodynamic evaluation of the first dose of mycophenolate mofetil before kidney transplantation.

Background And Objectives: The effect of mycophenolate mofetil (MMF) on T cell function has not been evaluated in patients undergoing kidney transplantation. The aim of this study was to assess the effect of 1g of MMF on T cell function, that is, intralymphocyte cytokine expression, T cell activation (CD25 and CD71), and T cell proliferation, as well as inosine monophosphate dehydrogenase (IMPDH) activity, to better understand the relationship between pharmacokinetic and pharmacodynamic markers in patients receiving the first dose of MMF before kidney transplantation.

Patients: Twenty-four patients undergoing a kidney transplantation from a living donor were enrolled in this study.

Cytokines correlate with age in healthy volunteers, dialysis patients and kidney-transplant patients.

T-cell functions are currently used as biomarkers for the pharmacodynamic monitoring of immunosuppressive drugs or as disease biomarkers of inflammation/sepsis and organ rejection. In order to evaluate co-factors potentially influencing the expression of the immunological biomarkers, we explored T-cell proliferation, T-cell activation (CD25 and CD71 expressions) and intra-lymphocyte cytokine production (interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha) in healthy volunteers, dialysis patients and stable kidney-transplant patients treated with standard immunosuppressive therapy, i.e.

In vitro mitogen-stimulated T-cell from hepatitis C virus-positive liver transplantation candidates, increases T-cell activation markers and T-cell proliferation.

The incidence of acute rejection is significantly higher in hepatitis C virus (HCV) liver-transplant patients than in patients who have received a graft for other liver diseases, i.e., mainly alcoholic cirrhosis.

Pharmacodynamic effects of everolimus on anti-CD3 antibody-stimulated T-lymphocyte proliferation and interleukin-10 synthesis in stable kidney-transplant patients.

Everolimus (rapamycin derivative, RAD) is a new immunosuppressive drug that prevents allograft rejection. Herein, the pharmacodynamics of everolimus in human renal-allograft recipients is evaluated. Single doses of everolimus (0.

Pharmacodynamic monitoring of the conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in stable kidney-allograft recipients.

Background: The formulations of mycophenolic acid, i.e., mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), seem to have different pharmacokinetic profiles.

Tabebuia avellanedae extracts inhibit IL-2-independent T-lymphocyte activation and proliferation.

In order to identify new, immune modulating compounds, aqueous extracts of plants pre-selected on ethno-pharmacological knowledge were screened for inhibitory effects in an anti-CD3 driven lymphocyte proliferation assay (MTT-assay). We found for the extract of the inner bark of Tabebuia avellanedae (Tabebuia) dose dependent and reproducible inhibitory effects on lymphocyte proliferation. We further analyzed Tabebuia in flow cytometry based whole blood T-cell function assays.

Reconstitution of immunodeficient SCID/beige mice with human cells: applications in preclinical studies.

Experimental studies of the in vivo behaviour of human cells and tissues have become possible with the development of immunodeficient mice strains. Such mice accept readily allogeneic or xenogeneic grafts, including grafts of human cells or tissues, without rejection. In this review we describe different immunodeficient mouse strains that have been used for reconstitution by human immune cells.

Current perspectives on FTY720.

The search for effective immunosuppressants with fewer side effects continues not only for transplantation, but also for autoimmune diseases. With a novel mechanism of action (sphingosine-1 receptor modulation), oral FTY720 (fingolimod) has the potential to address this need. FTY720 has been preclinically tested with promising results in transplantation and autoimmune disease models.

Validation of immunological biomarkers for the pharmacodynamic monitoring of immunosuppressive drugs in humans.

Pharmacodynamic monitoring (PD) can evaluate the efficacy of immunosuppressive drug therapies. In this study, the expressions of PD biomarkers [lymphocyte proliferation, CD25 and CD71 expression, interleukin-2 (IL-2), and tumor necrosis factor-alpha (TNF-alpha) synthesis] were determined in whole-blood assays and were validated for their application in PD of immune modulators in future clinical trials. Initially, the assay conditions were re-evaluated.

Differential effects of single dose FTY720 on CD62L+ B-cells in stable renal allograft recipients.

FTY720, a sphingosine-1-phosphate receptor agonist, is the archeotype of a new class of immune modulators, which redirects lymphocytes from the peripheral blood into secondary lymphatic tissue. Previously, it was shown that FTY720 differentially decreases peripheral T-cells, expressing specific chemokine and adhesion receptors. Here, we investigated the effect of single doses FTY720 on peripheral B-cells expressing CD62L, CD11a, CD49d and CXCR4 in stable human renal allograft recipients.

FTY720 (fingolimod) in renal transplantation.

FTY720 (Fingolimod) is a novel immunomodulator with a mode of action that is completely different from classical immunosuppressants. FTY is a structural and functional analogue of the natural serum lipid, sphingosine, and is the first in a new class of drugs called sphingosine 1-phosphate receptor (S1P-R) modulators. This review discusses the recent findings on the mechanism of action, preclinical models and outlines the results of the ongoing clinical development program.

FK506, transforming growth factor-beta1 and mesangial matrix synthesis: parallels and differences compared with cyclosporine A.

Cyclosporine A (CsA)-induced glomerulosclerosis is a well-described side effect of CsA treatment. Current evidence indicates that FK506 causes similar morphologic changes. Recently, we demonstrated that CsA up-regulates the expression of transforming growth factor-beta1 (TGF-beta1), its receptors type I (TbetaR-I) and type II (TbetaR-II), as well as related matrix protein synthesis in mesangial cells (MCs).

Profibrotic cytokines and lymphocyte proliferation in stable renal allograft recipients treated with or without cyclosporine A.

Profibrotic cytokines such as transforming growth factor-beta 1 (TGF-beta1) and endothelin-1 (ET-1) are involved in the pathogenesis of chronic allograft nephropathy. We assessed the effect of maintenance immunosuppression with or without cyclosporine A on TGF-beta1 and ET-1 expression as well as lymphocyte proliferation in renal allograft recipients. Patients were divided into groups according to their maintenance immunosuppression: A, azathioprine + methylprednisolone; B, cyclosporine A + azathioprine + methylprednisolone.

Mycophenolate mofetil slows progression in anti-thy1-induced chronic renal fibrosis but is not additive to a high dose of enalapril.

Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency.