Success of Ureteral Stents for Intrinsic Ureteral Obstruction

Purpose: Previous reports suggest a high success rate for retrograde ureteral stenting for intrinsic ureteral obstruction, but few preoperative predictors of success have been offered. We reviewed our experience to look for factors that suggest failure of stents for intrinsic ureteral obstruction. Materials and Methods: We retrospectively reviewed the outcome of retrograde ureteral stent placement for intrinsic ureteral obstruction without concurrent or intended definitive management of the obstruction. Results: Thirty-eight patients treated for intrinsic ureteral obstruction, representing 41 ureteral units (UUs), were monitored for an average of 25.5 months. The overall success rate was 88%. Of the successes, 13 UUs had definitive therapy to permanently remove the cause of obstruction, obstruction resolved in 12 UUs after stent placement, and 11 UUs were managed with indwelling stents. Therapy failed in five UUs, with a median time to failure of 1.9 months. Of the UUs in which failure occurred, three failures were caused by misdiagnosis; in the remaining two, the stent did not correct the obstruction. On univariate analysis, male sex (P = 0.006), increased creatinine level as a presenting symptom (P = 0.002), and more severe preoperative hydronephrosis (P = 0.042) were predictive of failure. Adverse events were low, with complications from stenting occurring on only four of 41 UUs. Conclusion: If initial stent placement was possible, intrinsic ureteral obstruction was managed successfully in 88% of patients. Given high success and minimal complications, retrograde placement of ureteral stents can be performed to treat patients with intrinsic ureteral obstruction. Treatment failure is more likely to occur in men and patients with severe hydronephrosis or an elevated creatinine level.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63109/1/end.2007.0201.pd

The role of c-FLIP splice variants in urothelial tumours

Deregulation of apoptosis is common in cancer and is often caused by overexpression of anti-apoptotic proteins in tumour cells. One important regulator of apoptosis is the cellular FLICE-inhibitory protein (c-FLIP), which is overexpressed, for example, in melanoma and Hodgkin's lymphoma cells. Here, we addressed the question whether deregulated c-FLIP expression in urothelial carcinoma impinges on the ability of death ligands to induce apoptosis. In particular, we investigated the role of the c-FLIP splice variants c-FLIPlong (c-FLIPL) and c-FLIPshort (c-FLIPS), which can have opposing functions. We observed diminished expression of the c-FLIPL isoform in urothelial carcinoma tissues as well as in established carcinoma cell lines compared with normal urothelial tissues and cells, whereas c-FLIPS was unchanged. Overexpression and RNA interference studies in urothelial cell lines nevertheless demonstrated that c-FLIP remained a crucial factor conferring resistance towards induction of apoptosis by death ligands CD95L and TRAIL. Isoform-specific RNA interference showed c-FLIPL to be of particular importance. Thus, urothelial carcinoma cells appear to fine-tune c-FLIP expression to a level sufficient for protection against activation of apoptosis by the extrinsic pathway. Therefore, targeting c-FLIP, and especially the c-FLIPL isoform, may facilitate apoptosis-based therapies of bladder cancer in otherwise resistant tumours

Hypoxia-inducible factor-1alpha is a critical mediator of hypoxia induced apoptosis in cardiac H9c2 and kidney epithelial HK-2 cells

<p>Abstract</p> <p>Background</p> <p>Hypoxia inducible factor-1 (HIF-1) is a transcription factor that functions to maintain cellular homeostasis in response to hypoxia. There is evidence that HIF-1 can also trigger apoptosis, possibly when cellular responses are inadequate to meet energy demands under hypoxic conditions.</p> <p>Methods</p> <p>Cardiac derived H9c2 and renal tubular epithelial HK-2 cells expressing either the wild type oxygen regulated subunit of HIF-1 (pcDNA3-Hif-1α) or a dominant negative version that lacked both DNA binding and transactivation domains (pcDNA3-DN-Hif-1α), were maintained in culture and exposed to hypoxia. An RNA interference approach was also employed to selectively knockdown expression of Hif-1α. Apoptosis was analyzed in both H9c2 and HK-2 cells by Hoechst and TUNEL staining, caspase 3 activity assays and activation of pro-apoptotic Bcl2 family member Bax.</p> <p>Results</p> <p>Overexpression of pcDNA3-DN-Hif-1α led to a significant reduction in hypoxia -induced apoptosis (17 ± 2%, <it>P </it>< 0.01) in H9c2 cells compared to both control-transfected and wild type Hif-1α transfected cells. Moreover, selective ablation of HIF-1α protein expression by RNA interference in H9c2 cells led to 55% reduction of caspase 3 activity and 46% reduction in the number of apoptotic cells as determined by Hoechst 33258 staining, after hypoxia. Finally, upregulation of the pro-apoptotic protein, Bax, was found in H9c2 cells overexpressing full-length pcDNA3-HA-HIF-1α exposed to hypoxia. In HK-2 cells overexpression of wild-type Hif-1α led to a two-fold increase in Hif-1α levels during hypoxia. This resulted in a 3.4-fold increase in apoptotic cells and a concomitant increase in caspase 3 activity during hypoxia when compared to vector transfected control cells. HIF-1α also induced upregulation of Bax in HK-2 cells. In addition, introduction of dominant negative Hif-1α constructs in both H9c2 and HK-2 -cells led to decreased active Bax expression.</p> <p>Conclusion</p> <p>These data demonstrate that HIF-1α is an important component of the apoptotic signaling machinery in the two cell types.</p

Eradication of Metastatic Renal Cell Carcinoma after Adenovirus-Encoded TNF-Related Apoptosis-Inducing Ligand (TRAIL)/CpG Immunotherapy

Despite evidence that antitumor immunity can be protective against renal cell carcinoma (RCC), few patients respond objectively to immunotherapy and the disease is fatal once metastases develop. We asked to what extent combinatorial immunotherapy with Adenovirus-encoded murine TNF-related apoptosis-inducing ligand (Ad5mTRAIL) plus CpG oligonucleotide, given at the primary tumor site, would prove efficacious against metastatic murine RCC. To quantitate primary renal and metastatic tumor growth in mice, we developed a luciferase-expressing Renca cell line, and monitored tumor burdens via bioluminescent imaging. Orthotopic tumor challenge gave rise to aggressive primary tumors and lung metastases that were detectable by day 7. Intra-renal administration of Ad5mTRAIL+CpG on day 7 led to an influx of effector phenotype CD4 and CD8 T cells into the kidney by day 12 and regression of established primary renal tumors. Intra-renal immunotherapy also led to systemic immune responses characterized by splenomegaly, elevated serum IgG levels, increased CD4 and CD8 T cell infiltration into the lungs, and elimination of metastatic lung tumors. Tumor regression was primarily dependent upon CD8 T cells and resulted in prolonged survival of treated mice. Thus, local administration of Ad5mTRAIL+CpG at the primary tumor site can initiate CD8-dependent systemic immunity that is sufficient to cause regression of metastatic lung tumors. A similar approach may prove beneficial for patients with metastatic RCC

In international law we (do not) trust: The persistent rejection of economic and social rights as a manifestation of cynicism

Despite a promising start in the Universal Declaration of Human Rights, economic and social rights still retain a second-class status in most national jurisdictions. What explains this reticence with which economic and social rights are (still) regarded? This chapter analyses how the sceptical gaze through which states view economic and social rights legitimises (or attempts to legitimise) government failures to provide for those members of their populace who are in most desperate need, and (unsuccessfully) masks the self-interest that pervades most of international law. The chapter commences with a brief introduction and subsequently proceeds in three subsequent parts. Section 2 demonstrates that cynicism was used as a sword to pierce the normative foundations of economic and social rights generally, and the International Covenant on Economic, Social and Cultural Rights particularly in the early days both before and after its adoption leading to economic and social rights’ lower status in the human rights family; Section 3 posits that cynicism has been relied upon as a shield to offer errant states a defence for not meeting their obligations under both international and national (constitutional) economic and social rights norms; and finally Section 4 argues that a certain amount of cynicism is inherent in the history of economic and social rights and how they advanced through the ages, but more optimistically that a light at the end of the tunnel exists because contemporary developments point to less rather than more cynicism in the area of economic and social rights in today’s world