Self-efficacy enhanced in a cross-cultural context through an initiative in under-resourced schools in KwaZulu-Natal, South Africa

This paper discusses the Khanyisa Programme, an initiative in KwaZulu-Natal, South Africa, where learners from under-resourced schools are supported by teachers and high achievers in Grade 11 and 12 from a previously advantaged state school under apartheid. A qualitative, evaluative study was undertaken to identify key elements in the ongoing success of the programme and collect participant suggestions for improvement. The findings, discussed within the framework of self-efficacy theory, identified enormous gains by Khanyisa learners, leading to vastly improved career prospects

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

Evidence of Henipavirus Infection in West African Fruit Bats

Henipaviruses are emerging RNA viruses of fruit bat origin that can cause fatal encephalitis in man. Ghanaian fruit bats (megachiroptera) were tested for antibodies to henipaviruses. Using a Luminex multiplexed microsphere assay, antibodies were detected in sera of Eidolon helvum to both Nipah (39%, 95% confidence interval: 27–51%) and Hendra (22%, 95% CI: 11–33%) viruses. Virus neutralization tests further confirmed seropositivity for 30% (7/23) of Luminex positive serum samples. Our results indicate that henipavirus is present within West Africa

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

Unconventional decoding of the AUA codon as methionine by mitochondrial tRNAMet with the anticodon f5CAU as revealed with a mitochondrial in vitro translation system

Mitochondrial (mt) tRNAMet has the unusual modified nucleotide 5-formylcytidine (f5C) in the first position of the anticodon. This tRNA must translate both AUG and AUA as methionine. By constructing an in vitro translation system from bovine liver mitochondria, we examined the decoding properties of the native mt tRNAMet carrying f5C in the anticodon compared to a transcript that lacks the modification. The native mt Met-tRNA could recognize both AUA and AUG codons as Met, but the corresponding synthetic tRNAMet lacking f5C (anticodon CAU), recognized only the AUG codon in both the codon-dependent ribosomal binding and in vitro translation assays. Furthermore, the Escherichia coli elongator tRNAMetm with the anticodon ac4CAU (ac4C = 4-acetylcytidine) and the bovine cytoplasmic initiator tRNAMet (anticodon CAU) translated only the AUG codon for Met on mt ribosome. The codon recognition patterns of these tRNAs were the same on E. coli ribosomes. These results demonstrate that the f5C modification in mt tRNAMet plays a crucial role in decoding the nonuniversal AUA codon as Met, and that the genetic code variation is compensated by a change in the tRNA anticodon, not by a change in the ribosome. Base pairing models of f5C-G and f5C-A based on the chemical properties of f5C are presented

Risk Prediction Scores for Recurrence and Progression of Non-Muscle Invasive Bladder Cancer: An International Validation in Primary Tumours

Abstract Objective: We aimed to determine the validity of two risk scores for patients with non-muscle invasive bladder cancer in different European settings, in patients with primary tumours. Methods: We included 1,892 patients with primary stage Ta or T1 non-muscle invasive bladder cancer who underwent a transurethral resection in Spain (n = 973), the Netherlands (n = 639), or Denmark (n = 280). We evaluated recurrence-free survival and progression-free survival according to the European Organisation for Research and Treatment of Cancer (EORTC) and the Spanish Urological Club for Oncological Treatment (CUETO) risk scores for each patient and used the concordance index (c-index) to indicate discriminative ability. Results: The 3 cohorts were comparable according to age and sex, but patients from Denmark had a larger proportion of patients with the high stage and grade at diagnosis (p,0.01). At least one recurrence occurred in 839 (44%) patients and 258 (14%) patients had a progression during a median follow-up of 74 months. Patients from Denmark had the highest 10- year recurrence and progression rates (75% and 24%, respectively), whereas patients from Spain had the lowest rates (34% and 10%, respectively). The EORTC and CUETO risk scores both predicted progression better than recurrence with c-indices ranging from 0.72 to 0.82 while for recurrence, those ranged from 0.55 to 0.61. Conclusion: The EORTC and CUETO risk scores can reasonably predict progression, while prediction of recurrence is more difficult. New prognostic markers are needed to better predict recurrence of tumours in primary non-muscle invasive bladder cancer patients.This research received funding from the European Community's Seventh Framework program FP7/2007-2011 under grant agreement 201663 (Uromol project, http://www.uromol.eu/

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