Novel expression of Haemonchus contortus vaccine candidate aminopeptidase H11 using the free-living nematode Caenorhabditis elegans

With the problem of parasitic nematode drug resistance increasing, vaccine development offers an alternative sustainable control approach. For some parasitic nematodes, native extracts enriched for specific proteins are highly protective. However, recombinant forms of these proteins have failed to replicate this protection. This is thought to be due to differences in glycosylation and/or conformation between native and recombinant proteins. We have exploited the free-living nematode Caenorhabditis elegans to examine its suitability as an alternative system for recombinant expression of parasitic nematode vaccine candidates. We focussed on Haemonchus contortus aminopeptidase H11 glycoprotein, which is enriched in a gut membrane fraction capable of inducing significant protection against this important ovine gastrointestinal nematode. We show that H. contortus H11 expressed in C. elegans is enzymatically active and MALDI mass spectrometry identifies similar di- and tri-fucosylated structures to those on native H11, with fucose at the 3- and/or 6-positions of the proximal GlcNAc. Some glycan structural differences were observed, such as lack of LDNF. Serum antibody to native H11 binds to C. elegans recombinant H11 and most of the antibody to rH11 or native H11 is directed to glycan moieties. Despite these similarities, no reduction in worm burden or faecal egg count was observed following immunisation of sheep with C. elegans-expressed recombinant H11 protein. The findings suggest that the di- and tri-fucosylated N-glycans expressed on rH11 do not contribute to the protective effect of H11 and that additional components present in native H11-enriched extract are likely required for enhancing the antibody response necessary for protection

Effects of EGFR Expression on Anti-tumor Efficacy of Vandetanib or Cediranib Combined with Radiotherapy (RT) in U87 Human Glioblastoma (GBM) Xenografts

Introduction: Vandetanib is a receptor tyrosine kinase inhibitor (RTKI) with activity against vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR). Cediranib is a highly potent VEGF RTKI that inhibits all three VEGF receptors. In this study we investigated the effect of exogenous overexpression of EGFR on sensitivity of human GBM U87 xenografts to vandetanib or cediranib, alone or in combination with RT. American Association for Cancer Research (AACR) 101st Annual Meeting April 17-21, Washington, DC

Toxicity of Phase I Radiation Oncology Trials: Worldwide Experience

Introduction: Informed consent involves understanding the risks and benefits of trial enrollment. This is challenging in the phase I setting since true quantitative information is never known. We therefore performed an analysis of published radiation oncology (RO) phase I trials emphasizing patient outcomes. To our knowledge, no such systemic analysis has previously been published. American Society for Therapeutic Radiation Oncology (ASTRO) 52nd Annual Meeting October 31 - November 4, San Diego, C

Comparison of a Novel Curvilinear Approach to Conventional Rectilinear Approach for Prostate Seed Implant

Purpose: To evaluate dosimetric benefit of curvilinear distribution of seeds for low-dose-rate (LDR) prostate brachytherapy with I-125 isotopes. American Association of Physicists in Medicine (AAPM) 52nd Annual Meeting July 18-22, Philadelphia, P

Evolving Role of Vorinostat Combined with Radiation Therapy in the Treatment of Brain Tumors, from the Lab to the Clinic

Purpose/Objective(s): Radiation therapy (RT) is a critical element in the treatment of both brain metastases and glioblastoma (GBM). Temozolomide (TMZ) has an established role in the upfront treatment of GBM. Down-regulated mismatch repair (MMR) is a known mechanism of resistance to TMZ. Vorinostat (SAHA), an HDAC inhibitor, has successfully been combined with a number of cytotoxic agents, including ionizing radiation (IR). We performed a series of preclinical and clinical studies to examine the role of SAHA in the treatment of brain tumors. American Society for Therapeutic Radiation Oncology (ASTRO) 52nd Annual Meeting October 31 - November 4, San Diego, C

The surgical workforce shortage and successes in retaining surgical trainees in Ethiopia: a professional survey

BACKGROUND: Medical workforce shortages represent a major challenge in low- and middle-income countries, including those in Africa. Despite this, there is a dearth of information regarding the location and practice of African surgeons following completion of their training. In response to the call by the WHO Global Code of Practice on the International Recruitment of Health Personnel for a sound evidence base regarding patterns of practice and migration of the health workforce, this study describes the current place of residence, practice and setting of Ethiopian surgical residency graduates since commencement of their surgical training in Ethiopia or in Cuba. METHODS: This study presents data from a survey of all Ethiopian surgical residency training graduates since the programme’s inception in 1985. RESULTS: A total of 348 Ethiopians had undergone surgical training in Ethiopia or Cuba since 1985; data for 327 (94.0 %) of these surgeons were collected and included in the study. The findings indicated that 75.8 % of graduates continued to practice in Ethiopia, with 80.9 % of these practicing in the public sector. Additionally, recent graduates were more likely to remain in Ethiopia and work within the public sector. The average total number of surgeons per million inhabitants in Ethiopia was approximately three and 48.0 % of Ethiopian surgeons practiced in Addis Ababa. CONCLUSIONS: Ethiopian surgeons are increasingly likely to remain in Ethiopia and to practice in the public sector. Nevertheless, Ethiopia continues to suffer from a drastic surgical workforce shortage that must be addressed through increased training capacity and strategies to combat emigration and attrition

Combination of Vorinostat with Whole-brain Radiotherapy in the Treatment of Brain Metastases

Background: A third of patients with solid malignancies develop brain metastases. Expected overall survival is 4-7 months depending on age, performance status, and extracranial disease. Standard treatment is controversial; however, the majority of patients receive wholebrain radiation therapy at some point. Vorinostat (suberoylanilide hydroxamic acid, SAHA), an FDA-approved HDAC inhibitor, has been demonstrated to radiosensitize tumor cells in vitro, as assessed by both radiation-induced DNA damage and clonogenic cell survival (Munshi et al. Molecular Cancer Therapeutics 5, 1967-1974, 2006). We have shown that vorinostat downregulates key genes involved in double-strand DNA repair (Rad50, Rad51, XRCC2, XRCC3, XRCC6), as assessed by quantitative PCR. This suggests that the drug’s mechanism of radiosensitization is epigenetic coordinated inhibition of the DNA repair process. We hypothesize that the combination of vorinostat with whole-brain radiation therapy will be both safe and efficacious. American Society of Clinical Oncology (ASCO) 46th Annual Meeting June 4-8, Chicago, IL