Memory Immune Responses against Pandemic (H1N1) 2009 Influenza Virus Induced by a Whole Particle Vaccine in Cynomolgus Monkeys Carrying Mafa-A1*052∶02

We made an H1N1 vaccine candidate from a virus library consisting of 144 ( = 16 HA×9 NA) non-pathogenic influenza A viruses and examined its protective effects against a pandemic (2009) H1N1 strain using immunologically naïve cynomolgus macaques to exclude preexisting immunity and to employ a preclinical study since preexisting immunity in humans previously vaccinated or infected with influenza virus might make comparison of vaccine efficacy difficult. Furthermore, macaques carrying a major histocompatibility complex class I molecule, Mafa-A1*052∶02, were used to analyze peptide-specific CD8+ T cell responses. Sera of macaques immunized with an inactivated whole particle formulation without addition of an adjuvant showed higher neutralization titers against the vaccine strain A/Hokkaido/2/1981 (H1N1) than did sera of macaques immunized with a split formulation. Neutralization activities against the pandemic strain A/Narita/1/2009 (H1N1) in sera of macaques immunized twice with the split vaccine reached levels similar to those in sera of macaques immunized once with the whole particle vaccine. After inoculation with the pandemic virus, the virus was detected in nasal samples of unvaccinated macaques for 6 days after infection and for 2.67 days and 5.33 days on average in macaques vaccinated with the whole particle vaccine and the split vaccine, respectively. After the challenge infection, recall neutralizing antibody responses against the pandemic virus and CD8+ T cell responses specific for nucleoprotein peptide NP262-270 bound to Mafa-A1*052∶02 in macaques vaccinated with the whole particle vaccine were observed more promptly or more vigorously than those in macaques vaccinated with the split vaccine. These findings demonstrated that the vaccine derived from our virus library was effective for pandemic virus infection in macaques and that the whole particle vaccine conferred more effective memory and broader cross-reactive immune responses to macaques against pandemic influenza virus infection than did the split vaccine

Eph receptors in breast cancer: roles in tumor promotion and tumor suppression

Eph receptor tyrosine kinase signaling regulates cancer initiation and metastatic progression through multiple mechanisms. Studies of tumor-cell-autonomous effects of Eph receptors demonstrate their dual roles in tumor suppression and tumor promotion. In addition, Eph molecules function in the tumor microenvironment, such as in vascular endothelial cells, influencing the ability of these molecules to promote carcinoma progression and metastasis. The complex nature of Eph receptor signaling and crosstalk with other receptor tyrosine kinases presents a unique challenge and an opportunity to develop therapeutic intervention strategies for targeting breast cancer

A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies

Heat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included characterisation of the safety profile, pharmacokinetics (PKs) and pharmacodynamics (PDs). Heat-shock protein 990 was administered orally once or two times weekly on a 28-day cycle schedule in patients with advanced solid tumours. Dose escalation was guided by a Bayesian logistic regression model with overdose control. A total of 64 patients were enrolled. Fifty-three patients received HSP990 once weekly at 2.5, 5, 10, 20, 30, 50 or 60 mg, whereas 11 patients received HSP990 two times weekly at 25 mg. Median duration of exposure was 8 weeks (range 1-116 weeks) and 12 patients remained on treatment for >16 weeks. Dose-limiting toxicities occurred in seven patients and included diarrhoea, QTc prolongation, ALT/AST elevations and central neurological toxicities. The most common drug-related adverse events were diarrhoea, fatigue and decreased appetite. Further dose escalation beyond 60 mg once weekly was not possible owing to neurological toxicity. Rapid absorption, no drug accumulation and large interpatient variability in PK exposures were observed. No objective responses were seen; 25 patients had a best overall response of stable disease. Heat-shock protein 990 is relatively well tolerated, with neurological toxicity being the most relevant DLT. The single agent MTD/RP2D of HSP990 was declared at 50 mg once weekly