Structure-Based Design of Hepatitis C Virus Vaccines That Elicit Neutralizing Antibody Responses to a Conserved Epitope

Despite recent advances in therapeutic options, hepatitis C virus (HCV) remains a severe global disease burden, and a vaccine can substantially reduce its incidence. Due to its extremely high sequence variability, HCV can readily escape the immune response; thus, an effective vaccine must target conserved, functionally important epitopes. Using the structure of a broadly neutralizing antibody in complex with a conserved linear epitope from the HCV E2 envelope glycoprotein (residues 412 to 423; epitope I), we performed structure-based design of immunogens to induce antibody responses to this epitope. This resulted in epitope-based immunogens based on a cyclic defensin protein, as well as a bivalent immunogen with two copies of the epitope on the E2 surface. We solved the X-ray structure of a cyclic immunogen in complex with the HCV1 antibody and confirmed preservation of the epitope conformation and the HCV1 interface. Mice vaccinated with our designed immunogens produced robust antibody responses to epitope I, and their serum could neutralize HCV. Notably, the cyclic designs induced greater epitope-specific responses and neutralization than the native peptide epitope. Beyond successfully designing several novel HCV immunogens, this study demonstrates the principle that neutralizing anti-HCV antibodies can be induced by epitope-based, engineered vaccines and provides the basis for further efforts in structure-based design of HCV vaccines. IMPORTANCE: Hepatitis C virus is a leading cause of liver disease and liver cancer, with approximately 3% of the world\u27s population infected. To combat this virus, an effective vaccine would have distinct advantages over current therapeutic options, yet experimental vaccines have not been successful to date, due in part to the virus\u27s high sequence variability leading to immune escape. In this study, we rationally designed several vaccine immunogens based on the structure of a conserved epitope that is the target of broadly neutralizing antibodies. In vivo results in mice indicated that these antigens elicited epitope-specific neutralizing antibodies, with various degrees of potency and breadth. These promising results suggest that a rational design approach can be used to generate an effective vaccine for this virus

Impact of efalizumab on patient-reported outcomes in high-need psoriasis patients: results of the international, randomized, placebo-controlled Phase III Clinical Experience Acquired with Raptiva (CLEAR) trial [NCT00256139]

BACKGROUND: Chronic psoriasis can negatively affect patients' lives. Assessing the impact of treatment on different aspects of a patient's health-related quality of life (HRQOL) is therefore important and relevant in trials of anti-psoriasis agents. The recombinant humanized IgG(1 )monoclonal antibody efalizumab targets multiple T-cell-dependent steps in the immunopathogenesis of psoriasis. Efalizumab has demonstrated safety and efficacy in several clinical trials, and improves patients' quality of life. Objective: To evaluate the impact of efalizumab on HRQOL and other patient-reported outcomes in patients with moderate to severe plaque psoriasis, including a large cohort of High-Need patients for whom at least 2 other systemic therapies were unsuitable because of lack of efficacy, intolerance, or contraindication. METHODS: A total of 793 patients were randomized in a 2:1 ratio to receive efalizumab 1 mg/kg/wk (n = 529) or placebo (n = 264) for 12 weeks. The study population included 526 High-Need patients (342 efalizumab, 184 placebo). The treatment was evaluated by patients using the HRQOL assessment tools Short Form-36 (SF-36) and Dermatology Life Quality Index (DLQI). Other patient-reported assessments included the Psoriasis Symptom Assessment (PSA), a visual analog scale (VAS) for itching, and the Patient's Global Psoriasis Assessment (PGPA). RESULTS: Efalizumab was associated with improvements at Week 12 from baseline in patient-reported outcomes, both in the total study population and in the High-Need cohort. Among all efalizumab-treated patients, the DLQI improved by 5.7 points from baseline to Week 12, relative to an improvement of 2.3 points for placebo patients (P < .001). Corresponding improvements in DLQI in the High-Need cohort were 5.4 points for efalizumab compared to 2.3 for placebo (P < .001). Improvements from baseline on the SF-36, PSA, PGPA, and itching VAS at Week 12 were also significantly greater in efalizumab-treated patients than for placebo. CONCLUSION: A 12-week course of efalizumab improved HRQOL and other patient-reported outcomes in patients with moderate to severe plaque psoriasis. The benefits of efalizumab therapy in High-Need patients were similar to those observed in the total study population, indicating that the beneficial impact of efalizumab on QOL is consistent regardless of disease severity, prior therapy, or contraindications to previous therapies

A-RAF Kinase Functions in ARF6 Regulated Endocytic Membrane Traffic

BACKGROUND: RAF kinases direct ERK MAPK signaling to distinct subcellular compartments in response to growth factor stimulation. METHODOLOGY/PRINCIPAL FINDINGS: Of the three mammalian isoforms A-RAF is special in that one of its two lipid binding domains mediates a unique pattern of membrane localization. Specific membrane binding is retained by an N-terminal fragment (AR149) that corresponds to a naturally occurring splice variant termed DA-RAF2. AR149 colocalizes with ARF6 on tubular endosomes and has a dominant negative effect on endocytic trafficking. Moreover actin polymerization of yeast and mammalian cells is abolished. AR149/DA-RAF2 does not affect the internalization step of endocytosis, but trafficking to the recycling compartment. CONCLUSIONS/SIGNIFICANCE: A-RAF induced ERK activation is required for this step by activating ARF6, as A-RAF depletion or inhibition of the A-RAF controlled MEK-ERK cascade blocks recycling. These data led to a new model for A-RAF function in endocytic trafficking

Light Quarks in the Instanton Vacuum at Finite Baryon Density

We consider the finite density, zero-temperature behaviour of quark matter in the instanton picture. Since the instanton-induced interactions are attractive in both $\bar{q}q$ and $qq$ channels, a competition ensues between phases of matter with condensation in either or both. It results in chiral symmetry restoration due to the onset of diquark condensation, a `colour supercondutor', at finite density. Also present is a state with both manners of condensation, however this phase is found to be thermodynamically disfavoured for equilibrium matter. Properties of quark matter in each phase are discussed, with emphasis on the microscopic effects of the effective mass and superconducting energy gap.Comment: 29 pages, 8 figures, LaTeX, minor typos correcte

Can weight loss prevent cancer?

We review and update evidence on obesity, weight gain and weight loss in relation to leading cancers since the International Agency for Research on Cancer report of 2002. Emphasis is placed on the time course of disease and implications for weight control to prevent cancer. We conclude that weight loss could prevent a major portion of common cancers

Blood Glucose and Risk of Incident and Fatal Cancer in the Metabolic Syndrome and Cancer Project (Me-Can): Analysis of Six Prospective Cohorts

Tanja Stocks and colleagues carry out an analysis of six European cohorts and confirm that abnormal glucose metabolism is linked with increased risk of cancer overall and at specific sites

The place and barriers of evidence based practice: knowledge and perceptions of medical, nursing and allied health practitioners in malaysia

<p>Abstract</p> <p>Background</p> <p>Despite a recent increase in activities to promote evidence-based practice (EBP), it was unclear how Malaysian hospital practitioners received this new approach in medicine. This study examines their confidence and perceptions on EBP.</p> <p>Findings</p> <p>We conducted cross-sectional surveys using a self-administered questionnaire during two EBP training courses in two Malaysian hospitals in January and June 2007. Our subjects (n = 144) were doctors and nursing and allied health staff (NAH) participating in the EBP courses. Our questionnaire covered three domains: confidence and understanding (six items), attitude (five items) and barriers to practice (four items). We presented simple descriptive statistics, including the sum ratings and the proportions with different responses for each item, and compared different groups using Mann-Whitney U test for scaled ratings and Chi-square test for dichotomous responses.</p> <p>Ninety-two doctors and 52 NAH staff completed the surveys. Overall, doctors expressed slightly higher confidence on EBP compared to NAH staff. Out of a maximum sum rating of 27 over six items, doctors reported an average of 18.3 (SD 3.2) and NAH staff reported an average of 16.0 (SD 3.4), p = 0.002. Doctors were also more positive in their views on EBP. For example, 67.4% of doctors disagreed, but 61% of NAH staff agreed that "the importance of EBP in patient care is exaggerated", and 79.3% of doctors disagreed, but 46.2% of NAH staff agreed that "EBP is too tedious and impractical". Similar responses were observed for other items in the domain.</p> <p>Doctors and NAH staff shared similar concerns on barriers to evidence-based practice. The highest proportions considered poor facilities to access evidence a barrier (76% of doctors and 90% of NAH), followed by poor awareness of evidence (62% of doctors and 70% of NAH) and time constraints (63% of doctors and 68% of NAH), p = 0.09 for the combined rating of four items in the domain.</p> <p>Conclusions</p> <p>The findings of our survey suggest a need for greater efforts in promoting EBP among Malaysian hospital practitioners especially for NAH staff. From the responses based on the barriers to EBP, improving facilities for accessing evidence and promoting more user-friendly resources to address time constraints appear to be the priorities.</p

Spelling improvement through letter-sound and whole-word training in two multilingual Greek- and English- speaking children

Case studies of two children with spelling difficulty are reported. LK was multilingual and ED bilingual. A training programme that targeted phonic decoding (or sublexical) spelling processes was conducted with both children. Immediate and delayed post-training assessments showed improvement in spelling nonwords for LK but not for ED. Training that targeted whole word (or lexical) spelling processes was then conducted with ED. Improvement in spelling of irregular words (a marker for lexical spelling processes) was observed. Research into literacy difficulties with multilingual children is sparse, although multilingualism is increasingly widespread. Up to now theoretically based training studies have focused on monolingual children and results were promising. The present findings indicate that theoretically based training programmes for literacy difficulties can also be effective for multilingual children