Clinical and immunological evaluation of anti-apoptosis protein, survivin-derived peptide vaccine in phase I clinical study for patients with advanced or recurrent breast cancer

<p>Abstract</p> <p>Background</p> <p>We previously reported that survivin-2B, a splicing variant of survivin, was expressed in various types of tumors and that survivin-2B peptide might serve as a potent immunogenic cancer vaccine. The objective of this study was to examine the toxicity of and to <b>c</b>linically and immunologically evaluate survivin-2B peptide in a phase I clinical study for patients with advanced or recurrent breast cancer.</p> <p>Methods</p> <p>We set up two protocols. In the first protocol, 10 patients were vaccinated with escalating doses (0.1–1.0 mg) of survivin-2B peptide alone 4 times every 2 weeks. In the second protocol, 4 patients were vaccinated with the peptide at a dose of 1.0 mg mixed with IFA 4 times every 2 weeks.</p> <p>Results</p> <p>In the first protocol, no adverse events were observed during or after vaccination. In the second protocol, two patients had induration at the injection site. One patient had general malaise (grade 1), and another had general malaise (grade 1) and fever (grade 1). Peptide vaccination was well tolerated in all patients. In the first protocol, tumor marker levels increased in 8 patients, slightly decreased in 1 patient and were within the normal range during this clinical trial in 1 patient. With regard to tumor size, two patients were considered to have stable disease (SD). Immunologically, in 3 of the 10 patients (30%), an increase of the peptide-specific CTL frequency was detected. In the second protocol, an increase of the peptide-specific CTL frequency was detected in all 4 patients (100%), although there were no significant beneficial clinical responses. ELISPOT assay showed peptide-specific IFN-γ responses in 2 patients in whom the peptide-specific CTL frequency in tetramer staining also was increased in both protocols.</p> <p>Conclusion</p> <p>This phase I clinical study revealed that survivin-2B peptide vaccination was well tolerated. The vaccination with survivin-2B peptide mixed with IFA increased the frequency of peptide-specific CTL more effectively than vaccination with the peptide alone, although neither vaccination could induce efficient clinical responses. Considering the above, the addition of another effectual adjuvant such as a cytokine, heat shock protein, etc. to the vaccination with survivin-2B peptide mixed with IFA might induce improved immunological and clinical responses.</p

Bias correction and Bayesian analysis of aggregate counts in SAGE libraries

<p>Abstract</p> <p>Background</p> <p>Tag-based techniques, such as SAGE, are commonly used to sample the mRNA pool of an organism's transcriptome. Incomplete digestion during the tag formation process may allow for multiple tags to be generated from a given mRNA transcript. The probability of forming a tag varies with its relative location. As a result, the observed tag counts represent a biased sample of the actual transcript pool. In SAGE this bias can be avoided by ignoring all but the 3' most tag but will discard a large fraction of the observed data. Taking this bias into account should allow more of the available data to be used leading to increased statistical power.</p> <p>Results</p> <p>Three new hierarchical models, which directly embed a model for the variation in tag formation probability, are proposed and their associated Bayesian inference algorithms are developed. These models may be applied to libraries at both the tag and aggregate level. Simulation experiments and analysis of real data are used to contrast the accuracy of the various methods. The consequences of tag formation bias are discussed in the context of testing differential expression. A description is given as to how these algorithms can be applied in that context.</p> <p>Conclusions</p> <p>Several Bayesian inference algorithms that account for tag formation effects are compared with the DPB algorithm providing clear evidence of superior performance. The accuracy of inferences when using a particular non-informative prior is found to depend on the expression level of a given gene. The multivariate nature of the approach easily allows both univariate and joint tests of differential expression. Calculations demonstrate the potential for false positive and negative findings due to variation in tag formation probabilities across samples when testing for differential expression.</p

A systematic review of natural health product treatment for vitiligo

<p>Abstract</p> <p>Background</p> <p>Vitiligo is a hypopigmentation disorder affecting 1 to 4% of the world population. Fifty percent of cases appear before the age of 20 years old, and the disfigurement results in psychiatric morbidity in 16 to 35% of those affected.</p> <p>Methods</p> <p>Our objective was to complete a comprehensive, systematic review of the published scientific literature to identify natural health products (NHP) such as vitamins, herbs and other supplements that may have efficacy in the treatment of vitiligo. We searched eight databases including MEDLINE and EMBASE for vitiligo, leucoderma, and various NHP terms. Prospective controlled clinical human trials were identified and assessed for quality.</p> <p>Results</p> <p>Fifteen clinical trials were identified, and organized into four categories based on the NHP used for treatment. 1) L-phenylalanine monotherapy was assessed in one trial, and as an adjuvant to phototherapy in three trials. All reported beneficial effects. 2) Three clinical trials utilized different traditional Chinese medicine products. Although each traditional Chinese medicine trial reported benefit in the active groups, the quality of the trials was poor. 3) Six trials investigated the use of plants in the treatment of vitiligo, four using plants as photosensitizing agents. The studies provide weak evidence that photosensitizing plants can be effective in conjunction with phototherapy, and moderate evidence that <it>Ginkgo biloba </it>monotherapy can be useful for vitiligo. 4) Two clinical trials investigated the use of vitamins in the therapy of vitiligo. One tested oral cobalamin with folic acid, and found no significant improvement over control. Another trial combined vitamin E with phototherapy and reported significantly better repigmentation over phototherapy only. It was not possible to pool the data from any studies for meta-analytic purposes due to the wide difference in outcome measures and poor quality ofreporting.</p> <p>Conclusion</p> <p>Reports investigating the efficacy of NHPs for vitiligo exist, but are of poor methodological quality and contain significant reporting flaws. L-phenylalanine used with phototherapy, and oral <it>Ginkgo biloba </it>as monotherapy show promise and warrant further investigation.</p

Consumers of natural health products: natural-born pharmacovigilantes?

<p>Abstract</p> <p>Background</p> <p>Natural health products (NHPs), such as herbal medicines and vitamins, are widely available over-the-counter and are often purchased by consumers without advice from a healthcare provider. This study examined how consumers respond when they believe they have experienced NHP-related adverse drug reactions (ADRs) in order to determine how to improve current safety monitoring strategies.</p> <p>Methods</p> <p>Qualitative semi-structured interviews were conducted with twelve consumers who had experienced a self-identified NHP-related ADR. Key emergent themes were identified and coded using content analysis techniques.</p> <p>Results</p> <p>Consumers were generally not comfortable enough with their conventional health care providers to discuss their NHP-related ADRs. Consumers reported being more comfortable discussing NHP-related ADRs with personnel from health food stores, friends or family with whom they had developed trusted relationships. No one reported their suspected ADR to Health Canada and most did not know this was possible.</p> <p>Conclusion</p> <p>Consumers generally did not report their suspected NHP-related ADRs to healthcare providers or to Health Canada. Passive reporting systems for collecting information on NHP-related ADRs cannot be effective if consumers who experience NHP-related ADRs do not report their experiences. Healthcare providers, health food store personnel, manufacturers and other stakeholders also need to take responsibility for reporting ADRs in order to improve current pharmacovigilance of NHPs.</p

Properties of Blood, Porphyrins, and Exposure to Legacy and Emerging Persistent Organic Pollutants in Surf Scoters (Melanitta perspicillata) Overwintering on the South Coast of British Columbia, Canada

The surf scoter (Melanitta perspicillata) is a little-studied species of North American sea duck. Estimates suggest it has experienced a precipitous decline in breeding numbers over the latter half of the past century. To investigate the potential role of contaminant uptake and toxicity in the population decline, this study undertook to measure blood chemistry, porphyrin concentrations, EROD, and organic contaminants in mature surf scoters wintering in the Strait of Georgia, BC, Canada. Hepatic organochlorine pesticide, polychlorinated dibenzo-p-dioxin, polychlorinated dibenzofuran, polychlorinated biphenyl (PCB), polybrominated diphenyl ether, and nonylphenol concentrations were relatively low; for example, ΣTEQs (toxic equivalents) for PCBs, dioxins, and furans combined ranged from 4.7 ng/kg wet weight in reference-site (Baynes Sound) birds to 11.4 ng/kg wet weight in birds from Vancouver Harbour. Nonetheless, elevated EROD activity indicated that birds in Howe Sound were responding to an Ah-receptor-mediated stressor, which was also affecting hematocrit values and possibly vitamin A status. In addition, a low proportion of lymphocytes in individuals across locations in early spring samples was associated with poor body condition. The apparent loss of fitness just prior to the onset of northerly migrations to breeding grounds is of particular concern. Compromised health of mature birds at this point in the season might impact negatively on the productivity and survival of some individuals, particularly those overwintering in Howe Sound

A qualitative exploration of Malaysian cancer patients' perspectives on cancer and its treatment

<p>Abstract</p> <p>Background</p> <p>Cancer patients' knowledge about cancer and experiences with its treatment play an important role in long-term adherence in their disease management. This study aimed to explore cancer patients' knowledge about cancer, their perceptions of conventional therapies and the factors that contribute to medication adherence in the Malaysian population.</p> <p>Methods</p> <p>A qualitative research approach was adopted to gain a better understanding of the current perceptions and knowledge held by cancer patients. Twenty patients were interviewed using a semi-structured interview guide. A saturation point was reached after the 18^thinterview, and no new information emerged with the subsequent 2 interviews. All interviews were transcribed verbatim and analysed by means of a standard content analysis framework.</p> <p>Results</p> <p>The majority of patients related the cause of their cancer to be God's will. Participants perceived conventional therapies as effective due to their scientific methods of preparations. A fear of side effects was main reasons given for delay in seeking treatment; however, perceptions were reported to change after receiving treatment when effective management to reduce the risk of side effects had been experienced.</p> <p>Conclusions</p> <p>This study provides basic information about cancer patients' perceptions towards cancer and its treatment. These findings can help in the design of educational programs to enhance awareness and acceptances of cancer screening. Priorities for future research should focus on patients who refused the conventional therapies at any stage.</p

GRADE Guidelines 30: the GRADE approach to assessing the certainty of modeled evidence—An overview in the context of health decision-making

Objectives: The objective of the study is to present the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) conceptual approach to the assessment of certainty of evidence from modeling studies (i.e., certainty associated with model outputs). / Study Design and Setting: Expert consultations and an international multidisciplinary workshop informed development of a conceptual approach to assessing the certainty of evidence from models within the context of systematic reviews, health technology assessments, and health care decisions. The discussions also clarified selected concepts and terminology used in the GRADE approach and by the modeling community. Feedback from experts in a broad range of modeling and health care disciplines addressed the content validity of the approach. / Results: Workshop participants agreed that the domains determining the certainty of evidence previously identified in the GRADE approach (risk of bias, indirectness, inconsistency, imprecision, reporting bias, magnitude of an effect, dose–response relation, and the direction of residual confounding) also apply when assessing the certainty of evidence from models. The assessment depends on the nature of model inputs and the model itself and on whether one is evaluating evidence from a single model or multiple models. We propose a framework for selecting the best available evidence from models: 1) developing de novo, a model specific to the situation of interest, 2) identifying an existing model, the outputs of which provide the highest certainty evidence for the situation of interest, either “off-the-shelf” or after adaptation, and 3) using outputs from multiple models. We also present a summary of preferred terminology to facilitate communication among modeling and health care disciplines. / Conclusion: This conceptual GRADE approach provides a framework for using evidence from models in health decision-making and the assessment of certainty of evidence from a model or models. The GRADE Working Group and the modeling community are currently developing the detailed methods and related guidance for assessing specific domains determining the certainty of evidence from models across health care–related disciplines (e.g., therapeutic decision-making, toxicology, environmental health, and health economics)

MicroRNA interactome analysis predicts post-transcriptional regulation of ADRB2 and PPP3R1 in the hypercholesterolemic myocardium

Little is known about the molecular mechanism including microRNAs (miRNA) in hypercholesterolemia-induced cardiac dysfunction. We aimed to explore novel hypercholesterolemia-induced pathway alterations in the heart by an unbiased approach based on miRNA omics, target prediction and validation. With miRNA microarray we identified forty-seven upregulated and ten downregulated miRNAs in hypercholesterolemic rat hearts compared to the normocholesterolemic group. Eleven mRNAs with at least 4 interacting upregulated miRNAs were selected by a network theoretical approach, out of which 3 mRNAs (beta-2 adrenergic receptor [Adrb2], calcineurin B type 1 [Ppp3r1] and calcium/calmodulin-dependent serine protein kinase [Cask]) were validated with qRT-PCR and Western blot. In hypercholesterolemic hearts, the expression of Adrb2 mRNA was significantly decreased. ADRB2 and PPP3R1 protein were significantly downregulated in hypercholesterolemic hearts. The direct interaction of Adrb2 with upregulated miRNAs was demonstrated by luciferase reporter assay. Gene ontology analysis revealed that the majority of the predicted mRNA changes may contribute to the hypercholesterolemia-induced cardiac dysfunction. In summary, the present unbiased target prediction approach based on global cardiac miRNA expression profiling revealed for the first time in the literature that both the mRNA and protein product of Adrb2 and PPP3R1 protein are decreased in the hypercholesterolemic heart