Immune Response Testing of Electrospun Polymers: An Important Consideration in the Evaluation of Biomaterials

Due primarily to cell sourcing issues, many in the field of tissue engineering have opted to create scaffolds that promote in situ regeneration, using the body as both the bioreactor and the cell source for the remodeling of scaffolds, resulting in the formation of native tissue. This practice raises many concerns, with the body’s immune response to such an implant often being neglected as a potential problem in preliminary design and biocompatibility testing. More importantly, what happens over time in terms of the immune responses as the biodegradable scaffold structures being utilized to promote in situ regeneration begin to degrade, forming structural fragments and degradation products? In summary, immune response evaluations are critical considerations that must be conducted when evaluating bioresorbable scaffolds. In addition, it is essential that these evaluations analyze materials for their potential dose-response and time-course effects on the various components of innate and acquired immunity

Optimisation of pharmacy content in clinical cancer research protocols: Experience of the United Kingdom Chemotherapy and Pharmacy Advisory Service

Background: Clarity and accuracy of the pharmacy aspects of cancer clinical trial protocols is essential. Inconsistencies and ambiguities in such protocols have the potential to delay research and jeopardise both patient safety and collection of credible data. The Chemotherapy and Pharmacy Advisory Service was established by the UK National Cancer Research Network, currently known as National Institute for Health Research Clinical Research Network, to improve the quality of pharmacy-related content in cancer clinical research protocols. This article reports the scope of Chemotherapy and Pharmacy Advisory Service, its methodology of mandated protocol review and pharmacy-related guidance initiatives and its current impact. Methods: Over a 6-year period (2008–2013) since the inception of Chemotherapy and Pharmacy Advisory Service, cancer clinical trial protocols were reviewed by the service, prior to implementation at clinical trial sites. A customised Review Checklist was developed and used by a panel of experts to standardise the review process and report back queries and inconsistencies to chief investigators. Based on common queries, a Standard Protocol Template comprising specific guidance on drug-related content and a Pharmacy Manual Template were developed. In addition, a guidance framework was established to address ‘ad hoc’ pharmacy-related queries. The most common remarks made at protocol review have been summarised and categorised through retrospective analysis. In order to evaluate the impact of the service, chief investigators were asked to respond to queries made at protocol review and make appropriate changes to their protocols. Responses from chief investigators have been collated and acceptance rates determined. Results: A total of 176 protocols were reviewed. The median number of remarks per protocol was 26, of which 20 were deemed clinically relevant and mainly concerned the drug regimen, support medication, frequency and type of monitoring and drug supply aspects. Further analysis revealed that 62% of chief investigators responded to the review. All responses were positive with an overall acceptance rate of 89% of the proposed protocol changes. Conclusion: Review of pharmacy content of cancer clinical trial protocols is feasible and exposes many undetected clinically relevant issues that could hinder efficient trial conduct. Our service audit revealed that the majority of suggestions were effectively incorporated in the final protocols. The refinement of existing and development of new pharmacy-related guidance documents by Chemotherapy and Pharmacy Advisory Service might aid in better and safer clinical research

Skunk River Review September 1989, vol 1 no 1

https://openspace.dmacc.edu/skunkriver/1004/thumbnail.jp

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Researching the Impact of Service provider Education (RISE) Project — a multiphase mixed methods protocol to evaluate implementation acceptability and feasibility

Abstract Background Health and social service providers receive limited education on recognizing and responding to family violence. With adequate education, providers could be prepared to identify individuals subjected to family violence and help reduce the risk of associated impairment. Informed by the Active Implementation Frameworks, our research will determine the scope of strategies needed for the uptake and sustainability of educational interventions focused on family violence for providers. It will also determine the acceptability, feasibility, and proof-of-concept for a new educational intervention, called VEGA (Violence, Evidence, Guidance, Action), for developing and improving primary care provider knowledge and skills in family violence. Methods This paper details the protocol for the Researching the Impact of Service provider Education (RISE) Project. The RISE Project follows a sequential multiphase mixed method research design; qualitative and quantitative data are being collected and integrated over three conceptually and methodologically linked research phases. Activities primarily occur in Ontario, Alberta, and Quebec. Phase 1 uses a sequential exploratory mixed method research design to characterize the scope and salience of learning and implementation needs and preferences for family violence education. Phase 2 will use an embedded mixed method research design to determine whether VEGA technology supports providers to achieve their family violence learning goals with effectiveness, efficiency, and satisfaction. Phase 3 will use a concurrent mixed method research design to determine acceptability, feasibility, and proof-of-concept for evaluating whether VEGA improves primary care providers’ knowledge and skills in family violence. This final phase will provide information on implementation strategies for family violence education in the “real world.” It will also generate data on provider recruitment, retention, and data completeness, as well as exploratory estimates of the effect for provider outcome measures proposed for a randomized controlled trial. Discussion The RISE Project comprehensively integrates an implementation approach to improve family violence education for the health and social service professions. It will provide important information about factors that could influence the uptake and effectiveness of a health profession’s educational intervention into the real world, as well as provide foundational evidence concerning the tenability of using a randomized controlled trial to evaluate the impact of VEGA in primary care settings

Modulation of murine innate and acquired immune responses following in vitro exposure to electrospun blends of collagen and polydioxanone

In light of cell sourcing issues and the lack of a bioreactor comparable to the body, many in the field of tissue engineering have focused their efforts on designing biomaterials capable of in situ regeneration. The theory is that, by using the body as both the bioreactor and the source for cell infiltration, scaffolds composed of bioresorbable materials can be remodeled into native tissue. Thus, research into the effects of such materials on the host immune response is increasingly important. This study applies an immunotoxicological approach to evaluate the effects of electrospun blends of polydioxanone (PDO) and collagen type I on murine innate and acquired immune responses. Results indicated that these materials had few effects on innate immune responses, yet they produced significant immunomodulatory effects in multiple endpoints evaluating both branches of acquired immunity (i.e., cell-mediated and humoral immunity). Specifically, collagen content appeared to be responsible for suppression of cell-mediated immunity, while blends of PDO and collagen appeared to be more suppressive of antibodyforming cell responses than either PDO or collagen alone. These results demonstrate the importance of completing evaluations into the immunotoxicological effects of biomaterials, and they suggest that such testing should become a primary focus when evaluating a material\u27s potential for use in tissue engineering applications. © 2009 Wiley Periodicals, Inc

In vitro evaluations of innate and acquired immune responses to electrospun polydioxanone-elastin blends

Immune response testing of biomaterials is an essential component of biocompatibility assessment, particularly when the materials of interest are used to design bioresorbable scaffolds with the potential to promote in situ regeneration. Current trends in immune response testing of biomaterials typically examine few elements of the immune system, and they often undertake a mechanistic approach without first determining if material exposure results in physiologically relevant modulation of both innate and acquired immunity. Here, we present a comprehensive in vitro evaluation of biomaterial-induced modulation of acquired (i.e. cell-mediated and humoral) and innate immune responses following exposure to electrospun blends of polydioxanone (PDO) and elastin (ELAS). Results indicated that in vitro exposure of murine spleen cells to PDO-ELAS blends produced statistically significant immunosuppression in multiple cell-mediated and humoral endpoints. Results suggested that ELAS is the primary cause of cell-mediated immunosuppression. In contrast, PDO and ELAS were equally suppressive of humoral immune responses, while blends of the two were more immunosuppressive than either pure polymer alone. Evaluations of innate immune responses demonstrated few significant effects, with statistically significant immunosuppression observed in natural killer cell activity but not in macrophage functional assays. This work presents an approach for assessing potential modulation of immune responses resulting from exposure to biomaterials, and such evaluations are essential to obtaining comprehensive assessments of biocompatibility. © 2008 Elsevier Ltd. All rights reserved

A Qualitative Description of Resident Physicians’ Understanding of Child Maltreatment: Impacts, Recognition, and Response

Child maltreatment (CM) is a public health problem with devastating effects on individuals, families, and communities. Resident physicians have varied formal education in CM, and report feeling inadequately trained in identifying and responding to CM. The purpose of this study is to explore residents’ understanding of the impacts of CM, and their perceptions of their role in recognizing and responding to CM to better understand their educational needs. This study analyzed qualitative data obtained from a larger project on family violence education. Twenty-nine resident physicians enrolled in pediatric, family medicine, emergency medicine, obstetrics and gynecology, and psychiatry training programs in Alberta, Ontario, and Québec participated in semi-structured interviews to elicit their ideas, experiences, and educational needs relating to CM. Conventional (inductive) content analysis guided the development of codes and categories. Residents had thorough knowledge about the impacts of CM and their duty to recognize CM, but there was less consistency in how residents understood their role in responding to CM. Residents identified the need for more education about recognizing and responding to CM, and the need for educational content to be responsive to training, patient and family factors, and systemic issues. Despite knowledge about the impacts of CM and laws pertaining to mandated reporting, residents reported challenges with responding to concerns of CM. Findings of this study emphasize the need for better training in response to CM. Future educational interventions should consider a multidisciplinary, experiential approach

El centro penitenciario del Estado de México

A disease-related, corticosteroid-insensitive increase in the expression of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium has been shown previously by the current authors. To determine whether this is associated with enhanced intracellular signalling, the aim of this study was to evaluate epithelial tyrosine phosphorylation. Bronchial biopsies were analysed for the presence of phosphotyrosine by immunohistochemistry. Bronchial epithelial cells were exposed to EGF, hydrogen peroxide or tumour necrosis factor- in vitro for measurement of tyrosine phosphorylated signalling intermediates and interleukin (IL)-8 release. Phosphotyrosine was increased significantly in the epithelium of severe asthmatics when compared with controls or mild asthmatics; however, in mild asthma, phosphotyrosine levels were significantly decreased when compared with controls. There was no significant difference between phosphotyrosine levels before or after 8 weeks of treatment with budesonide. Stimulation of bronchial epithelial cells resulted in tyrosine phosphorylation of several proteins, including EGFR, Shc and p42/p44 mitogen-activated protein kinase. In the presence of salbutamol, a transient partial suppression of EGFR phosphorylation occurred, whereas dexamethasone was without effect. Neither salbutamol nor dexamethasone inhibited EGF-stimulated IL-8 release. These data indicate that regulation of protein tyrosine kinase activity is abnormal in severe asthma. The epidermal growth factor receptor and/or other tyrosine kinase pathways may contribute to persistent, corticosteroid-unresponsive inflammation in severe asthma