Renal Cancer Resistance to VEGF Receptor Tyrosine Kinase Inhibitors.

PhDAim: To investigates the molecular changes that occur in response to VEGFr TKI therapy to better understand the acquired resistance process. A further goal is to investigate the potential of SRC inhibitors to slow or prevent VEGFr TKI resistance. Methods: Work was conducted in in vitro assays (MTS assays, scratch and transwell migration assays), a preclinical in vivo model of resistance (786-O xenografts) and IHC was conducted in sequential RCC patient tissue taken before and after 12-16 weeks of VEGFr TKI therapy. Findings: 100% (n=15) of 786-O xenografts developed a resistant phenotype when continually exposed to VEGFr-TKI treatment. PCR with species-specific probes showed VEGFr-TKI induced significant up-regulation of several pro-angiogenic factors in both the tumour and host compartments. These factors included VEGF ligand, FGF-2, HGF, and MET receptor. In addition, genes associated with epithelial mesenchymal transition were up-regulated in treated xenografts. Interestingly, the pro-angiogenic factor PGF and the pro-metastatic gene s100a4 were up-regulated with time, independently of treatment. Gene pathway analysis suggested VEGFr-TKI treatment induced a process resembling fibrosis or wound healing. Furthermore, collagen was increased in treated xenografts. IHC in RCC patient tissue verified that some of the above pathways were affected in the clinical setting. VEGFr-TKI treatment caused a significant reduction in vessel density (CD31), and up-regulation of FGF-2 ligand and vessel-bound MET receptor. Collagen was also increased in VEGFr-TKI treated clinical samples. In vitro assays demonstrated that VHL gene mutation promoted resistance to SRC TKIs. Adding a SRC TKI to VEGFr-TKI therapy had a synergistic anti-tumour effect on 786-O xenografts. However, the combination could not prevent growth in tumours that had acquired a VEGFr TKI resistant phenotype. There was no evidence that the addition of a SRC TKI affected genes implicated in the resistance process. Interpretation: VEGFr-TKI treatment is associated with dynamic molecular changes to several relevant biomarkers. Targeting any one pathway in isolation may have an incremental anti-tumour effect, but because multiple pathways are affected, it is perhaps unlikely to result in a sustained improvement in tumour response. Heterogeneity of protein expression adds further complication to a targeted approach. Collagen deposition increases with VEGFr TKI therapy. Collagen has been shown to promote angiogenesis and metastasis. Further investigation is warranted to understand whether the addition of anti-fibrotic agents to anti-angiogenic therapy could have an incremental benefit on patient outcome

Inappropriate flushing of menstrual sanitary products

This paper explores the disposal strategies of menstrual sanitary products through in-depth semi-structured interviews of women aged 18-30 years. There have been many educational campaigns to encourage solid stream waste disposal, however inappropriate disposal and blockages are still a major problem for the water industry. Whilst there have been quantitative studies exploring self-reporting of flushing norms, there is evidence to suggest these results may not take into account the complex set of socio-cultural factors associated with menstrual product disposal. Bridging this gap, our interviews found that although all participants had a desire to responsibly dispose, their ability to utilise solid waste streams or to minimise waste by using reusable products was not always possible because they felt, to some degree, restricted by the wider societal requirements for discretion and the design, accessibility and availability of bins and bathroom facilities. Based on these findings Industry recommendations are suggested

Clinical performance characteristics for bordered foam dressings in the treatment of complex wounds: an international wound dressing technology expert panel review

The aim of this article is to identify and describe clinical practice performance characteristics for bordered foam dressings in the treatment of complex wounds. Our recently published systematic review of outcomes and applied measurement instruments for the use of bordered foam dressings in complex wounds has led to us identifying a range of important clinical and patient-centred issues related to this dressing class. Specifically, here, we focus on an overview of performance criteria in the areas of application, adhesion, exudate management and debridement functions of bordered foam dressings. Our hope is that by highlighting the clinical performance criteria, future testing standards for wound dressings will more closely match our clinical expectations and, thereby, assist clinicians to make better wound treatment choices based on meaningful and clinically relevant dressing product performance standards. complex wounds, complex wound care, treatment, bordered foam dressings, dressing performance.info:eu-repo/semantics/publishedVersio

How should clinical wound care and management translate to effective engineering standard testing requirements from foam dressings? Mapping the existing gaps and needs

Significance: Wounds of all types remain one of the most important, expensive, and common medical problems, for example, up to approximately two-thirds of the work time of community nurses is spent on wound management. Many wounds are treated by means of dressings. The materials used in a dressing, their microarchitecture, and how they are composed and constructed form the basis for the laboratory and clinical performances of any advanced dressing. Recent Advances: The established structure/function principle in material science is reviewed and analyzed in this article in the context of wound dressings. This principle states that the microstructure determines the physical, mechanical, and fluid transport and handling properties, all of which are critically important for, and relevant to the, adequate performances of wound dressings. Critical Issues: According to the above principle, once the clinical requirements for wound care and management are defined for a given wound type and etiology, it should be theoretically possible to translate clinically relevant characteristics of dressings into physical test designs resulting specific metrics of materials, mechanical, and fluid transport and handling properties, all of which should be determined to meet the clinical objectives and be measurable through standardized bench testing. Future Directions: This multidisciplinary review article, written by an International Wound Dressing Technology Expert Panel, discusses the translation of clinical wound care and management into effective, basic engineering standard testing requirements from wound dressings with respect to material types, microarchitecture, and properties, to achieve the desirable performance in supporting healing and improving the quality of life of patients.info:eu-repo/semantics/publishedVersio

Inclusion of CD80 in HSV Targets the Recombinant Virus to PD-L1 on DCs and Allows Productive Infection and Robust Immune Responses

CD80 plays a critical role in stimulation of T cells and subsequent control of infection. To investigate the effect of CD80 on HSV-1 infection, we constructed a recombinant HSV-1 virus that expresses two copies of the CD80 gene in place of the latency associated transcript (LAT). This mutant virus (HSV-CD80) expressed high levels of CD80 and had similar virus replication kinetics as control viruses in rabbit skin cells. In contrast to parental virus, this CD80 expressing recombinant virus replicated efficiently in immature dendritic cells (DCs). Additionally, the susceptibility of immature DCs to HSV-CD80 infection was mediated by CD80 binding to PD-L1 on DCs. This interaction also contributed to a significant increase in T cell activation. Taken together, these results suggest that inclusion of CD80 as a vaccine adjuvant may promote increased vaccine efficacy by enhancing the immune response directly and also indirectly by targeting to DC