Strategic momentum: the immediate outcome of an effective strategy formation process

strategy

Exogenously added GPI-anchored tissue inhibitor of matrix metal loproteinase-1 (TIMP-1) displays enhanced and novel biological activities

The family of tissue inhibitors of metalloproteinases (TIMPs) exhibits diverse physiological/biological functions including the inhibition of active matrix metalloproteinases, regulation of proMMP activation, cell growth, and the modulation of angiogenesis. TIMP-1 is a secreted protein that can be detected on the cell surface through its interaction with surface proteins. The diverse biological functions of TIMP-1 are thought to lie, in part, in the kinetics of TIMP-1/MMP/surface protein interactions. Proteins anchored by glycoinositol phospholipids (GPIs), when purified and added to cells in vitro, are incorporated into their surface membranes. A GPI anchor was fused to TIMP-1 to generate a reagent that could be added directly to cell membranes and thus focus defined concentrations of TIMP-1 protein on any cell surface independent of protein-protein interaction. Unlike native TIMP-1, exogenously added GPI-anchored TIMP-1 protein effectively blocked release of MMP-2 and MMP-9 from osteosarcoma cells. TIMP-1-GP1 was a more effective modulator of migration and proliferation than TIMP-1. While control hTIMP-1 protein did not significantly affect migration of primary microvascular endothelial cells at the concentrations tested, the GPI-anchored TIMP-1 protein showed a pronounced suppression of endothelial cell migration in response to bFGF. In addition, TIMP-1-GPI was more effective at inducing microvascular endothelial proliferation. In contrast, fibroblast proliferation was suppressed by the agent. Reagents based on this method should assist in the dissection of the protease cascades and activities involved in TIMP biology. Membrane-fixed TIMP-1 may represent a more effective version of the protein for use in therapeutic expression

A mixed methods evaluation of medical tattooing for people who have experienced a burn injury

Introduction: There are no existing studies examining the psychological merits of using facial medical tattooing (MT) following burn injury. This study evaluated an MT service supported by The Katie Piper Foundation. It examined accessibility, satisfaction and whether there were improvements in quality of life (QoL). Methods: Thirty-five service-users were invited to participate in a cross-sectional online survey. Twenty-five (71%) responded (24 women; age range = 21–64 years), and of these five (4 women; age range = 26–59 years) also participated in telephone interviews, which were analysed using descriptive thematic analysis. Findings: The service was largely considered easy to access (22/25) and convenient (25/25). Most service-users (22/25) were satisfied with the results of MT. Some areas of dissatisfaction were described, by a minority of service-users, including: the procedure being painful (1/25); the tattoo being below expectation or fading over time (3/25). The majority reported that MT had improved confidence (22/25); mood (19/25); and ability to socialise (19/25). The procedure improved some service-users’ ability to carry out essential activities (14/25) and enjoyable activities (16/25). The qualitative responses provided during interview, indicated that all respondents found the procedure useful to their adjustment, although a minority (3/5) found it painful and also commented on fading (1/5). All described MT as contributing to a sense of increased normality. Conclusions: MT had the largest impact on emotional wellbeing and interpersonal domains of QoL. MT services should now improve awareness of the procedure, lobby for further support to provide wider access to the procedure, and routinely use measures assessing psychosocial outcomes

In Vitro-Selected drug-resistant Varicella-Zoster Virus mutants in the thymidine kinase and DNA polymerase genes yield novel Phenotype-Genotype associations and highlight differences between antiherpesvirus drugs

Varicella zoster virus (VZV) is usually associated with mild to moderate illness in immunocompetent patients. However, older age and immune deficiency are the most important risk factors linked with virus reactivation and severe complications. Treatment of VZV infections is based on nucleoside analogues, such as acyclovir (ACV) and its valyl prodrug valacyclovir, penciclovir (PCV) as its prodrug famciclovir, and bromovinyldeoxyuridine (BVDU; brivudin) in some areas. The use of the pyrophosphate analogue foscarnet (PFA) is restricted to ACV-resistant (ACVr) VZV infections. Since antiviral drug resistance is an emerging problem, we attempt to describe the contributions of specific mutations in the viral thymidine kinase (TK) gene identified following selection with ACV, BVDU and its derivative BVaraU (sorivudine), and the bicyclic pyrimidine nucleoside analogues (BCNAs), a new class of potent and specific anti-VZV agents. The string of 6 Cs at nucleotides 493 to 498 of the VZV TK gene appeared to function as a hot spot for nucleotide insertions or deletions. Novel amino acid substitutions (G24R and T86A) in VZV TK were also linked to drug resistance. Six mutations were identified in the “palm domain” of VZV DNA polymerase in viruses selected for resistance to PFA, PCV, and the 2-phophonylmethoxyethyl (PME) purine derivatives. The investigation of the contributions of specific mutations in VZV TK or DNA polymerase to antiviral drug resistance and their impacts on the structures of the viral proteins indicated specific patterns of cross-resistance and highlighted important differences, not only between distinct classes of antivirals, but also between ACV and PC

Systemic ablation of MMP9 triggers invasive growth and metastasis of pancreatic cancer via deregulation of IL-6 expression in the bone marrow

Matrix metalloproteinase 9 (MMP9/Gelatinase B) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and plays a central role in tumor cell invasion and metastasis. Here we complemented mechanistic insights in the cancer biology of MMP9 and investigated the effects of specific long-term loss-of-function, by genetic ablation, of MMP9 on PDAC initiation and progression in the well-established KPC mouse model of spontaneous PDAC. Tumor growth and progression were analyzed by histopathology and immunohistochemistry. Invasive growth of PDAC cells was analyzed by both in vitro (proliferation, survival, migration, invasion assays) and in vivo (experimental metastasis assays) methods. Retroviral shRNAi was used to knockdown target genes (MMP9, IL6R). Gene expression was analyzed by qRT-PCR, immunoblot, ELISA, in situ hybridization and zymography. PDAC tumors from MMP9-deficient mice were dramatically larger, more invasive and contained more stroma. Yet, ablation of MMP9 in PDAC cells did not directly promote invasive growth. Interestingly, systemic ablation of MMP9 led to increased IL-6 levels resulting from abrogation of MMP9-dependent SCF-signaling in the bone marrow (BM). IL-6 levels in MMP9-/- mice were sufficient to induce invasive growth and STAT3 activation in PDAC cells via IL-6 receptor (IL6R). Interference with IL6R blocked the increased invasion and metastasis of PDAC cells in MMP9-deficient hosts. In conclusion, ablation of systemic MMP9 initiated fatal communication between maintenance of physiological functions of MMP9 in the BM and invasive growth of PDAC via the IL-6/IL6R/STAT3 axis. Implications: Thus, the beneficial effects of host MMP9 on PDAC are an important caveat for the use of systemic MMP9 inhibitors in cancer

Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke.

Numerous studies have documented increases in matrix metalloproteinases (MMPs), specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB), increased risk of hemorrhagic complications, and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen activator (tPA) treatment. The aim of the present review is to examine the relationship between neutrophils, MMP-9 and tPA following ischemic stroke to elucidate which cells are responsible for the increases in MMP-9 and resultant barrier changes and hemorrhage observed following stroke

Understanding the relationship transitions and associated end of life clinical needs of young adults with life-limiting illnesses:a triangulated longitudinal qualitative study

Background: Care of young adults with life-limiting illnesses can often be complex due to the fact that they are growing and developing within the continuing presence of their illness. There is little research conducted nationally and internationally, which has examined the life issues of young adults or taken a longitudinal approach to understand such issues over a period of time. Aim: To gain clear understanding of one particular and pertinent life issue—relationship transition—occurring in the context of being a young adult with a life-limiting illness and the clinical needs arising from this. Design: This was a triangulated, longitudinal, qualitative study involving young adults with life-limiting illnesses and their significant others, namely, family members and healthcare professionals. Semi-structured interviews were conducted with participants and analysed using thematic analysis. Clinical case note reviews were also carried out. Setting/participants: A total of 12 young adults (aged between 17 and 23 years) from 2 hospices and 22 nominated significant others participated in a total of 58 interviews. Results: Thematic analysis revealed 4 main themes and 11 subthemes. The main themes were ‘Dependence dichotomy’, ‘In it together’, ‘Biographical uncertainty’, and ‘Conserving integrity’. These themes helped to establish the nature of relationship transitions that the young adult participants from the study experienced and additionally allowed insight into their possible needs at their end of life. Conclusion: This study has identified the nature of relationship transitions pertinent to young adults and has highlighted associated end of life clinical needs. This study can influence further research into the transitions and end of life needs of this particular patient group receiving palliative care, while informing the lacking evidence base which exists internationally