Survivin a radiogenetic promoter for glioblastoma viral gene therapy independently from CArG motifs

BACKGROUND: Radiogenetic therapy is a novel approach in the treatment of cancer, which employs genetic modification to alter the sensitivity of tumor cells to the effect of applied radiation. AIM: To select a potent radiation inducible promoter in the context of brain tumors and to investigate if CArG radio responsive motifs or other elements in the promoter nucleotide sequences can correlate to its response to radiation. METHODS: To select initial candidates for promoter inducible elements, the levels of mRNA expression of six different promoters were assessed using Quantitative RTPCR in D54 MG cells before and after radiation exposure. Recombinant Ad/reporter genes driven by five different promoters; CMV, VEGF, FLT-1, DR5 and survivin were constructed. Glioma cell lines were infected with different multiplicity of infection of the (promoter) Ad or CMV Ad. Cells were then exposed to a range of radiation (0–12 Gy) at single fraction. Fluorescent microscopy, Luc assay and X-gal staining was used to detect the level of expression of related genes. Different glioma cell lines and normal astrocytes were infected with Ad survivin and exposed to radiation. The promoters were analyzed for presence of CArG radio-responsive motifs and CCAAT box consensus using NCBI blast bioinformatics software. RESULTS: Radiotherapy increases the expression of gene expression by 1.25–2.5 fold in different promoters other than survivin after 2 h of radiation. RNA analysis was done and has shown an increase in copy number of tenfold for survivin. Most importantly cells treated with RT and Ad Luc driven by survivin promoter showed a fivefold increase in expression after 2 Gy of radiation in comparison to non-irradiated cells. Presence or absence of CArG motifs did not correlate with promoter response to radiation. Survivin with the best response to radiation had the lowest number of CCAAT box. CONCLUSION: Survivin is a selective potent radiation inducible promoter for glioblastoma viral gene therapy and this response to radiation could be independent of CArG motifs

The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma

The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations.Performance of the msGPA was assessed in Cohort I (1997-2008, n=231) and Cohort II (2008-2013, n=162) using Kaplan-Meier methods and Harrell's c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance.The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models.An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care

Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases

PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning

Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases

PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning

A comparative study of biodegradation of vinyl acetate by environmental strains

Four Gram-negative strains, E3_2001, EC1_2004, EC3_3502 and EC2_3502, previously isolated from soil samples, were subjected to comparative studies in order to select the best vinyl acetate degrader for waste gas treatment. Comparison of biochemical and physiological tests as well as the results of fatty acids analyses were comparable with the results of 16S rRNA gene sequence analyses. The isolated strains were identified as Pseudomonas putida EC3_2001, Pseudomonas putida EC1_2004, Achromobacter xylosoxidans EC3_3502 and Agrobacterium sp. EC2_3502 strains. Two additional strains, Pseudomonas fluorescens PCM 2123 and Stenotrophomonas malthophilia KB2, were used as controls. All described strains were able to use vinyl acetate as the only source of carbon and energy under aerobic as well as oxygen deficiency conditions. Esterase, alcohol dehydrogenase and aldehyde dehydrogenase were involved in vinyl acetate decomposition under aerobic conditions. Shorter degradation times of vinyl acetate were associated with accumulation of acetic acid, acetaldehyde and ethanol as intermediates in the culture fluids of EC3_2001 and KB2 strains. Complete aerobic degradation of vinyl acetate combined with a low increase in biomass was observed for EC3_2001 and EC1_2004 strains. In conclusion, P. putida EC1_2004 is proposed as the best vinyl acetate degrader for future waste gas treatment in trickle-bed bioreactors

Implementation of preventive strength training in residential geriatric care: a multi-centre study protocol with one year of interventions on multiple levels

<p>Abstract</p> <p>Background</p> <p>There is scientific evidence that preventive physical exercise is effective even in high age. In contrast, there are few opportunities of preventive exercise for highly aged people endangered by or actually in need of care. For example, they would not be able to easily go to training facilities; standard exercises may be too intensive and therefore be harmful to them; orientation disorders like dementia would exacerbate individuals and groups in following instructions and keeping exercises going. In order to develop appropriate interventions, these and other issues were assigned to different levels: the individual-social level (ISL), the organisational-institutional level (OIL) and the political-cultural level (PCL). Consequently, this conceptional framework was utilised for development, implementation and evaluation of a new strength and balance exercise programme for old people endangered by or actually in need of daily care. The present paper contains the development of this programme labeled "fit for 100", and a study protocol of an interventional single-arm multi-centre trial.</p> <p>Methods</p> <p>The intervention consisted of (a) two group training sessions every week over one year, mainly resistance exercises, accompanied by sensorimotor and communicative group exercises and games (ISL), (b) a sustainable implementation concept, starting new groups by instructors belonging to the project, followed by training and supervision of local staff, who stepwise take over the group (OIL), (c) informing and convincing activities in professional, administrative and governmental contexts, public relation activities, and establishing an advisory council with renowned experts and public figures (PCL). Participating institutions of geriatric care were selected through several steps of quality criteria assessment. Primary outcome measures were continuous documentation of individual participation (ISL), number of groups continued without external financial support (at the end of the project, and after one year) (OIL). Secondary outcome was measured by sensorimotor tests and care-related assessments in the beginning and every 16 weeks (ISL), by qualitative outcome descriptions 12 months after group implementation (OIL) and by analysis of media response and structured interviews with stakeholders, also after 12 months (PCL).</p> <p>Conclusion</p> <p>Exemplarily, preventive exercise has been established for a neglected target population. The multi-level approach used here seems to be helpful to overcome institutional and individual (attitude) barriers.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN55213782</p