New p53-based anti-cancer therapeutic strategies

Thep53 gene is frequently mutated in human tumours and therefore an important target for therapeutic intervention. Several p53-based strategies for treatment of cancer are currently under development.p53 gene therapy has resulted in tumour regression in patients with lung cancer. A mutant adenovirus can obliterate tumour cells carrying mutant p53 or lacking p53, but is unable to replicate in normal cells. Furthermore, current studies suggest that reactivation of mutant p53 proteins in tumours using small p53-activating molecules may initiate p53-dependent apoptosis and thus eliminate the tumour.     

In vitro capacity of various cyclooxygenase inhibitors to revert immune suppression caused by radiation therapy for breast cancer

Radiation therapy triggers blood monocytes to an increased secretion of immunosuppressive prostaglandins (PGs), which in part can explain the post-irradiation impairment of lymphocyte blastogenesis. Since low mitogen responses of lymphocytes in irradiated breast cancer patients is linked to a poor prognosis a clinical trial is planned to examine if treatment with inhibitors of PG-synthesis during irradiation can counteract immunosuppression and increase survival. In the present investigation we have compared nine different inhibitors of PG-synthesis for capacity to enhance phytohemagglutinin responses of blood lymphocytes before and after irradiation for breast cancer. Five of the drugs (aspisol, indomethacin, meclofenamic acid, ketoprofen and diclofenac) enhanced the reactivity to more than 150%. In general, the strongest enhancements were observed in lymphocyte preparations obtained at completion of irradiation when reactivity was most depressed followed by those obtained at one month and before irradiation.     

Strong interference of hemoglobin concentration on CSF total protein measurement using the trichloroacetic acid precipitation method.

BACKGROUND: Among other methods, trichloroacetic acid precipitation is used to quantify total protein in cerebrospinal fluid (CSF). METHODS: We analyzed the influence of hemoglobin on total protein concentration assayed by the trichloroacetic acid method and compared the results to the benzethonium chloride method. RESULTS: Four CSF samples were spiked with different amounts of hemoglobin, leading to overestimation of protein concentration when assayed by the trichloroacetic acid method. Using the benzethonium chloride method, measurement of protein concentration was minimally disturbed. In addition, albumin and total protein concentrations were measured in 135 clinical samples. The total protein/albumin ratio remained constant when protein was measured with the benzethonium chloride method, while ratios increased when protein was assayed by the trichloroacetic acid method. CONCLUSIONS: Strong interference by hemoglobin leads to overestimation of the total protein concentration in CSF when assayed by the trichloroacetic acid method and may lead to false conclusions when evaluating the blood-brain barrier.     

Self-Replicating RNAs Drive Protective Anti-tumor T Cell Responses to Neoantigen Vaccine Targets in a Combinatorial Approach

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Systematic review of organisation‐wide,trauma‐informed care models in out‐of‐home care (OoHC) settings

Trauma in early childhood has been shown to adversely affect children's social, emotional, and physical development. Children living in out‐of‐home care (OoHC) have better outcomes when care providers are present for children, physically, psychologically, and emotionally. Unfortunately, the high turnover of out‐of‐home carers, due to vicarious trauma (frequently resulting in burnout and exhaustion) can result in a child's trauma being re‐enacted during their placement in OoHC. Organisation‐wide therapeutic care models (encompassing the whole organisation, from the CEO to all workers including administration staff) that are trauma‐informed have been developed to respond to the complex issues of abuse and neglect experienced by children who have been placed in OoHC. These models incorporate a range of therapeutic techniques, and provide an overarching approach and common language that is employed across all levels of the organisation. The aim of this study was to investigate the current empirical evidence for organisation‐wide, trauma‐informed therapeutic care models in OoHC. A systematic review searching leading databases was conducted for evidence of organisation‐wide, trauma‐informed, out‐of‐home care studies, between 2002 and 2017. Seven articles were identified covering three organisational models. Three of the articles assessed the Attachment Regulation and Competency framework (ARC), one study assessed the Children and Residential Experiences programme (CARE), and three studies assessed The Sanctuary Model. Risk of bias was high in six of the seven studies. Only limited information was provided on the effectiveness of the models identified through this systematic review, although the evidence did suggest that trauma‐informed care models may have significantly positive outcomes for children in OoHC. Future research should focus on evaluating components of trauma‐informed care models and assessing the efficacy of the various organisational care models currently available.     

Active video gaming improves body coordination in survivors of childhood brain tumours

Purpose: We investigated whether active video gaming (AVG) could bring about regular, enjoyable, physical exercise in children treated for brain tumours, what level of physical activity could be reached and if the children’s physical functioning improved.

Methods: Thirteen children, aged 7–17 years, were randomised to either AVG or waiting-list. After 10–12 weeks they crossed-over. Weekly Internet coaching sessions were used to sustain motivation and evaluate enjoyment. Energy expenditure (EE) levels were measured as Metabolic Equivalent of Task (MET), using a multisensory activity monitor. Single-blinded assessments of physical functioning were done, using the Bruininks–Osteretsky Test of Motor Performance, second edition, evaluating participants before and after the intervention period, as well as comparing the randomisation groups after the first period.

Results: All patients completed the study. AVG sessions (mean duration 47?minutes) were performed on 72% of all days. Mean EE level during AVG sessions was 3.0 MET, corresponding to moderate physical activity. The Body Coordination score improved by 15% (p?=?0.021) over the intervention period.

Conclusions: In this group of childhood brain tumour survivors, home-based AVG, supported by a coach, was a feasible, enjoyable and moderately intense form of exercise that improved Body Coordination.

• Implications for Rehabilitation

• Childhood brain tumour survivors frequently have cognitive problems, inferior physical functioning and are less physically active compared to their healthy peers.

• Active video gaming (AVG), supported by Internet coaching, is a feasible home-based intervention in children treated for brain tumours, promoting enjoyable, regular physical exercise of moderate intensity.

• In this pilot study, AVG with Nintendo Wii improved Body Coordination.

     

The growth hormone secretagogue hexarelin increases cell proliferation in neurogenic regions of the mouse hippocampus

ObjectiveRadiation therapy (RT) to the brain is often used in the treatment of children with different types of malignant diseases affecting the brain. However, RT in childhood may also have severe side effects including impaired brain maturation and intellectual development. For childhood cancer survivors these adverse effects of RT can cause lifelong disability and suffering. Therefore, there is an unmet need to limit late effects after RT. Precursor cells in the subgranular zone of the dentate gyrus (DG) in the hippocampus are particularly sensitive to irradiation (IR). This may be of significance as newly generated neurons in the DG are important for memory and learning. GH secretagogues (GHS) have previously been shown to promote neurogenesis and to have neuroprotective effects. In addition, several parts of the brain, including the hippocampus, have been shown to express the GHS receptor 1a (GHS-R1a). The aim of this study was to evaluate the potential effect of the GHS hexarelin on proliferation and survival of progenitor cells in the hippocampus after brain IR in a mouse model.DesignIn the present study, 10-day-old male mice received 6 Gy cranial IR. Non-irradiated sham animals were used as controls. We treated one group of irradiated and one sham group with hexarelin (100 μg/kg/day) for 28 days and used immunohistochemical labeling of bromo-deoxy uridine (BrdU) and phospho-histone H3 of the granular cell layer of the DG to evaluate proliferation and cell survival after IR at postnatal day ten.ResultsOur results show that hexarelin significantly increased the number of BrdU-positive cells in the granule cell layer by approximately 50% compared to controls.ConclusionThe increased number of BrdU-positive cells in the granule cell layer suggests a partial restoration in the pool of proliferating cells by hexarelin after IR.     

Quantitative effects of diet on fecal corticosterone metabolites in two strains of laboratory mice

The analysis of glucocorticoids excreted in feces is becoming a widespread technique for determining animal wellbeing in a wide variety of settings. In the present study an extraction protocol and an ELISA assay for quantifying fecal corticosterone metabolites (FCM) in BALB/c and C57bl/6 mice were validated. Lower ratios of solvent (ethanol) to mass of fecal sample were found to be sufficient in extracting FCM compared to what has been reported previously. Feeding mice a high energy diet, high in fat content (60% of calories from fat), significantly lowered the FCM excretion, approximately halving the FCM output. This diet also reduced the fecal mass voided to approximately a third of that of the regular diet. The two reductions were not correlated. A difference in defecation pattern was seen between the two strains, with the BALB/c mice having a more pronounced diurnal rhythm compared to the C57bl/6 mice. Furthermore, throughout the experiment, the C57bl/6 mice excreted significantly higher levels of FCM compared to the BALB/c mice. The mice were also challenged with synthetic adrenocorticotropic hormone (ACTH) and dexamethasone (DEX). The effect of the challenges could readily be detected, but had a considerably lesser impact on data than did the difference in diet. The study demonstrates some problematic consequences of expressing FCM excretion as a measure of fecal dry mass. The study also serves to emphasize the caution that must be exercised when interpreting FCM excretion in conjunction with an uncontrolled or varied diet, or perturbations of gastro-intestinal functioning.     

NK cell function and antibodies mediating ADCC in HIV-1-infected viremic and controller patients

Natural killer (NK) cells have been suggested to play a protective role in HIV disease progression. One potent effector mechanism of NK cells is antibody-dependent cellular cytotoxicity (ADCC) mediated by antiviral antibodies binding to the FcγRIIIa receptor (CD16) on NK cells. We investigated NK cell-mediated ADCC function and the presence of ADCC antibodies in plasma from 20 HIV-1-infected patients and 10 healthy donors. The HIV-positive patients were divided into two groups: six who controlled viremia for at least 8 y without treatment (controllers), and 14 who were persistently viremic and not currently on treatment. Plasma from both patient groups induced NK cell IFN-γ expression and degranulation in response to HIV-1 envelope (Env) gp140-protein-coated cells. Patient antibodies mediating ADCC were largely directed towards the Env V3 loop, as identified by a gp140 protein lacking the V3 loop. Interestingly, in two controllers ADCC-mediating antibodies were more broadly directed to other parts of Env. A high viral load in patients correlated with decreased ADCC-mediated cytolysis of gp140-protein-coated target cells. NK cells from both infected patients and healthy donors degranulated efficiently in the presence of antibody-coated HIV-1-infected Jurkat cells. In conclusion, the character of ADCC-mediating antibodies differed in some controllers compared to viremic patients. NK cell ADCC activity is not compromised in HIV-infected patients.     

Extracorporeal shock wave lithotripsy at 60 shock waves/min reduces renal injury in a porcine model

OBJECTIVE

To determine if extracorporeal shock wave lithotripsy (ESWL) at 60 shock waves (SWs)/min reduces renal damage and haemodynamic impairment compared to treatment at 120 SWs/min.

MATERIALS AND METHODS

One kidney in each of 19 juvenile pigs (7–8 weeks old) was treated at 120 or at 60 SWs/min (2000 SWs, 24 kV) with an unmodified HM‐3 lithotripter (Dornier Medical Systems, Kennesaw, GA, USA). Renal function was determined before and after ESWL treatment by inulin clearance, extraction and clearance of para‐aminohippuric acid. Both kidneys were then removed to measure parenchymal lesion size by sectioning the entire kidney and quantifying the size of the haemorrhagic lesion in each slice.

RESULTS

ESWL at 60 SWs/min significantly reduced the size of the acute morphological lesion compared to 120 SWs/min (0.42% vs 3.93% of functional renal volume, P = 0.011) and blunted the decrease in glomerular filtration rate and renal plasma flow normally seen after treatment at 120 SWs/min.

CONCLUSIONS

Treatment at a firing rate of 60 SWs/min produces less morphological injury and causes less alteration in renal haemodynamics than treatment at 120 SWs/min in the pig model of ESWL‐induced renal injury.