Seeking and accessing professional support for child anxiety in a community sample

There is a lack of current data on help-seeking, and barriers to accessing professional support for child anxiety disorders. This study aimed to provide current data on the frequency and type of parental help-seeking, professional support received, and parent-reported barriers/facilitators in the context of child anxiety, and to explore factors associated with help-seeking, and parent-reported barriers among help-seekers and non help-seekers. We conducted a survey of help-seeking in parents of 222 children (aged 7-11) with elevated anxiety symptoms identified through screening in schools, 138 children of whom met diagnostic criteria for an anxiety disorder. Almost two-thirds (64.5%) of parents of children with an anxiety disorder reported seeking help from a professional; in 38.4% of cases parents reported that their child had received support from a professional to help manage and overcome their anxiety difficulties, and < 3% had received evidence-based treatment (CBT). Frequently reported parental barriers related to difficulties differentiating between developmentally appropriate and clinically significant anxiety, a lack of help-seeking knowledge, perceived negative consequences of help-seeking, and limited service provision. Non-help seekers were more likely than help seekers to report barriers related to thinking a child's anxiety may improve without professional support, and the absence of professional recognition. Findings identify the need for (i) tools for parents and primary school staff to help identify children who may benefit from professional support to overcome difficulties with anxiety; and (ii) increased evidence-based provision for child anxiety disorders, including delivery within schools and direct support for parents

Transcriptional changes in trichothiodystrophy cells

Mutations in three of the genes encoding the XPB, XPD and TTDA components of transcription factor TFIIH can result in the clinical phenotype of trichothiodystrophy (TTD). Different mutations in XPB and XPD can instead cause xeroderma pigmentosum (XP). The completely different features of these disorders have been attributed to TTD being a transcription syndrome. In order to detect transcriptional differences between TTD and XP cells from the XP-D complementation group, we have compared gene expression profiles in cultured fibroblasts from normal, XP and TTD donors. Although we detected transcriptional differences between individual cell strains, using an algorithm of moderate stringency, we did not identify any genes whose expression was reproducibly different in proliferating fibroblasts from each type of donor. Following UV-irradiation, many genes were up- and down-regulated in all three cell types. The microarray analysis indicated some apparent differences between the different donor types, but on more detailed inspection, these turned out to be false positives. We conclude that there are minimal differences in gene expression in proliferating fibroblasts from TTD, XP-D and normal donors

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Retargeted adenoviruses for radiation-guided gene delivery

The combination of radiation with radiosensitizing gene delivery or oncolytic viruses promises to provide an advantage that could improve the therapeutic results for glioblastoma. X-rays can induce significant molecular changes in cancer cells. We isolated the GIRLRG peptide that binds to radiation-inducible 78 kDa glucose-regulated protein (GRP78), which is overexpressed on the plasma membranes of irradiated cancer cells and tumor-associated microvascular endothelial cells. The goal of our study was to improve tumor-specific adenovirus-mediated gene delivery by selectively targeting the adenovirus binding to this radiation-inducible protein. We employed an adenoviral fiber replacement approach to conduct a study of the targeting utility of GRP78-binding peptide. We have developed fiber-modified adenoviruses encoding the GRP78-binding peptide inserted into the fiber-fibritin. We have evaluated the reporter gene expression of fiber-modified adenoviruses in vitro using a panel of glioma cells and a human D54MG tumor xenograft model. The obtained results demonstrated that employment of the GRP78-binding peptide resulted in increased gene expression in irradiated tumors following infection with fiber-modified adenoviruses, compared with untreated tumor cells. These studies demonstrate the feasibility of adenoviral retargeting using the GRP78-binding peptide that selectively recognizes tumor cells responding to radiation treatment

Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol

© 2017 The Author(s). Toll-like receptors (TLRs) are major players of the innate immune system. Once activated, they trigger a signalling cascade that leads to NF-ΰ B translocation from the cytoplasm to the nucleus. Single cell analysis shows that NF-ΰ B signalling dynamics are a critical determinant of transcriptional regulation. Moreover, the outcome of innate immune response is also affected by the cross-talk between TLRs and estrogen signalling. Here, we characterized the dynamics of TLR5 signalling, responsible for the recognition of flagellated bacteria, and those changes induced by estradiol in its signalling at the single cell level. TLR5 activation in MCF7 cells induced a single and sustained NF-k B translocation into the nucleus that resulted in high NF-k B transcription activity. The overall magnitude of NF-k B transcription activity was not influenced by the duration of the stimulus. No significant changes are observed in the dynamics of NF-k B translocation to the nucleus when MCF7 cells are incubated with estradiol. However, estradiol significantly decreased NF-k B transcriptional activity while increasing TLR5-mediated AP-1 transcription. The effect of estradiol on transcriptional activity was dependent on the estrogen receptor activated. This fine tuning seems to occur mainly in the nucleus at the transcription level rather than affecting the translocation of the NF-k B transcription factor

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1-5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&amp;Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings

Reuse of materials from a Sustainable Drainage System device: Health, Safety and Environment assessment for an end-of-life Pervious Pavement Structure

Pervious pavement systems can have a life span of about 20 years but, at end-of-life, it becomes necessary to evaluate the state of the infrastructure to determine whether they pose a health and safety risk to workers during dismantling, and also determine potential reuse of the waste material generated. In this paper, we report of an investigation conducted to evaluate whether Pervious pavement systems are hazardous to human health at end-of-life and also to assess the mobility of the stormwater pollutants trapped in the system as a measure of their potential release to receiving systems such as water-bodies and groundwater systems. After decommissioning, the pervious pavement structure was sampled for analysis including Gas Chromatography, inductively coupled plasma spectroscopy and, leachate analysis. Results show that carcinogenic risks were significantly below the regulatory limit of 1 × 10–6 while, the hazard quotients and cumulative hazard indices were also below regulatory value of 1, based on United States Environmental Protection Agency standards. Furthermore, mean concentrations of benzene, toluene, ethylbenzene and xylene were significantly less than the UK soil guideline values. The results of the leachate analysis show that the metals of concern, Pb, Zn, Cr, Ni, Cd and Cu were all below the threshold for reuse applications such as irrigation purposes as they were all below the regulatory limits such as Food and Agriculture Organization and, United States Environmental Protection Agency standards. Finally, the evaluation of potential reuse and recycling purposes indicate that wastes generated from the dismantling of the PPS are within limits for recycling as aggregates for other civil engineering projects as per European Union standards. This has potential to enhance UK's drive to achieve the target of 70% level of construction &amp; demolition waste recovery for reuse and recycling by the year 2020 as per European Union Water Framework Directive

Phase II clinical trial of bortezomib and bevacizumab combination in recurrent glioblastoma.

2056 Background: The only approved 2nd-line treatment for glioblastoma is Bevacizumab (Avastin), with estimated 6-month progression-free survival (PFS) rate of 42.6% and overall survival (OS) of 9.2 months. Laboratory data show Bortezomib (Velcade) is an effective agent in glioma models. We evaluated the combination of Avastin and Velcade in patients with recurrent GBM in a phase II, 2 center, open-label trial.Eligible patients were over 18 years of age, with WHO grade 4 glioma, Karnofsky score 70%. Bevacizumab was given 15 mg/kg IV every 3 weeks, and Bortezomib was given on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42 day cycle, at 1.7 mg/m2 for patients on non-enzyme-inducing antiepileptic drugs (EIAED) and 2.5 mg/m2 for patients on EIAED. Primary end points were 6-month PFS; secondary endpoints were toxicity, PFS, OS and radiographic response.There were a total of 61 patients enrolled, 32 patients on non-EIAEDs, and 29 patients on EIADs. Median age was 55.2. Six-month PFS was 40.6% for patients on non-EIAEDs, and 24.1% for patients on EIAEDs (p=0.17). Eleven patients are still alive; median OS was 9.1 months, with 8.8 months for non-EIAED patients, and 9.6 months for EIAED patients (p = 0.9). Of the patients on non-EIAEDs, best radiographic response included 11 patients (34.4%) with partial response, 13 with stable disease (40.6%), and 8 with progressive disease. Of patients on EIAEDs, 3 patients (10.3%) had a partial response, 18 (62.1%) with stable disease, and 6 with progression. On comparison of partial response rates between the 2 groups, p=0.03 was obtained. Most frequent grade 3 non-hematologic toxicities included fatigue (15.9%), sensory neuropathy (10.2%), diarrhea (9%), and thrombosis (8%). There were 2 episodes of grade 4 hyponatremia and 1 episode of epistaxis from a nasal septal ulcer. 14 patients eventually had to be taken off of Velcade and continued Avastin alone, due to sensory neuropathy.Bevacizumab and Bortezomib appear to be an effective treatment for recurrent malignant gliomas with a moderate toxicity profile. However, this phase II clinical study suggests that the combination is not superior to single-agent Bevacizumab and that the response may be blunted in the presence of EIAEDs