Amifostine analog, DRDE-30, alleviates radiation induced lung damage by attenuating inflammation and fibrosis.

BACKGROUND: Radiotherapy of thoracic neoplasms and accidental radiation exposure often results in pneumonitis and fibrosis of lungs. Here, we investigated the potential of amifostine analogs: DRDE-07, DRDE-30, and DRDE-35, in alleviating radiation-induced lung damage. METHODS: C57BL/6 mice were exposed to 13.5 Gy thoracic irradiation, 30 min after intraperitoneal administration of the analogs, and assessed for modulation of the pathological response at 12 and 24 weeks. KEY FINDINGS: DRDE-07, DRDE-30 and DRDE-35 increased the survival of irradiated mice from 20% to 30%, 80% and 70% respectively. Reduced parenchymal opacity (X-ray CT) in the lungs of DRDE-30 pre-treated mice corroborated well with the significant decrease in Ashcroft score (p < 0.01). Two-fold increase in SOD and catalase activities (p < 0.05), coupled with a 50% increase in GSH content and a 60% decrease in MDA content (p < 0.05) suggested restoration of the antioxidant defence system. A 20% to 40% decrease in radiation-induced apoptotic and mitotic death in the lung tissue (micronuclei: p < 0.01), resulted in attenuated lung and vascular permeability (FITC-Dextran leakage) by 50% (p < 0.01), and a commensurate reduction (~50%) in leukocyte infiltration in the injured tissue (p < 0.05). DRDE-30 abrogated the activation of pro-inflammatory NF-κB and p38/MAPK signaling cascades, suppressing the release of pro-inflammatory cytokines (IL-1ß: p < 0.05; TNF-α: p < 0.05; IL-6: p < 0.05) and up-regulation of CAMs on the endothelial cell surface. Reduction in hydroxyproline content (p < 0.01) and collagen suggested inhibition of lung fibrosis which was associated with attenuation of TGF-ß/Smad pathway-mediated-EMT. CONCLUSION: DRDE-30 could be a potential prophylactic agent against radiation-induced lung injury.

Systematic overview of systematic reviews and clinical guidelines: assessment and prevention of behavioural risk factors associated with oral cancer to inform dental professionals in primary care dental practices.

Aims/objectives Tobacco and alcohol are recognised as the major modifiable risk factors for oral cancer, the incidence of which is rising globally and predicted to increase. This paper aimed to: 1) appraise and synthesise best practice evidence for assessing the major behavioural risk factors for oral cancer and delivering behaviour change interventions (for example, advice, counselling, signposting/referral to preventive services); and 2) assess appropriateness for implementation by dental professionals in primary care.Methods A systematic overview was undertaken of systematic reviews and international clinical guidelines. This involved: systematically searching and collating the international literature on assessing oral cancer risk and delivering preventive interventions within primary care; quality appraising and assessing the risk of bias using validated tools; synthesising the evidence for best practice; and assessing application of key findings to the dental setting.Results and conclusions There is clear evidence for the effectiveness of a 'brief', in-person, motivational intervention for sustained tobacco abstinence or reduced alcohol consumption, following risk factor assessment. Evidence for combined behavioural interventions is lacking. There is no firm conclusion with regards to optimal duration of brief interventions (range 5-20 minutes). For tobacco users, longer (10-20 minutes) and intensive (more than 20 minutes, with follow-up visits) interventions are more effective in increasing quit rates compared to no intervention; very brief (less than five minutes) interventions in a single session show comparable effectiveness to the longer/more intensive interventions. For alcohol users, 10-15-minute multi-contact interventions were most effective, compared to no intervention or very brief (less than five minutes) intervention or intensive intervention; brief interventions of five-minute duration were equally effective. There is limited direct evidence from the dental practice setting (one high-quality systematic review relating to tobacco prevention and none relating to alcohol). Thus, very brief, or brief advice of up to five minutes, should be trialled for tobacco and alcohol respectively in a dental practice setting, after risk assessment tailored to patient motivational status. Exploring delivery by the dental team is supported, as effectiveness was generally independent of primary care provider.

Amifostine Analog, DRDE-30, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice.

Bleomycin (BLM) is an effective curative option in the management of several malignancies including pleural effusions; but pulmonary toxicity, comprising of pneumonitis and fibrosis, poses challenge in its use as a front-line chemotherapeutic. Although Amifostine has been found to protect lungs from the toxic effects of radiation and BLM, its application is limited due to associated toxicity and unfavorable route of administration. Therefore, there is a need for selective, potent, and safe anti-fibrotic drugs. The current study was undertaken to assess the protective effects of DRDE-30, an analog of Amifostine, on BLM-induced lung injury in C57BL/6 mice. Whole body micro- computed tomography (CT) was used to non-invasively observe tissue damage, while broncheo-alveolar lavage fluid (BALF) and lung tissues were assessed for oxidative damage, inflammation and fibrosis. Changes in the lung density revealed by micro-CT suggested protection against BLM-induced lung injury by DRDE-30, which correlated well with changes in lung morphology and histopathology. DRDE-30 significantly blunted BLM-induced oxidative stress, inflammation and fibrosis in the lungs evidenced by reduced oxidative damage, endothelial barrier dysfunction, Myeloperoxidase (MPO) activity, pro-inflammatory cytokine release and protection of tissue architecture, that could be linked to enhanced anti-oxidant defense system and suppression of redox-sensitive pro-inflammatory signaling cascades. DRDE-30 decreased the BLM-induced augmentation in BALF TGF-ß and lung hydroxyproline levels, as well as reduced the expression of the mesenchymal marker α-smooth muscle actin (α-SMA), suggesting the suppression of epithelial to mesenchymal transition (EMT) as one of its anti-fibrotic effects. The results demonstrate that the Amifostine analog, DRDE-30, ameliorates the oxidative injury and lung fibrosis induced by BLM and strengthen its potential use as an adjuvant in alleviating the side effects of BLM.

Assessment and prevention of behavioural and social risk factors associated with oral cancer: protocol for a systematic review of clinical guidelines and systematic reviews to inform Primary Care dental professionals.

BACKGROUND: Tobacco and alcohol are recognised as the major risk factors for both oral cavity (mouth) and oropharyngeal (throat) cancers, with increasing acceptance of the role of human papillomavirus (HPV) in the aetiology of oropharyngeal cancers. In addition, there is a significant increased risk for oral cancer among lower socioeconomic groups, males and older age groups. There is a growing evidence for the potential role of primary care professionals in smoking cessation and reducing alcohol-related harm. However, there are uncertainties about the best approaches/strategies to assess risk factors associated with oral cancer, effective components of preventive interventions for behaviour change and implementation strategies in primary care dental settings. Thus, in order to contribute to the prevention of oral cancer effectively, dental professionals need to assess patients on the major risk factors (tobacco, alcohol and HPV/sexual behaviours) and deliver appropriate prevention, taking into account the patient's sociodemographic context. AIM: The study aims to synthesise evidence on the best practice for undertaking an assessment of major behavioural risk factors associated with oral cancer and delivering effective behaviour change preventive interventions (e.g. advice, counselling, patient recall, signposting/referral to preventive services) by dental professionals in primary care dental settings. METHOD: The study involves a systematic review and evidence appraisal. We will search for clinical guidelines and systematic reviews from the following databases: Cochrane Library, Ovid MEDLINE, EMBASE, Web of Science, PsychINFO, PubMed, TRIP and Google Scholar. We will also search websites of professional organisations/agencies and bibliographies/reference lists of selected papers. Quality will be assessed with the AGREE II (Appraisal of Guidelines for Research & Evaluation II) instrument for included clinical guidelines and the AMSTAR (A Measurement Tool to Assess Systematic Reviews) and ROBIS instruments for included systematic reviews. The best practice evidence will be assessed via a narrative synthesis of extracted data, considering publication quality. DISCUSSION: This systematic review will synthesise evidence on the best practice for oral cancer risk factor assessment and prevention and evaluate the relationship between available clinical guidelines and the review evidence base. This collation of evidence will be useful for making recommendations for future intervention, research and guideline development. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015025289.

Ketoximes to N-substituted thioamides via PSCl3 mediated Beckmann rearrangement.

N-Substituted thioamides were accessed from ketoximes by utilising PSCl3 as a uniquely capable reagent to induce Beckmann rearrangement as well as to capture the intermediate nitrilium ion.