No / Epidemiological evidence suggests that nonsteroidal, anti-inflammatory drugs (NSAIDs) may retard the progression of Alzheimer's disease (AD). In the present study, we have chronically treated adult (4¿5 months old) and aged (20+ months) rats with water adulterated with aspirin, and examined spatial learning in a swim maze. Adult rats (n=40) and aged rats (n=20) were divided into separate groups assigned to receive either normal drinking water or water with 2 mg/ml of aspirin dissolved in it. For 6 weeks, we monitored daily water and/or drug intake before testing all rats in a standard swim maze over an 8-day period. On average, each rat drank approximately 25 ml of water/day with no apparent control versus aspirin group differences. There was no effect of aspirin in young adult rats except during a visible platform trial where aspirin-treated rats performed better than controls. In contrast, aspirin markedly improved performance in the aged rats during hidden and visible platform trials. Such group differences abated by the eighth test day when all rats performed equally well. The improvements in performance were not correlated with changes in swim speeds indicating that the enhancement was not due to facilitated motor output. These data reveal that a modest, 6-week treatment regimen with aspirin in aged rats is sufficient to induce improvements in both speed of learning and strength of the learned response. We have yet to address the key question as to underlying physiological mechanism(s) that might underpin this augmented cognitive performance. Moreover, it would be useful to ascertain whether or not chronic NSAID treatment might reduce the extent of learning impairments in aged, cognitively impaired animals.

Yes / BACKGROUND: Venous leg ulcers (VLUs) are the commonest cause of leg ulceration, affecting 1 in 100 adults. There is a significant health burden associated with VLUs - it is estimated that the cost of treatment for 1 ulcer is up to pound1300 per year in the NHS. The mainstay of treatment is with graduated compression bandaging; however, treatment is often prolonged and up to one quarter of venous leg ulcers do not heal despite standard care. Two previous trials have suggested that low-dose aspirin, as an adjunct to standard care, may hasten healing, but these trials were small and of poor quality. Aspirin is an inexpensive, widely used medication but its safety and efficacy in the treatment of VLUs remains to be established. METHODS/DESIGN: AVURT is a phase II randomised double blind, parallel-group, placebo-controlled efficacy trial. The primary objective is to examine whether aspirin, in addition to standard care, is effective in patients with chronic VLUs (i.e. over 6 weeks in duration or a history of VLU). Secondary objectives include feasibility and safety of aspirin in this population. A target of 100 participants, identified from community leg ulcer clinics and hospital clinics, will be randomised to receive either 300 mg of aspirin once daily or placebo. All participants will receive standard care with compression therapy. The primary outcome will be time to healing of the reference ulcer. Follow-up will occur for a maximum of 27 weeks. The primary analysis will use a Cox proportional hazards model to compare time to healing using the principles of intention-to-treat. Secondary outcomes will include ulcer size, pain evaluation, compliance and adverse events. DISCUSSION: The AVURT trial will investigate the efficacy and safety of aspirin as a treatment for VLU and will inform on the feasibility of proceeding to a larger phase III study. This study will address the paucity of information currently available regarding aspirin therapy to treat VLU. TRIAL REGISTRATION: The study is registered on a public database with clinicaltrials.gov ( NCT02333123 ; registered on 5 November 2014).

No / Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX enzyme activity, a significant mechanism of action of NSAIDs. Inflammation is associated with increasing cancer incidence. Recent pre-clinical and clinical studies have shown that NSAID treatment could cause an anti-tumour effect in cancers. Such studies are lengthy and expensive. The present study, however, examined DNA damage in the Comet and micronucleus assays in peripheral blood lymphocytes of patients with respiratory diseases and healthy individuals using the nanoparticle (NP) and bulk versions of the NSAIDs, aspirin and ibuprofen. Lymphocytes are suitable surrogate cells for cancers and other disease states. DNA damage decreased in lymphocytes from healthy individuals, asthma, COPD and lung cancer patient groups after treatment with aspirin nano-suspension (ASP N) and ibuprofen nano-suspension (IBU N) compared to their bulk version (micro-suspension) in both assays. However, when ASP N was compared to untreated lymphocytes in all groups in the Comet assay, DNA damage significantly decreased in all groups, except the asthma group. When IBU N was compared to untreated lymphocytes, in healthy individuals and the lung cancer group, DNA damage decreased, but increased in asthma and COPD groups. Similarly, micronuclei (MNi) increased after ASP N and IBU N in the healthy individual and lung cancer groups, and decreased in asthma and COPD groups. Also shows that whilst there are basic similarities with different genetic endpoints in terms of nano and bulk forms, but highlights some differences between the disease states examined. Furthermore, lymphocyte responses after IBU N and ibuprofen bulk were investigated by patch-clamp experiments demonstrating that IBU N inhibited ion channel activity by 20%. This molecular epidemiology approach mirrors pre-clinical and clinical findings, and provides new information using nanoparticles.

Yes / Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) may be protective against tumours, including breast cancer. We have studied the effects of ibuprofen and aspirin on DNA damage in lymphocytes obtained from breast cancer patients and healthy female controls. Both nanoparticle (NPs) and bulk formulations were used in the comet and micronucleus (MN) assays. Non-toxic doses (250 ng/ml ibuprofen; 500 ng/ml aspirin) were tested. Aspirin, both bulk and nano formulations, significantly reduced DNA damage measured with the comet and micronucleus assays; the nano formulation was more effective. Ibuprofen was not effective in the comet assay but showed a significant reduction in MN frequency, with the nano formulation being more effective. NPs may have better penetration through the nuclear membrane relative to the bulk formulation. NSAIDs such as aspirin and ibuprofen may have a promising role in cancer prevention and treatment. / LIBYAN GOVERNMENT

Yes / Backgorund Prior data suggest pre-diagnostic aspirin use impacts breast tumour biology and patient outcome. Here, we employed faithful surgical resection models of HER2+ and triple-negative breast cancer (TNBC), to study outcome and response mechanisms across breast cancer subtypes. Method NOD/SCID mice were implanted with HER2+ MDA-MB-231/LN/2-4/H2N, trastuzumab-resistant HER2+ HCC1954 or a TNBC patient-derived xenograft (PDX). A daily low-dose aspirin regimen commenced until primary tumours reached ~250 mm3 and subsequently resected. MDA-MB-231/LN/2-4/H2N mice were monitored for metastasis utilising imaging. To interrogate the survival benefit of pre-treatment aspirin, 3 weeks post-resection, HCC1954/TNBC animals received standard-of-care (SOC) chemotherapy for 6 weeks. Primary tumour response to aspirin was interrogated using immunohistochemistry. Results Aspirin delayed time to metastasis in MDA-MB-231/LN/2-4/H2N xenografts and decreased growth of HER2+/TNBC primary tumours. Lymphangiogenic factors and lymph vessels number were decreased in HER2+ tumours. However, no survival benefit was seen in aspirin pre-treated animals (HCC1954/TNBC) that further received adjuvant SOC, compared with animals treated with SOC alone. In an effort to study mechanisms responsible for the observed reduction in lymphangiogenesis in HER2+ BC we utilised an in vitro co-culture system of HCC1954 tumour cells and mesenchymal stromal cells (MSC). Aspirin abrogated the secretion of VEGF-C in MSCs and also decreased the lymph/angiogenic potential of the MSCs and HCC1954 by tubule formation assay. Furthermore, aspirin decreased the secretion of uPA in HCC1954 cells potentially diminishing its metastatic capability. Conclusion Our data employing clinically relevant models demonstrate that aspirin alters breast tumour biology. However, aspirin may not represent a robust chemo-preventative agent in the HER2+ or TNBC setting. / Funding is acknowledged from the Irish Cancer Society Collaborative Cancer Research Centre under BREAST- PREDICT grant CCRC13GAL (www.breas tpred ict.com). I.S.M, E.M and A.T.B, are members of the EurOPDX Consortium, and receive funding from the European Union's Horizon 2020 research and innovation programme, grant agreement no. #731105 (EurOPDX Research Infrastructure, www.europ dx.eu).

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23760号 / 医博第4806号 / 新制||医||1056(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 湊谷 謙司, 教授 森信 暁雄 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The base excision repair protein, MBD4 (also known as MED1) is known to be transcriptionally coupled to a mismatch repair protein MLH1. To date the significance of this coupling has not been elucidated and the significance of MBD4 within the mismatch repair system and apoptotic pathway is still being understood. Recently a novel alternatively spliced form of MBD4 has been identified and termed sMBD4. To date the significance of sMBD4 is unknown. MBD4 and sMBD4 share a common glycosylase domain and this is the domain through which MBD4 is reported to interact with MLH1. It was the aim of this study to determine if sMBD4 was also a binding partner of MLH1 to help elucidate a potential role of sMBD4 and to further characterise the binding domain between MLH1 and MBD4. Recombinant proteins were utilised in binding assays however, a specific protein – protein interaction could not be determined. Regular aspirin intake is associated with a reduction in the incidence of colorectal cancer. Aspirin has been shown to be cytotoxic to colorectal cancer cells in vitro. The molecular basis for this cytotoxicity is controversial, with a number of competing hypotheses in circulation. One suggestion is that the protective effect is related to the induction of DNA mismatch repair (MMR) proteins in DNA MMR proficient cells. As MBD4 has previously been suggested to be coupled to MLH1 expression by a post‐translational mechanism the cytotoxicy of aspirin in relation to MBD4 expression was examined. This study reports that aspirin does not up‐regulate MBD4 gene transcription in vitro in the DNA mismatch repair proficient/p53 mutant colorectal cancer cell line SW480. However, MBD4 gene transcription was up‐regulated upon treatment with the aspirin precursor, salicylic acid. The suggested involvement of the DNA repair proteins in the mechanism of action of aspirin promoted the investigation into the expression of DNA damage signalling pathways genes upon aspirin exposure. This study utilised a commercially available PCR array to analyse the expression of 84 DNA damage signalling genes in the SW480 colorectal cancer cell line upon aspirin treatment. It is reported that treatment of the SW480 cell line with aspirin caused changes in mRNA expression of several key genes involved in DNA damage signalling including a significant down‐regulation in expression of the genes encoding ATR, BRCA1 and MAPK12 and increases in the expression of XRCC3 and GADD45α genes. Regulation of these genes could potentially have profound effects on colorectal cancer cells and may play a role in the observed chemo‐protective effect of aspirin in vivo.Further to this, protein expression was analysed to determine if correlation could be established with the changes in mRNA expression observed. Although a correlation was not seen between transcript and protein levels of ATR, BRCA1 and GADD45α, an increase in XRCC3 protein expression upon aspirin treatment in SW480 cells was observed by immunoblotting, immunofluorescence and immunohistochemical analysis. This study indicates that alterations in gene expression seen in microarray studies need to be verified at the protein level. Furthermore, this study reports the novel discovery of XRCC3 gene and protein expression being susceptible to exposure to the non‐steroidal anti‐inflammatory drug, aspirin.

In this paper, we provide a mathematical model of the effect of aspirin on blood clotting. The model tracks the enzyme prostaglandin H synthase and an important blood clotting factor, thromboxane A2, in the form of thromboxane B2. Through model analysis, we determine conditions under which the reactions of prostaglandin H synthase are self-sustaining. Lastly, through numerical simulations, we demonstrate that the model accurately captures the steady-state chemical concentrations of interest in blood, both with and without aspirin treatment.

Class of 2017 Abstract / Objectives: The first aim is to assess efficacy of aspirin versus enoxaparin in preventing a venous thromboembolism (VTE) after a total knee arthroplasty (TKA) or total hip arthroplasty (THA) within 30 days after discharge. The second aim is to assess the safety of aspirin versus enoxaparin in preventing major bleeding events after a TKA or THA within 30 days after discharge. Methods: This study was a retrospective cohort study with data obtained from an online Veterans Affairs (VA) hospital database. For analysis, the primary outcome was assessed with a Chi-Square test, and the secondary outcome was reported with descriptive statistics.Results: Results: Demographics for 374 patients (TKA, n = 275; THA, n = 99): 90% male, average age of 65, average body mass index (BMI) of 32, 26% smokers, 72% had a history of hypertension, and 60% had a history of dyslipidemia. VTE events 30 days post-operatively: enoxaparin (n = 2), enoxaparin/aspirin (n = 1), and aspirin (n = 2) (P-value = 0.78). Safety events (major bleeding events): enoxaparin (n = 42), enoxaparin/aspirin (n = 7), and aspirin (n = 4). Conclusions: There was no significant difference between the treatment groups for VTE rate 30 days post- operation. The enoxaparin treatment group had the greatest number of safety events compared to the other groups.