Aspirin and ibuprofen, in bulk and nanoforms: Effects on DNA damage in peripheral lymphocytes from breast cancer patients and healthy individuals

YesRegular 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 GOVERNMEN

The effect of thermal processing in oil on the macromolecular integrity and acrylamide formation from starch of three potato cultivars organically fertilized

Starches from three organically produced cultivars of potato tuber (Lady Rosetta, Spunta and Voyager) have been studied in relation to (i) acrylamide production (ii) macromolecular integrity after frying with extra virgin olive oil, soybean oil and corn oil. During cultivation, a treatment involving the combination of nitrogen, phosphorus and potassium fertilization under organic farming was applied (N1, P2, K1 where Ν1 = 1.3 g Ν per plant, P2 = 5.2 g P2O5 per plant, Κ1 = 4.0 g K2O per plant). Potatoes fried in olive oil retained the highest glucose concentrations for all cultivars 0.85 ± 0.2 mmol/kg, followed by 0.48 ± 0.2 for those fried in corn oil and 0.40 ± 0.1 mmol/kg for those fried in soybean oil. The highest average fructose concentration was recorded for the samples fried in corn oil as 0.81 ± 0.2, followed by 0.80 ± 0.2 and 0.68 ± 0.3 mmol/kg for the samples fried in olive and soybean oils, respectively. Asparagine was the most abundant free amino acid in the three varieties tested, followed by glutamine and aspartic acid. The mean initial concentration of asparagine in raw potatoes tubers was 42.8 ± 1.6 mmoles kg−1 for Lady Rosetta, 34.6 ± 1.2 mmoles kg−1 (dry weight) for Spunta and 36.2 ± 2.0 mmoles kg−1 for Voyager. Lady Rosetta contained a significantly higher concentration of asparagine compared to the other two varieties (p < 0.05). The greatest quantity of acrylamide was observed in French fries derived from the potato variety Lady Rosetta when fried in soybean oil and it was 2,600 ± 440 μg/kg, followed by Spunta which was 2,280 ± 340 μg/kg and Voyager 1,120 ± 220 μg/kg. There is a significant reduction in the formation of acrylamide in the variety Voyager compared to the others (p = 0.05)

Identification of Stage-Specific Breast Markers using Quantitative Proteomics

YesMatched healthy and diseased tissues from breast cancer patients were analyzed by quantitative proteomics. By comparing proteomic profiles of fibroadenoma (benign tumors, three patients), DCIS (noninvasive cancer, three patients), and invasive ductal carcinoma (four patients), we identified protein alterations that correlated with breast cancer progression. Three 8-plex iTRAQ experiments generated an average of 826 protein identifications, of which 402 were common. After excluding those originating from blood, 59 proteins were significantly changed in tumor compared with normal tissues, with the majority associated with invasive carcinomas. Bioinformatics analysis identified relationships between proteins in this subset including roles in redox regulation, lipid transport, protein folding, and proteasomal degradation, with a substantial number increased in expression due to Myc oncogene activation. Three target proteins, cofilin-1 and p23 (increased in invasive carcinoma) and membrane copper amine oxidase 3 (decreased in invasive carcinoma), were subjected to further validation. All three were observed in phenotype-specific breast cancer cell lines, normal (nontransformed) breast cell lines, and primary breast epithelial cells by Western blotting, but only cofilin-1 and p23 were detected by multiple reaction monitoring mass spectrometry analysis. All three proteins were detected by both analytical approaches in matched tissue biopsies emulating the response observed with proteomics analysis. Tissue microarray analysis (361 patients) indicated cofilin-1 staining positively correlating with tumor grade and p23 staining with ER positive status; both therefore merit further investigation as potential biomarkers.Cyprus Research Promotion Foundation, Yorkshire Cancer Researc

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Breast Reconstruction Outcomes with and without Strattice:Long-Term Outcomes of a Multicenter Study Comparing Strattice Immediate Implant Breast Reconstruction with Submuscular Implant Reconstruction

BACKGROUND: Over half of immediate implant-based breast reconstructions (IBBR) are performed with an acellular dermal matrix, despite limited long-term outcome data.METHODS: The Breast Reconstruction Outcomes with and without Strattice, or BROWSE, study was a retrospective multicenter cohort study comparing consecutive patients who had undergone immediate Strattice IBBR with those who had undergone immediate IBBR with a submuscular technique between January of 2009 and December of 2015.RESULTS: This study compared 553 Strattice reconstructions with 242 submuscular reconstructions, with a median follow-up of 4.3 years (range, 2 to 9.3 years) and 5.7 years (range, 2 to 8.1 years), respectively, demonstrating an equivalent total complication rate [Strattice, n = 204 (36.9%); submuscular, n = 77 (31.8%); P = 0.17] and implant loss rate (8.5% versus 5.4%, respectively; P = 0.12). Infection rates and wound dehiscence rates were higher in the Strattice cohort [ n = 114 (20.6%) versus n = 31 (12.8%), P = 0.009; and n = 90 (16.3%) versus n = 25 (10.4%), P = 0.03, respectively]. Overall revision rates were comparable [ n = 226 (46.7%) versus n = 79 (41.1%); P = 0.2], but significantly fewer Strattice reconstructions required revision surgery for capsular contracture (5.3% versus 15.6%; P &lt; 0.001).CONCLUSION: Although the risk of complications associated with Strattice reconstruction is numerically higher than that for submuscular coverage, the difference is small and not statistically significant, and likely outweighed by the clear reduced rate of revision surgery because of capsular contracture when Strattice is used.CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.</p

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Parathyroid hormone–related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer — it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention