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Background: Oncotype DX (ODX) is a genomic assay of tumor tissue that is utilized to predict the likelihood of recurrence and benefit of chemotherapy in breast cancer patients. Five to 10% of breast cancers are hereditary, and hereditary syndromes may not be uncovered through family history alone. We hypothesized that high ODX recurrence score (RS) may signal a potential hereditary cancer risk., Patients and Methods: We performed a retrospective analysis of data from hormone receptor-positive breast cancer patients who had undergone ODX and germline genetic testing. The chi-square test and Fisher exact test were used to examine univariable association between RS and germline mutation status. Multivariable logistic regression was utilized to examine if there was an association of RS with germline mutation status., Results: In univariable analysis, the association of RS with germline mutation status was significant (P < .0001). In the multivariable logistic regression model predicting germline mutation status, RS level remained significantly associated with germline mutation, in particular BRCA1 or BRCA2. The mean RS for those with non-BRCA1/2 germline mutations versus those without germline mutations was not significant (P = .38)., Conclusion: High RS is associated with germline mutation status. Breast cancer patients with high RS are more likely to harbor a mutation in the BRCA1 or BRCA2 genes. If confirmed prospectively, oncologists may consider referring patients with high RS for genetic risk assessment and counseling to inform management plans, as well as counseling of family members., (Copyright © 2020. Published by Elsevier Inc.)

Wegener's granulomatosis (WG) is a complex autoimmune disease of unknown etiology, frequently involving localized inflammation of the nasal mucosa as an early manifestation. The current hypothesis suggests that the disease is triggered by a disturbed interaction between genetic and environmental effects, such as an altered microflora at mucosal layers. In this study, a systematic assessment of 49 transcripts with potential pathophysiological relevance was performed using quantitative real-time PCR in nasal mucosa samples of more than 80 individuals, including normal control (NC) individuals and disease controls. In addition, colonization with Staphylococcus aureus was quantified in the same individuals to assess its impact on transcriptomic signatures. Transcription profiles show an increased heterogeneity in diseased individuals. In all, 10 transcripts were identified to be differentially expressed (P≤0.05, false discovery rate ≤0.05) between patients with WG and NC individuals. These transcripts include antimicrobial peptides (human β-defensin (DEFB)1: fold-change WG vs. controls: +4.45, lysozyme: -3.4, DEFB4 and S100A7 (S100 calcium-binding protein A7): both "switched on" in WG), innate immune receptors (Toll-like receptor 4: -2.1, NOD-like receptor C3: -2.1, scavenger receptor CD36: +2.9), and cytokines (interferon-γ: -14, transforming growth factor-β 1: -1.4, interleukin-17D: -2.7). These transcriptional profiles are independent of S. aureus colonization. This study for the first time describes that, on the basis of data obtained from the primary nasal tissue, WG exhibits molecular features that allow its differentiation from other inflammatory disorders with involvement of the nasal mucosa. Further studies based on these findings may enable the identification of subphenotypes, which are currently discussed as an important target for a personalized medicine approach, aiming to reduce side effects and the number of therapy non-responders.

Several coding variants of NOD2 and ATG16L1 are associated with increased risk of Crohn disease (CD). NOD2, a cytosolic receptor of the innate immune system activates pro-inflammatory signalling cascades upon recognition of bacterial muramyl dipeptide, but seems also to be involved in antiviral and anti-parasitic defence programs. The CD associated variant L1007fsinsC leads to impaired pro-inflammatory signalling and diminished bacterial clearance. ATG16L1 is a protein essential for autophagosome formation at the phagophore assembly site. The CD associated T300A variant is located in the c-terminal WD40 domain, whose function is still unknown. Basal autophagy is not affected by the T300A variant, but antibacterial autophagy (xenophagy) is impaired, a finding that relates ATG16L1 as well as NOD2 to pathogen defence. Notably, combination of disease-associated alleles of ATG16L1 and NOD2/CARD15 leads to synergistically increased susceptibility for CD, indicating a possible crosstalk between NOD2- and ATG16L1-mediated processes in the pathogenesis of CD. This review surveys current research results and discusses the functional models of potential interplay between NLR-pathways and xenophagy. Interaction between pathways is discussed in the context of reactive oxygen species (ROS), membrane co-localisation, antigen processing and implications of disturbed Paneth cell vesicle export. These effects on pathogen response might imbalance the intestinal barrier epithelia towards chronic inflammation and promote development of Crohn disease. Further elucidation of NOD2/ATG16L1 interplay in xenophagy is relevant for understanding the aetiology of chronic intestinal inflammation and host-microbe interaction in general and could lead to principal new insights to xenophagy induction., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

There is increasing interest in the role of anthocyanidins as potential skin protective phytochemicals. However, little is known if and to what extent anthocyanidins are taken up by the human skin. In the present study cellular uptake (as determined by HPLC), stability, and gene-regulatory activity of cyanidin were determined in human HaCaT keratinocytes in culture. Using the fluorescent dye Naturstoff reagent A cyanidin was visualized in order to determine its cellular accumulation via flow cytometry and fluorescence microscopy. Cyanidin was rapidly taken up by HaCaT cells at relatively low concentrations. Following incubation, cellular cyanidin levels decreased time-dependently most likely due to degradation into protocatechuic acid and phloroglucinol aldehyde. Confocal laser scanning microscopy data demonstrated that cyanidin was mainly present in the cytoplasm. Cellular uptake of cyanidin was accompanied by an inhibition of multidrug resistance protein 1 (involved in cellular efflux of flavonoids) mRNA-levels indicating its gene-regulatory activity. Naturstoff reagent A seems to be a promising fluorescent dye to visualize cyanidin in keratinocytes., (2009 Elsevier Ltd. All rights reserved.)