- ItemMetabolomic pathway activity with genomic single-nucleotide polymorphisms associated with colorectal cancer recurrence and 5-year overall survival(Springer Nature Switzerland AG, 2022-03-03) Fleming, Christina A.; Mohan, Helen M.; O'Leary, Donal P.; Corrigan, M.; Redmond, H. PaulPurpose: Metabolomic analysis in colorectal cancer (CRC) is an emerging research area with both prognostic and therapeutic targeting potential. We aimed to identify metabolomic pathway activity prognostic for CRC recurrence and overall survival and cross-reference such metabolomic data with prognostic genomic single-nucleotide polymorphisms (SNPs). Methods: A systematic search of PubMed, Embase and Cochrane Library was performed for studies reporting prognostic metabolomic pathway activity in CRC in keeping with PRISMA guidelines. The QUADOMICS tool was used to assess study quality. MetaboAnalyst software (version4.0) was used to map metabolites that were associated with recurrence and survival in CRC to recognise metabolic pathways and identify genomic SNPs associated with CRC prognosis, referencing the following databases: Human Metabolome Database (HMDB), the Small Molecule Pathway Database (SMPDB), PubChem and Kyoto Encyclopaedia of Genes and Genomes (KEGG) Pathway Database. Results: Nine studies met the inclusion criteria, reporting on 1117 patients. Increased metabolic activity in the urea cycle (p = 0.002, FDR = 0.198), ammonia recycling (p = 0.004, FDR = 0.359) and glycine and serine metabolism (p = 0.004, FDR = 0.374) was prognostic of CRC recurrence. Increased activity in aspartate metabolism (p < 0.001, FDR = 0.079) and ammonia recycling (p = 0.004, FDR = 0.345) was prognostic of survival. Eight resulting SNPs were prognostic for CRC recurrence (rs2194980, rs1392880, rs2567397, rs715, rs169712, rs2300701, rs313408, rs7018169) and three for survival (rs2194980, rs169712, rs12106698) of which two overlapped with recurrence (rs2194980, rs169712). Conclusions: With a caveat on study heterogeneity, specific metabolites and metabolic pathway activity appear evident in the setting of poor prognostic colorectal cancers and such metabolic signatures are associated with specific genomic SNPs.
- ItemGallstone ileus in an elderly orthopaedic patient managed with enterolithotomy: a video vignette(John Wiley & Sons, Inc., 2021-08-25) Ryan, Jessica M.; Flanagan, Michael; Connelly, Tara M.; Cooke, Fiachra; McCullough, Peter; Neary, Peter
- ItemEvaluation of the cytotoxic effects of the novel antineoplastic agent 1,4,5-Oxathiazinane-4,4-dioxide on triple negative breast cancer cells(International Institute of Anticancer Research, 2021-05) Jinih, Marcel; Wang, Jiang Huai; Pfirrmann, Rolf W.; O'Leary, D. Peter; Corrigan, Mark A.; Redmond, Henry PaulBackground/Aim: Adjuvant therapeutic options are limited for triple negative breast cancer (TNBC). Thus, we evaluated the cytotoxic effects of the newly synthesized antineoplastic agent 1,4,5-Oxathiazinane-4,4-dioxide (OTD) on TNBC cells as a potential cancer therapeutic strategy. Materials and Methods: TNBC primary BT-20 and metastatic MDA-MB-231 cell lines were treated with increasing concentrations of OTD for various time periods to assess cell viability. Cell necrosis, apoptosis, necroptosis, autophagy, and ROS generation were evaluated using assay kits or specific inhibitors. Results: Treatment with OTD resulted in a dose-and time-dependent cell death of TNBC BT-20 and MDA-MB-231 cells. OTD also dose-dependently arrested TNBC cell proliferation. Notably, treatment with OTD induced both necrosis and apoptosis of TNBC cells, while the pan-caspase inhibitor Z-VAD-FMK partially attenuated OTD-induced cell death. Importantly, abrogated OTD-induced cell death was observed in the presence of the ROS scavenger N-acetylcysteine (NAC), whereas enhanced OTD-induced cell death was observed after the addition of the glutathione synthesis inhibitor BSO, indicating OTDinduced killing of TNBC cells via a reactive oxygen species dependent mechanism. Conclusion: OTD is strongly cytotoxic to both primary and metastatic TNBC cells, possibly by inducing multiple cell death pathways.
- ItemPiezoelectric inkjet coating of injection moulded, reservoir-tipped microneedle arrays for transdermal delivery(IOP Publishing, 2019-06-04) O'Mahony, Conor; Bocchino, Andrea; Haslinger, Michael J.; Brandstätter, Stefan; Außerhuber, Helene; Schossleitner, Klaudia; Clover, Anthony J. P.; Fechtig, Daniel; Österreichische Forschungsförderungsgesellschaft; Science Foundation Ireland; Higher Education Authority; Enterprise IrelandCoated microneedles have significant potential for use in transdermal delivery applications. In this paper, we describe the fabrication of microneedle master templates using microstereolithography techniques and subsequently use a commercial injection moulding process to replicate these microneedles in biocompatible cyclic olefin polymer (COP) materials. Notably, the 475 μm-tall needle designs feature a shallow pit or reservoir at the tip, thereby providing both a target and holder for incoming droplets that are deposited using a piezoelectric inkjet printer. Using this design, no tilting or rotation of the needle array is required during the filling process. In the preliminary tests reported here, the reservoir is filled with a FITC-labelled dye that acts as a model drug, and ex vivo skin tests are used to verify skin penetration, the transfer of this model drug to the skin and to measure the reliability of the needles themselves. To our knowledge, this is the first time that such an inkjet-filled, reservoir-tipped microneedle has been demonstrated.
- ItemActivation of both TLR and NOD signaling confers host innate immunity-mediated protection against microbial infection(Frontiers Media, 2019-01-14) Zhou, Huiting; Coveney, Andrew P.; Wu, Ming; Huang, Jie; Blankson, Siobhan; Zhao, He; O'Leary, D. Peter; Bai, Zhenjiang; Li, Yiping; Redmond, H. Paul; Wang, Jiang Huai; Wang, Jian; National Natural Science Foundation of China; Natural Science Foundation of Jiangsu Province; Science and Technology Program of Suzhou; Pediatric Solid Tumor Multidisciplinary Team; Pediatric Precise Surgical Clinical Medical Center of SuzhouThe detection of microbial pathogens relies on the recognition of highly conserved microbial structures by the membrane sensor Toll-like receptors (TLRs) and cytosolic sensor NOD-like receptors (NLRs). Upon detection, these sensors trigger innate immune responses to eradicate the invaded microbial pathogens. However, it is unclear whether TLR and NOD signaling are both critical for innate immunity to initiate inflammatory and antimicrobial responses against microbial infection. Here we report that activation of both TLR and NOD signaling resulted in an augmented inflammatory response and the crosstalk between TLR and NOD led to an amplified downstream NF-kB activation with increased nuclear transactivation of p65 at TNF-a and IL-6 promoters. Furthermore, co-stimulation of macrophages with TLR and NOD agonists maximized antimicrobial activity with accelerated phagosome maturation. Importantly, administration of both TLR and NOD agonists protected mice against polymicrobial sepsis-associated lethality with increased serum levels of inflammatory cytokines and accelerated bacterial clearance from the circulation and visceral organs. These results demonstrate that activation of both TLR and NOD signaling synergizes to induce efficient inflammatory and antimicrobial responses, thus conferring protection against microbial infection.