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The novel C-terminal Chromogranin A-derived serpinin and pyroglutaminated serpinin act as cardiacβ-adrenergic agonists

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The novel C-terminal Chromogranin A-derived serpinin and pyr...

Brain repair for Parkinson's disease:is the answer in the matrix?

第十六届嗜铬细胞国际学术会议

作者： Bruno Tota Stefano Gentile Teresa Pasqua Hisatsugu Koshimizu niamh x.cawley Maria Carmela Cerra Y Peng Loh Tommaso Angelone Department of Cell Biology University of Calabria Section of Cellular Neurobiology Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of HealthBethesda Department of Pharmaco-Biology University of Calabria

＜正＞Very recently,Koshimizu et al.（2011） showed that three forms of serpinin peptides,serpinin （AIa26Leu）,pyroglutaminated（pGIu）-serpinin（pGlu23Leu） and serpinin-Arg-Arg-Gly （Ala29Gly） are derived from cleavage at pairs of basic residues in the highly conserved C terminus of Chromogranin A（CgA）.Serpinin induces PN-1 expression in（neuro）endocrine

关键词： Serpinin heart β1-Adrenergic Receptor inotropism lusitropism

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Neural Regeneration Research 2018年第7期13卷 1187-1188页

作者： niamh Moriarty Eilís Dowd Pharmacology & Therapeutics and Galway Neuroscience Centre National University of Ireland

Two hundred years after James Parkinson first described the cardinal motor symptoms of the disorder that would later bear his name,there is still an irrefutable need for a therapy that targets the underlying pathophys... 详细信息

关键词： Brain repair for Parkinson’s disease:is the answer in the matrix

Characterization of the Drosophila Atlastin Interactome Reveals VCP as a Functionally Related Interactor

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Journal of Genetics and Genomics 2013年第6期40卷 297-306页

作者： niamh C.O'Sullivan Nina Drger Cahir J.O'Kane 4th Floor Burlington Danes BuildingDepartment of MedicineImperial College LondonW12 ONNUnited Kingdom Department of Genetics University of CambridgeDowning StreetCambridge CB2 3EHUnited Kingdom

At least 25 genes,many involved in trafficking,localisation or shaping of membrane organelles,have been identified as causative genes for the neurodegenerative disorder hereditary spastic paraplegia（HSP）.One of the most commonly mutated HSP genes,atlastin-1, encodes a dynamin-like GTPase that mediates homotypic fusion of endoplasmic reticulum（ER） membranes.However,the molecular mechanisms of atlastin-1-related membrane fusion and axonopathy remain unclear.To better understand its mode of action,we used affinity purification coupled with mass spectrometry to identify protein interactors of atlastin in Drosophila.Analysis of 72 identified proteins revealed that the atlastin interactome contains many proteins involved in protein processing and transport,in addition to proteins with roles in mRNA binding,metabolism and mitochondrial proteins.The highest confidence interactor from mass spectrometry analysis, the ubiquitin-selective AAA-ATPase valosin-containing protein（VCP）,was validated as an atlastin-interacting protein,and VCP and atlastin showed overlapping subcellular distributions.Furthermore,VCP acted as a genetic modifier of atlastin：loss of VCP partially suppressed an eye phenotype caused by atlastin overexpression,whereas overexpression of VCP enhanced this phenotype.These interactions between atlastin and VCP suggest a functional relationship between these two proteins,and point to potential shared mechanisms between HSP and other forms of neurodegeneration.

关键词： Endoplasmic reticulum Hereditary spastic paraplegias Atlastin Valosin-containing protein

Development and validation of a rapid chromatographic method for the analysis of flunarizine and its main production impurities

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Journal of Pharmaceutical Analysis 2013年第3期3卷 211-214页

作者： niamh O'Connor Michael Geary Mary Wharton Paul Sweetman Department of Applied Science Limerick Institute of TechnologyMoylish ParkIreland Janssen Pharmaceutical Limited Little IslandCorkIreland

A rapid selective method for the analysis of flunarizine and its associated impurities was developed and validated according to ICH guidelines. The separation was carried out using a Thermo Scientific Hypersil Gold C18 column （50 mm × 4.6 mm i.d., 1.9 μm particle size） with a gradient mobile phase of acetonitrile-ammonium acetate-tetrabutylammoniumhydrogen sulfate buffer, at a flow rate of 1,8 mL/min and UV detection at 230 nm. Naturally aged samples were also tested to determine sample stability. A profile of sample and impurity breakdown was also presented.

关键词： Flunarizine Sub 2 gm column Active pharmaceuticalingredient HPLC

Potential of damage associated molecular patterns in synergising radiation and the immune response in oesophageal cancer

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World Journal of Gastrointestinal Oncology 2023年第8期15卷 1349-1365页

作者： Noel E Donlon Maria Davern Andrew Sheppard Fiona O'Connell Brendan Moran Timothy S Nugent Aisling Heeran James J Phelan Anshul Bhardwaj Christine Butler Narayanasamy Ravi Claire L Donohoe niamh Lynam-Lennon Stephen Maher John V Reynolds Joanne Lysaght Cancer Immunology and Immunotherapy Group Department of SurgeryTrinity Translational Medicine Institute and Trinity St James’s Cancer InstituteTrinity College DublinSt James’s HospitalDublin D08Ireland

BACKGROUND There is an intimate crosstalk between cancer formation,dissemination,treatment response and the host immune system,with inducing tumour cell death the ultimate therapeutic goal for most anti-cancer treatments.However,inducing a purposeful synergistic response between conventional therapies and the immune system remains evasive.The release of damage associated molecular patterns(DAMPs)is indicative of immunogenic cell death and propagation of established immune responses.However,there is a gap in the literature regarding the importance of DAMP expression in oesophageal adenocarcinoma(OAC)or by immune cells themselves.AIM To investigate the effects of conventional therapies on DAMP expression and to determine whether OAC is an immunogenic cancer.METHODS We investigated the levels of immunogenic cell death-associated DAMPs,calreticulin(CRT)and HMGB1 using an OAC isogenic model of radioresistance.DAMP expression was also assessed directly using ex vivo cancer patient T cells(n=10)and within tumour biopsies(n=9)both pre and post-treatment with clinically relevant chemo(radio)therapeutics.RESULTS Hypoxia in combination with nutrient deprivation significantly reduces DAMP expression by OAC cells in vitro.Significantly increased frequencies of T cell DAMP expression in OAC patients were observed following chemo-(radio)therapy,which was significantly higher in tumour tissue compared with peripheral blood.Patients with high expression of HMGB1 had a significantly better tumour regression grade(TRG 1-2)compared to low expressors.CONCLUSION In conclusion,OAC expresses an immunogenic phenotype with two distinct subgroups of high and low DAMP expressors,which correlated with tumour regression grade and lymphatic invasion.It also identifies DAMPs namely CRT and HMGB1 as potential promising biomarkers in predicting good pathological responses to conventional chemo(radio)therapies currently used in the multimodal management of locally advanced disease.

关键词： Damage associated molecular patterns HMGB1 Calreticulin Oesophageal adenocarcinoma T cells Radiation

Impact of radiotherapy on the immune landscape in oesophageal adenocarcinoma

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World Journal of Gastroenterology 2022年第21期28卷 2302-2319页

作者： Noel E Donlon Maria Davern Fiona O'Connell Andrew Sheppard Aisling Heeran Anshul Bhardwaj Christine Butler Ravi Narayanasamy Claire Donohoe James J Phelan niamh Lynam-Lennon Margaret R Dunne Stephen Maher Jacintha O'Sullivan John V Reynolds Joanne Lysaght Department of Surgery Trinity Translational Medicine InstituteSt James HospitalDublin D08Ireland

BACKGROUND In the contemporary era of cancer immunotherapy,an abundance of clinical and translational studies have reported radiotherapy(RT)and immunotherapies as a viable option for immunomodulation of many cancer subtypes,with many related clinical trials ongoing.In locally advanced disease,chemotherapy or chemoradiotherapy followed by surgical excision of the tumour remain the principal treatment strategy in oesophageal adenocarcinoma(OAC),however,the use of the host immune system to improve anti-tumour immunity is rapidly garnering increased support in the curative setting.AIM To immunophenotype OAC patients’immune checkpoint(IC)expression with and without radiation and evaluate the effects of checkpoint blockade on cell viability.METHODS In the contemporary era of cancer immunotherapy,an abundance of studies have demonstrated that combination RT and IC inhibitors(ICIs)are effective in the immunomodulation of many cancer subtypes,with many related clinical trials ongoing.Although surgical excision and elimination of tumour cells by chemotherapy or chemoradiotherapy remains the gold standard approach in OAC,the propagation of anti-tumour immune responses is rapidly garnering increased support in the curative setting.The aim of this body of work was to immunophenotype OAC patients’IC expression with and without radiation and to establish the impact of checkpoint blockade on cell viability.This study was a hybrid combination of in vitro and ex vivo models.Quantification of serum immune proteins was performed by enzyme-linked immunosorbent assay.Flow cytometry staining was performed to evaluate IC expression for in vitro OAC cell lines and ex vivo OAC biopsies.Cell viability in the presence of radiation with and without IC blockade was assessed by a cell counting kit-8 assay.RESULTS We identified that conventional dosing and hypofractionated approaches resulted in increased IC expression(PD-1,PD-L1,TIM3,TIGIT)in vitro and ex vivo in OAC.There were two distinct subcohorts with one demonstrating significant upregul

关键词： Oesophageal Cancer Radiotherapy Immunotherapy Immunology Surgery Oncology

Roles for the VCP co-factors Npl4 and Ufd1 in neuronal function in Drosophila melanogaster

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Journal of Genetics and Genomics 2017年第10期44卷 493-501页

作者： Dwayne J.Byrne Mark J.Harmon Jeremy C.Simpson Craig Blackstone niamh C. O'Sullivan UCD School of Biomolecular and Biomedical Science UCD Conway Institute University College Dublin Dublin 4 Ireland UCD School of Biology and Environmental Science UCD Conway Institute of Biomolecular and Biomedical Research University College Dublin Dublin 4Ireland Cell Biology Section Neurogenetics Branch National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD 20892 USA

The VCP-Ufd1-Npl4 complex regulates proteasomal processing within cells by delivering ubiquitinated proteins to the proteasome for degradation.Mutations in VCP are associated with two neurodegenerative diseases,amyotrophic lateral sclerosis（ALS） and inclusion body myopathy with Paget＇s disease of the bone and frontotemporal dementia（IBMPFD）,and extensive study has revealed crucial functions of VCP within neurons.By contrast,little is known about the functions of Npl4 or Ufd1 in vivo.Using neuronalspecific knockdown of Npl4 or Ufd1 in Drosophila melanogaster,we infer that Npl4 contributes to microtubule organization within developing motor neurons.Moreover,Npl4 RNAi flies present with neurodegenerative phenotypes including progressive locomotor deficits,reduced lifespan and increased accumulation of TAR DNA-binding protein-43 homolog（TBPH）.Knockdown,but not overexpression,of TBPH also exacerbates Npl4 RNAi-associated adult-onset neurodegenerative phenotypes.In contrast,we find that neuronal knockdown of Ufd1 has little effect on neuromuscular junction（NMJ） organization,TBPH accumulation or adult behaviour.These findings suggest the differing neuronal functions of Npl4 and Ufd1 in vivo.

关键词： Proteasome TDP-43 accumulation Neurodegeneration Drosophila

The Ugly Side of Statins. Systemic Appraisal of the Contemporary Un-Known Unknowns

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Open Journal of Endocrine and Metabolic Diseases 2013年第3期3卷 179-185页

作者： Sherif Sultan niamh Hynes Department of Vascular and Endovascular Surgery Western Vascular Institute University College Hospital Galway Galway Ireland

Cardio-vascular specialists have witnessed and actively participated in the revolutionary developments that have occurred in their field of specialization over the last few years. Cutting-edge technologies have led to dramatic improvements in life-expectancy and quality of life. An open-mind and pioneering attitude are necessary when exploring new frontiers to improve our patients’ health. However, naive indiscriminate acceptance of novel mainstream therapies is not always advisable and prudence is required in unearthing harmful, covert side effects. An objective review of contemporary vascular research was performed and industrial bias was sifted out for a fresh prospective on how to promote primary cardiovascular prevention with attainable lifestyle adjustments [1]. A comprehensive review of Pubmed, EM-BASE and Cochrane review databases was undertaken for articles relating to cardiovascular primary prevention and statin side effects with the aim of harmonising their roles within contemporary clinic practice. Particular attention was paid to large-scale randomised controlled trials on contemporary cardiovascular pharmacotherapies and their specific adverse effects on metabolic pathways which feature prominently in cardiovascular primary prevention and regenerative programmes. There is a categorical lack of clinical evidence to support the use of statin therapy in primary prevention. Not only is there a dearth of evidence for primary cardiovascular protection, there is ample evidence to show that statins actually augment cardiovascular risk in women, patients with Diabetes Mellitus and in the young. Furthermore statins are associated with triple the risk of coronary artery and aortic artery calcification. Cardiovascular primary prevention and regeneration programmes, through life style changes and abstaining from tobacco use have enhanced clinical efficacy and quality of life over any pharmaceutical or other conventional intervention.

关键词： Statin Primary Prevention Side-Effects Diabetes Mellitus

Critical appraisal of stem cell therapy in peripheral arterial disease: Do current scientific breakthroughs offer true promise or false hope?

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Journal of Biomedical Science and Engineering 2014年第2期7卷 75-85页

作者： Sherif Sultan niamh Hynes Department of Vascular & Endovascular Surgery Western Vascular Institute University Hospital Galway Galway Ireland Department of Vascular and Endovascular Surgery Galway Clinic Doughiska Galway Ireland

Over the last forty years in the field of peripheral arterial disease, there has been a plethora of research into cell-based therapies for tissue repair, regeneration and angiogenesis, progressing from protein-based therapies to gene therapies to stem cell research. Initial pre-clinical research successes have given birth to a whole industry, aimed at translating these laboratory hopes into clinical successes. However, heretofore these expected clinical results have failed to materialize, in part due to the lack of attention to the ischaemic desert like tissue and systemically diseased patient into which the stem cells are being implanted. Unsatisfactory clinical outcomes on the treatment of Critical Limb Ischaemia (CLI) have forced researchers to direct their efforts to the less intimidating challenge of claudication and to lower their clinical outcome thresholds from superior to “non-inferior”. Major questions on safety and durability have also arisen. What needs to be objectively established is the impact on the net health outcome of these therapies. Infusion or injection for stem cell therapy is still considered experimental and investigational. In this review we examine the clinical evidence for angiogenic therapies, focusing specifically on stem cell trials, in an attempt to answer the question “Is stem cell therapy a failed experiment or will there be light at the end of the tunnel?”

关键词： Peripheral Arterial Disease Stem Cell Therapy Therapeutic Angiogenesis