National Institute for Cellular Biotechnology

Glasnevin, Ireland

National Institute for Cellular Biotechnology

Glasnevin, Ireland
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Bhattacharya R.,Bose Institute of India | Banerjee K.,Bose Institute of India | Mukherjee N.,National Institute for Cellular Biotechnology | Sen M.,Bose Institute of India | Mukhopadhyay A.,Bose Institute of India
Pathology Research and Practice | Year: 2017

Aim of the present study was to analyze the molecular pathogenesis of TNBC, therapeutic practice, challenges, and future goals in treatment strategies. Based on the alterations of distinct pathways, Lehmann's subgroups of TNBCs were further categorized. Those with defective DNA damage repair and replication pathways, viz. Basal Like 1 & 2 (BL1, BL2) were found susceptible to DNA intercalating drugs while those with upregulated cell signalling & motility (mesenchymal (M), mesemchymal stem like (MSL)), cell survival (BL2, M, MSL), angiogenesis (BL2, MSL), T cell signalling (Immunomodulatory/IM) pathways required targeted therapies. Our Meta-analysis categorized 12 randomized previous trial cases, solely under the following drug regimens: [1] DNA destabilizers, [2] PARP inhibitors, [3] Microtubule stabilizers, [4] Angiogenesis inhibitors, [5] Antimetabolite, [6] T cell targeted therapy; as single or combinational therapy. Best therapeutic efficacies of DNA destabilizers with angiogenesis inhibitors in combination than monotherapy with either (OR: 5.011-7.286; p value < 0.001) indicated a significant prevalence of BL1 type TNBCs in populations. Statistical significance with antimetabolites as combination therapy (OR: 2.343; p value: 0.018) and not with microtubule stabilizer (OR: 0.377) were observed. Thus, for best ORR in TNBC, personalized medicine should be the therapeutic choice for the clinicians. © 2017 Elsevier GmbH


Di Luca A.,National Institute for Cellular Biotechnology | Henry M.,National Institute for Cellular Biotechnology | Meleady P.,National Institute for Cellular Biotechnology | O'Connor R.,National Institute for Cellular Biotechnology
DARU, Journal of Pharmaceutical Sciences | Year: 2015

Background: Human epidermal growth-factor receptor (HER)-2 is overexpressed in 25 % of breast-cancers and is associated with an aggressive form of the disease with significantly shortened disease free and overall survival. In recent years, the use of HER2-targeted therapies, monoclonal-antibodies and small molecule tyrosine-kinase inhibitors has significantly improved the clinical outcome for HER2-positive breast-cancer patients. However, only a fraction of HER2-amplified patients will respond to therapy and the use of these treatments is often limited by tumour drug insensitivity or resistance and drug toxicities. Currently there is no way to identify likely responders or rational combinations with the potential to improve HER2-focussed treatment outcome. Methods: In order to further understand the molecular mechanisms of treatment-response with HER2-inhibitors, we used a highly-optimised and reproducible quantitative label-free LC-MS strategy to characterize the proteomes of HER2-overexpressing breast-cancer cell-lines (SKBR3, BT474 and HCC1954) in response to drug-treatment with HER2-inhibitors (lapatinib, neratinib or afatinib). Results: Following 12 hours treatment with different HER2-inhibitors in the BT474 cell-line; compared to the untreated cells, 16 proteins changed significantly in abundance following lapatinib treatment (1 μM), 21 proteins changed significantly following neratinib treatment (150 nM) and 38 proteins changed significantly following afatinib treatment (150 nM). Whereas following 24 hours treatment with neratinib (200 nM) 46 proteins changed significantly in abundance in the HCC1954 cell-line and 23 proteins in the SKBR3 cell-line compared to the untreated cells. Analysing the data we found that, proteins like trifunctional-enzyme subunit-alpha, mitochondrial; heterogeneous nuclear ribonucleoprotein-R and lamina-associated polypeptide 2, isoform alpha were up-regulated whereas heat shock cognate 71 kDa protein was down-regulated in 3 or more comparisons. Conclusion: This proteomic study highlights several proteins that are closely associated with early HER2-inhibitor response and will provide a valuable resource for further investigation of ways to improve efficacy of breast-cancer treatment. © 2015 Di Luca et al.


Coughlan C.A.,Royal College of Surgeons in Ireland | Chotirmall S.H.,Royal College of Surgeons in Ireland | Renwick J.,Trinity College Dublin | Hassan T.,Royal College of Surgeons in Ireland | And 12 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2012

Rationale: Aspergillus fumigatus (A. fumigatus) in cystic fibrosis (CF) is increasingly recognized. Although allergic bronchopulmonary aspergillosis (ABPA) leads to deterioration of pulmonary function, the effect of A. fumigatus colonization in the absence of ABPA remains unclear. Objectives: To address this, we examined individuals with CF with A. fumigatus who were ABPA negative to identify the effects of itraconazole therapy on Aspergillus-induced lung inflammation. Methods: The effect of A. fumigatus on nuclear vitamin D receptor (VDR) expression was investigated using qRT-PCR and Western blotting. IL-5 and IL-13 levels were quantified by ELISA. The effect of itraconazole was assessed by a combination of high-resolution computed tomography, lung function test, and microbiological analysis. Measurements and Main Results: We demonstrate that A. fumigatus down-regulates VDR in macrophages and airway epithelial cells and that the fungal metabolite gliotoxin (Gt) is themain causative agent. Gt overcame the positive effect of 1,25-OH vitamin D3 on VDR expression in vitro, resulting in increased IL-5 and IL-13 production. In vivo, A. fumigatus positivity was associated with increased Gt in CF bronchoalveolar lavage fluid and increased bronchoalveolar lavage fluid levels of IL-5 and IL-13. After airway eradication of A. fumigatus with itraconazole, we observed decreased Gt, IL-5 and IL-13, improved respiratory symptoms, and diminished high-resolution computed tomographymosaic pattern consistent with sustained pulmonary function. Conclusions: This study provides a rationale for the therapeutic effect of itraconazole and implied that the therapeutic potential of vitamin D supplementation in preventing ABPA is only feasible with concurrent elimination of A. fumigatus to permit VDR expression and its positive functional consequences. Copyright © 2012 by the American Thoracic Society.


Stolarczyk J.K.,Ludwig Maximilians University of Munich | Deak A.,Institute for Technical Physics and Materials Science | Brougham D.F.,National Institute for Cellular Biotechnology | Brougham D.F.,University College Dublin
Advanced Materials | Year: 2016

The current state of the art in the use of colloidal methods to form nanoparticle assemblies, or clusters (NPCs) is reviewed. The focus is on the two-step approach, which exploits the advantages of bottom-up wet chemical NP synthesis procedures, with subsequent colloidal destabilization to trigger assembly in a controlled manner. Recent successes in the application of functional NPCs with enhanced emergent collective properties for a wide range of applications, including in biomedical detection, surface enhanced Raman scattering (SERS) enhancement, photocatalysis, and light harvesting, are highlighted. The role of the NP–NP interactions in the formation of monodisperse ordered clusters is described and the different assembly processes from a wide range of literature sources are classified according to the nature of the perturbation from the initial equilibrium state (dispersed NPs). Finally, the future for the field and the anticipated role of computational approaches in developing next-generation functional NPCs are briefly discussed. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim


Corry A.J.,Dublin City University | Goel A.,Dublin City University | Kenny P.T.M.,Dublin City University | Kenny P.T.M.,National Institute for Cellular Biotechnology
Inorganica Chimica Acta | Year: 2012

Standard peptide coupling reactions were use to prepare the N-(ferrocenyl) 2 and N-(ferrocenoyl) 2 cystine dimethyl ester derivatives 4-11. The ferrocene carboxylic acids 1 and 3 were treated with 1-hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N′- ethylcarbodiimide hydrochloride (EDC), l-cystine methyl ester hydrochloride and triethylamine in dichloromethane at 0 °C to furnish compounds 4-9. The preparation of compounds 10 and 11 employed the dipeptide derivatives (glycine) 2-l-cystine dimethyl ester and (β-alanine) 2-l-cystine dimethyl ester respectively. The N-(ferrocenyl) 2 and N-(ferrocenoyl) 2 cystine dimethyl ester derivatives 4-11, which are potential anion sensing agents, were spectroscopically characterized by a combination of 1H NMR, 13C NMR, IR, UV, DEPT-135 and 1H- 13C COSY (HMQC) spectroscopy, mass spectrometry and cyclic voltammetry. The electrochemical detection of dihydrogen phosphate and adenosine nucleotide anions in aqueous electrolyte by monolayers of {N-(ferrocenoyl)-β-alanine} 2-l-cystine dimethyl ester 11 immobilized on gold electrodes using cyclic voltammetry is described. Immobilization of this receptor on a gold electrode surface enabled the recognition process to be detected in aqueous media. The recognition process is as a result of electrostatic interactions between the ferricenium cation and the anion, and hydrogen bonding interactions between the peptide amide bonds and the anion. The complexation process was amperometrically sensed via a reduction in the peak current of the ferrocene/ferricenium redox couple. A linear relationship (R 2 = c. 0.99) was observed between anion concentration and change in peak current in both cases. © 2011 Elsevier B.V. All rights reserved.


PubMed | Ludwig Maximilians University of Munich, Institute for Technical Physics and Materials Science and National Institute for Cellular Biotechnology
Type: Journal Article | Journal: Advanced materials (Deerfield Beach, Fla.) | Year: 2016

The current state of the art in the use of colloidal methods to form nanoparticle assemblies, or clusters (NPCs) is reviewed. The focus is on the two-step approach, which exploits the advantages of bottom-up wet chemical NP synthesis procedures, with subsequent colloidal destabilization to trigger assembly in a controlled manner. Recent successes in the application of functional NPCs with enhanced emergent collective properties for a wide range of applications, including in biomedical detection, surface enhanced Raman scattering (SERS) enhancement, photocatalysis, and light harvesting, are highlighted. The role of the NP-NP interactions in the formation of monodisperse ordered clusters is described and the different assembly processes from a wide range of literature sources are classified according to the nature of the perturbation from the initial equilibrium state (dispersed NPs). Finally, the future for the field and the anticipated role of computational approaches in developing next-generation functional NPCs are briefly discussed.


PubMed | Ludwig Maximilians University of Munich, Institute for Technical Physics and Materials Science and National Institute for Cellular Biotechnology
Type: Journal Article | Journal: Advanced materials (Deerfield Beach, Fla.) | Year: 2016

Clusters or assemblies of nanoparticles exhibit unique features which arise from the enhancement of properties of single nanoparticles or due to new collective properties. On page 5400, D. F. Brougham and co-workers review the role of nanoparticle interactions in controlling cluster formation, and classify the assembly mechanisms. Emerging applications for surface-enhanced Raman scattering (SERS), optical labeling, light harvesting, magnetic resonance imaging (MRI), hyperthermia, photocatalysis, enrichment, and separation are presented. Cover image by Christoph Hohmann, Nanosystems Initiative Munich (NIM).


Kelly J.,National Institute for Cellular Biotechnology | Kavanagh K.,National Institute for Cellular Biotechnology
Journal of Medical Microbiology | Year: 2011

The echinocandins (e.g. caspofungin) function by inhibiting the synthesis of 1,3-β-glucan in the fungal cell wall. While the potent antifungal activity of caspofungin has been well characterized in mammals, this study investigated the in vivo antifungal effect of caspofungin using larvae of the insect Galleria mellonella. Caspofungin was successful in increasing the survival of larvae that were inoculated with Candida albicans 1 h before the drug was administered, particularly when a concentration of 0.19 μg ml -1 was used. Pre-injecting larvae with caspofungin also increased their survival when they were inoculated with either Staphylococcus aureus or C. albicans. Caspofungin administration resulted in an increase in the number of circulating immune cells (haemocytes), an increase in the expression of the genes encoding IMPI and transferrin, and an increase in the expression of a number of proteins (identified by liquid chromatography-mass spectrometry) some of which have immune functions. This work indicates that administration of caspofungin can increase the survival of infected G. mellonella larvae, and this is due to the antifungal properties of caspofungin and also to the ability of caspofungin to prime the insect's immune response. © 2011 SGM.


Mowlds P.,National Institute for Cellular Biotechnology | Coates C.,National Institute for Cellular Biotechnology | Renwick J.,National Institute for Cellular Biotechnology | Kavanagh K.,National Institute for Cellular Biotechnology
Microbes and Infection | Year: 2010

Galleria mellonella larvae were inoculated with different doses of β-glucan by injection into the haemocoel. Those larvae that had received high doses of β-glucan (15, 30 or 60 μg/larva) demonstrated increased survival following infection with the yeast Candida albicans. High concentrations of glucan induced an increase in haemocyte density and a reduction in yeast proliferation within the haemocoel. Proteomic analysis of glucan-treated larvae revealed increased expression of a variety of peptides some of which may possess antimicrobial properties. Analysis of expression profiles revealed that low doses of β-glucan (3.75 μg/larva) triggered the increased expression of certain peptides (e.g. hemolin) while high dose inoculation was required before the increased expression of others (e.g. archaemetzincin) was evident. These results indicate that low doses of β-glucan induce a limited immune response while high doses induce an immune response that has the potential to curtail the threat within the haemocoel but also withstand a subsequent infection. Immune priming gives insects the ability to withstand a potentially lethal infection if exposed to a low level of the pathogen 24-48 h previously. Immune priming has resource implications and this work indicates that a graded immune response is initiated depending upon the amount of the immune priming agent encountered. © 2009 Elsevier Masson SAS. All rights reserved.


PubMed | National Institute for Cellular Biotechnology
Type: | Journal: Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences | Year: 2015

Human epidermal growth-factor receptor (HER)-2 is overexpressed in 25 % of breast-cancers and is associated with an aggressive form of the disease with significantly shortened disease free and overall survival. In recent years, the use of HER2-targeted therapies, monoclonal-antibodies and small molecule tyrosine-kinase inhibitors has significantly improved the clinical outcome for HER2-positive breast-cancer patients. However, only a fraction of HER2-amplified patients will respond to therapy and the use of these treatments is often limited by tumour drug insensitivity or resistance and drug toxicities. Currently there is no way to identify likely responders or rational combinations with the potential to improve HER2-focussed treatment outcome.In order to further understand the molecular mechanisms of treatment-response with HER2-inhibitors, we used a highly-optimised and reproducible quantitative label-free LC-MS strategy to characterize the proteomes of HER2-overexpressing breast-cancer cell-lines (SKBR3, BT474 and HCC1954) in response to drug-treatment with HER2-inhibitors (lapatinib, neratinib or afatinib).Following 12 ours treatment with different HER2-inhibitors in the BT474 cell-line; compared to the untreated cells, 16 proteins changed significantly in abundance following lapatinib treatment (1 M), 21 proteins changed significantly following neratinib treatment (150 nM) and 38 proteins changed significantly following afatinib treatment (150 nM). Whereas following 24 hours treatment with neratinib (200 nM) 46 proteins changed significantly in abundance in the HCC1954 cell-line and 23 proteins in the SKBR3 cell-line compared to the untreated cells. Analysing the data we found that, proteins like trifunctional-enzyme subunit-alpha, mitochondrial; heterogeneous nuclear ribonucleoprotein-R and lamina-associated polypeptide 2, isoform alpha were up-regulated whereas heat shock cognate 71 kDa protein was down-regulated in 3 or more comparisons.This proteomic study highlights several proteins that are closely associated with early HER2-inhibitor response and will provide a valuable resource for further investigation of ways to improve efficacy of breast-cancer treatment.

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