25 results on '"Laczkó D"'
Search Results
2. GPCR-induced paracrine transactivation of CB1 cannabinoid receptors in vascular smooth muscle cells modulates calcium signaling and ERK pathways: P2.13
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Soltész-Katona, E., Szekeres, M., Laczkó, D., Tóth, A., Turu, G., and Hunyady, L.
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- 2014
3. Bile acid cocktail (BAC) induces similar changes in the expression of ion transporter MRNA in cultured esophageal epithelial cells (EEC) as observed in biopsies of Barrett's esophagus (BE).
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Laczkó, D, primary, Venglovecz, V, additional, Hegyi, P, additional, Rakonczay, Z, additional, Inczefi, O, additional, Róka, R, additional, Wittmann, T, additional, and Rosztóczy, A, additional
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- 2015
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4. Gastro-esophageal reflux (GER) related symptoms are less common in south-east Hungarian subjects than expected on the basis of epidemiologic studies of the western countries
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Rosztóczy, A, primary, Laczkó, D, additional, Bálint, L, additional, Gyetvai, Á, additional, Kiss, P, additional, Róka, R, additional, Inczefi, O, additional, Szekeres, L, additional, and Wittmann, T, additional
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- 2015
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5. Epidemiologic characteristics of Helicobacter Pylori infection in South-East Hungary. A population based study
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Bálint, L, primary, Tiszai, A, additional, Dóczi, I, additional, Szekeres, V, additional, Róka, R, additional, Laczkó, D, additional, Inczefi, O, additional, Wittmann, T, additional, and Rosztóczy, A, additional
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- 2014
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6. The prevalence of gastrooesophageal reflux (GOR) related symptoms in healthy South-East Hungarian subjects
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Rosztóczy, A, primary, Laczkó, D, additional, Bálint, L, additional, Gyetvai, Á, additional, Kiss, P, additional, Róka, R, additional, Inczefi, O, additional, Szekeres, V, additional, and Wittmann, T, additional
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- 2014
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7. Acute and chronic effects of bile acids on the epithelial acid-base transporters in barrett's esophagus
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Laczkó, D, primary, Venglovecz, V, additional, Hegyi, P, additional, Rakonczay, Z, additional, Izbéki, F, additional, Róka, R, additional, Wittmann, T, additional, and Rosztóczy, A, additional
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- 2014
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8. Effects of non-conjugated bile acid on the acid-base transporters of the human esophageal epithelial cells
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Laczkó, D, primary, Venglovecz, V, additional, Hegyi, P, additional, Rakonczay, Z, additional, Izbéki, F, additional, Róka, R, additional, Wittmann, T, additional, and Rosztóczy, A, additional
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- 2013
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9. Endoscopic radiofrequency ablation (HALO-RFA) of the metaplastic mucosa in patients with Barrett's esophagus. The first Hungarian experience
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Rosztóczy, A, primary, Izbéki, F, additional, Róka, R, additional, Annaházi, A, additional, Laczkó, D, additional, Kocsis, M, additional, Fuszkó, M, additional, Polyák, É, additional, Benkő, É, additional, Vadászi, K, additional, and Wittmann, T, additional
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- 2012
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10. Functional evaluation of metaplastic human oesophageal epithelial cells
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Laczkó, D, primary, Venglovecz, V, additional, Hegyi, P, additional, Rakonczay, Z, additional, Izbéki, F, additional, Róka, R, additional, Wittmann, T, additional, and Rosztóczy, A, additional
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- 2012
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11. 17-Oxime ethers of oxidized ecdysteroid derivatives modulate oxidative stress in human brain endothelial cells and dose-dependently might protect or damage the blood-brain barrier.
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Vágvölgyi M, Laczkó D, Santa-Maria AR, Vigh JP, Walter FR, Berkecz R, Deli MA, Tóth G, and Hunyadi A
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- Animals, Humans, Endothelial Cells, Ethers, Oximes pharmacology, Oxidative Stress, Mammals, Ecdysteroids, Blood-Brain Barrier
- Abstract
20-Hydroxyecdysone and several of its oxidized derivatives exert cytoprotective effect in mammals including humans. Inspired by this bioactivity of ecdysteroids, in the current study it was our aim to prepare a set of sidechain-modified derivatives and to evaluate their potential to protect the blood-brain barrier (BBB) from oxidative stress. Six novel ecdysteroids, including an oxime and five oxime ethers, were obtained through regioselective synthesis from a sidechain-cleaved calonysterone derivative 2 and fully characterized by comprehensive NMR techniques revealing their complete 1H and 13C signal assignments. Surprisingly, several compounds sensitized hCMEC/D3 brain microvascular endothelial cells to tert-butyl hydroperoxide (tBHP)-induced oxidative damage as recorded by impedance measurements. Compound 8, containing a benzyloxime ether moiety in its sidechain, was the only one that exerted a protective effect at a higher, 10 μM concentration, while at lower (10 nM- 1 μM) concentrations it promoted tBHP-induced cellular damage. Brain endothelial cells were protected from tBHP-induced barrier integrity decrease by treatment with 10 μM of compound 8, which also mitigated the intracellular reactive oxygen species production elevated by tBHP. Based on our results, 17-oxime ethers of oxidized ecdysteroids modulate oxidative stress of the BBB in a way that may point towards unexpected toxicity. Further studies are needed to evaluate any possible risk connected to dietary ecdysteroid consumption and CNS pathologies in which BBB damage plays an important role., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Vágvölgyi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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12. Trastuzumab Resistance in Patients With HER2-Positive Advanced Breast Cancer: Results From the SONABRE Registry.
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Ibragimova KIE, Geurts SME, Laczkó D, Meegdes M, Erdkamp F, Heijns JB, Tol J, Vriens BEPJ, Aaldering KNA, Dercksen MW, Pepels MJAE, Peters NAJB, van de Winkel LMH, van de Wouw AJ, de Fallois A, van Kats MACE, and Tjan-Heijnen VCG
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- Humans, Female, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols adverse effects, Receptor, ErbB-2 metabolism, Progression-Free Survival, Proportional Hazards Models, Breast Neoplasms pathology
- Abstract
Background: This study aims to explore whether first-line pertuzumab use modifies the effect of prior use of (neo-) adjuvant trastuzumab on the PFS of first-line HER2-targeted therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC)., Methods: Patients diagnosed with HER2-positive ABC in 2008 to 2018 in 9 Dutch hospitals were derived from the SONABRE Registry (NCT03577197). Patients diagnosed with de novo metastatic breast cancer were excluded. Patients receiving first-line trastuzumab-based therapy for ABC were selected and divided into trastuzumab naïve (n = 113) and trastuzumab pretreated (n = 112). Progression-free survival (PFS) was compared using multivariable Cox proportional hazard models. The interaction effect of first-line pertuzumab was tested using the likelihood-ratio test., Results: The median follow-up time was 47 months (95% confidence interval [CI]: 42-52). When comparing trastuzumab pretreated with trastuzumab naïve patients, the hazard ratio for first-line progression was 2.07 (CI:1.47-2.92). For trastuzumab pretreated patients who received first-line trastuzumab without pertuzumab, the hazard ratio for progression was 2.60 (95% CI:1.72-3.93), whereas for those who received first-line trastuzumab with pertuzumab the hazard ratio was 1.43 (95% CI: 0.81-2.52) (P interaction = .10)., Conclusions: Prior use of trastuzumab as (neo-)adjuvant treatment had a negative impact on PFS of first-line HER2-targeted therapy outcomes. Adding pertuzumab to first-line trastuzumab-based therapy decreased the negative impact of prior (neo-)adjuvant trastuzumab use on first-line PFS. Further studies are needed to assess the effect of prior (neo-)adjuvant pertuzumab use on the outcomes of first-line pertuzumab-based therapy., Competing Interests: Disclosure Khava I.E. Ibragimova: Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Novartis BV; Roche; Pfizer; Eli Lilly; Sandra M.E. Geurts: Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Novartis BV; Roche; Pfizer; Eli Lilly; AstraZeneca, Gilead, Daiichi-Sankyo; Marissa Meegdes: Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Novartis BV; Roche; Pfizer Eli Lilly; AstraZeneca, Gilead; Aude de Fallois: Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Novartis BV; Roche; Pfizer Eli Lilly; AstraZeneca, Gilead; Vivianne C.G. Tjan-Heijnen: Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Accord Healthcare; Novartis BV; Roche; Pfizer Eli Lilly; AstraZeneca; Gilead; Daiichi-Sankyo. All remaining authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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13. Diacylglycerol kinase zeta deficiency attenuates papain-induced type 2 airway inflammation.
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Singh BK, Yokoyama Y, Tanaka Y, Laczkó D, Deshpande DA, and Kambayashi T
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- Animals, Mice, Papain, Diacylglycerol Kinase genetics, Diacylglycerol Kinase metabolism, Lymphocytes, Inflammation, Immunity, Innate, Hypersensitivity
- Abstract
Allergic airway diseases are caused by inappropriate immune responses directed against inhaled environmental antigens. We previously reported that the inhibition of diacylglycerol (DAG) kinaseζ (DGKζ),an enzyme that terminates DAG-mediated signaling,protects against T cell-mediated allergic airway inflammation by blocking Th2 cell differentiation.In this study, we tested whether DGKζ deficiency also affects allergic airway disease mediated by type 2 innate lymphoid cells (ILC2)s. DGKζ-deficient mice displayed diminished ILC2 function and reduced papain-induced airway inflammation compared to wildtype mice. Unexpectedly, however, mice with hematopoietic cell-specific deletion ofDGKζ displayed intact airway inflammation upon papain challenge. Rather, bone marrow chimera studies revealed thatDGKζ deficiency in the non-hematopoietic compartment was responsible for the reduction in papain-induced airway inflammation. These data suggest that DGK might represent a novel therapeutic target not only for T cell-dependent but also ILC2-dependent allergic airway inflammation by affecting non-hematopoietic cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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14. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses.
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Alameh MG, Tombácz I, Bettini E, Lederer K, Sittplangkoon C, Wilmore JR, Gaudette BT, Soliman OY, Pine M, Hicks P, Manzoni TB, Knox JJ, Johnson JL, Laczkó D, Muramatsu H, Davis B, Meng W, Rosenfeld AM, Strohmeier S, Lin PJC, Mui BL, Tam YK, Karikó K, Jacquet A, Krammer F, Bates P, Cancro MP, Weissman D, Luning Prak ET, Allman D, Locci M, and Pardi N
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- 2022
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15. Lyophilization provides long-term stability for a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine.
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Muramatsu H, Lam K, Bajusz C, Laczkó D, Karikó K, Schreiner P, Martin A, Lutwyche P, Heyes J, and Pardi N
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- Animals, Freeze Drying, Liposomes, Mice, Nucleosides, RNA, Messenger genetics, Vaccines, Synthetic, mRNA Vaccines, COVID-19 prevention & control, Influenza Vaccines, Nanoparticles chemistry
- Abstract
Lipid nanoparticle (LNP)-formulated nucleoside-modified mRNA vaccines have proven to be very successful in the fight against the coronavirus disease 2019 (COVID-19) pandemic. They are effective, safe, and can be produced in large quantities. However, the long-term storage of mRNA-LNP vaccines without freezing is still a challenge. Here, we demonstrate that nucleoside-modified mRNA-LNPs can be lyophilized, and the physicochemical properties of the lyophilized material do not significantly change for 12 weeks after storage at room temperature and for at least 24 weeks after storage at 4°C. Importantly, we show in comparative mouse studies that lyophilized firefly luciferase-encoding mRNA-LNPs maintain their high expression, and no decrease in the immunogenicity of a lyophilized influenza virus hemagglutinin-encoding mRNA-LNP vaccine was observed after 12 weeks of storage at room temperature or for at least 24 weeks after storage at 4°C. Our studies offer a potential solution to overcome the long-term storage-related limitations of nucleoside-modified mRNA-LNP vaccines., Competing Interests: Declaration of interests N.P. is named on a patent describing the use of nucleoside-modified mRNA in LNPs as a vaccine platform. He has disclosed those interests fully to the University of Pennsylvania, and he has in place an approved plan for managing any potential conflicts arising from licensing of that patent. K.K. is an employee of BioNTech., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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16. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses.
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Alameh MG, Tombácz I, Bettini E, Lederer K, Sittplangkoon C, Wilmore JR, Gaudette BT, Soliman OY, Pine M, Hicks P, Manzoni TB, Knox JJ, Johnson JL, Laczkó D, Muramatsu H, Davis B, Meng W, Rosenfeld AM, Strohmeier S, Lin PJC, Mui BL, Tam YK, Karikó K, Jacquet A, Krammer F, Bates P, Cancro MP, Weissman D, Luning Prak ET, Allman D, Locci M, and Pardi N
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- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Adjuvants, Immunologic, Animals, HEK293 Cells, Humans, Immunity, Humoral, Interleukin-6 genetics, Interleukin-6 metabolism, Liposomes administration & dosage, Mice, Mice, Inbred BALB C, Nanoparticles administration & dosage, Protein Subunits genetics, mRNA Vaccines genetics, B-Lymphocytes immunology, COVID-19 immunology, COVID-19 Vaccines immunology, Germinal Center immunology, SARS-CoV-2 physiology, T-Lymphocytes, Helper-Inducer immunology, mRNA Vaccines immunology
- Abstract
Adjuvants are critical for improving the quality and magnitude of adaptive immune responses to vaccination. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines have shown great efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanism of action of this vaccine platform is not well-characterized. Using influenza virus and SARS-CoV-2 mRNA and protein subunit vaccines, we demonstrated that our LNP formulation has intrinsic adjuvant activity that promotes induction of strong T follicular helper cell, germinal center B cell, long-lived plasma cell, and memory B cell responses that are associated with durable and protective antibodies in mice. Comparative experiments demonstrated that this LNP formulation outperformed a widely used MF59-like adjuvant, AddaVax. The adjuvant activity of the LNP relies on the ionizable lipid component and on IL-6 cytokine induction but not on MyD88- or MAVS-dependent sensing of LNPs. Our study identified LNPs as a versatile adjuvant that enhances the efficacy of traditional and next-generation vaccine platforms., Competing Interests: Declaration of interests In accordance with the University of Pennsylvania policies and procedures and our ethical obligations as researchers, we report that D.W. and N.P. are named on a patent describing the use of nucleoside-modified mRNA in lipid nanoparticles as a vaccine platform. We have disclosed those interests fully to the University of Pennsylvania, and we have in place an approved plan for managing any potential conflicts arising from licensing of our patents. K.K. is an employee of BioNTech. P.J.C.L., B.L.M., and Y.K.T. are employees of Acuitas Therapeutics, a company involved in the development of mRNA-LNP therapeutics. Y.K.T., D.W., and M.G.A. are named on patents that describe lipid nanoparticles for delivery of nucleic acid therapeutics, including mRNA and the use of modified mRNA in lipid nanoparticles as a vaccine platform. The Icahn School of Medicine at Mount Sinai has filed patent applications regarding SARS-CoV-2 and influenza virus vaccines that name F.K. as co-inventor., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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17. Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs.
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Tombácz I, Laczkó D, Shahnawaz H, Muramatsu H, Natesan A, Yadegari A, Papp TE, Alameh MG, Shuvaev V, Mui BL, Tam YK, Muzykantov V, Pardi N, Weissman D, and Parhiz H
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- Animals, COVID-19 immunology, COVID-19 Vaccines immunology, Humans, Immunotherapy methods, Lymph Nodes immunology, Mice, Mice, Inbred C57BL, Recombination, Genetic immunology, SARS-CoV-2 immunology, Spleen immunology, Transfection methods, CD4-Positive T-Lymphocytes immunology, Lipids genetics, Lipids immunology, Nanoparticles administration & dosage, RNA, Messenger genetics, RNA, Messenger immunology, Recombination, Genetic genetics
- Abstract
Nucleoside-modified messenger RNA (mRNA)-lipid nanoparticles (LNPs) are the basis for the first two EUA (Emergency Use Authorization) COVID-19 vaccines. The use of nucleoside-modified mRNA as a pharmacological agent opens immense opportunities for therapeutic, prophylactic and diagnostic molecular interventions. In particular, mRNA-based drugs may specifically modulate immune cells, such as T lymphocytes, for immunotherapy of oncologic, infectious and other conditions. The key challenge, however, is that T cells are notoriously resistant to transfection by exogenous mRNA. Here, we report that conjugating CD4 antibody to LNPs enables specific targeting and mRNA interventions to CD4+ cells, including T cells. After systemic injection in mice, CD4-targeted radiolabeled mRNA-LNPs accumulated in spleen, providing ∼30-fold higher signal of reporter mRNA in T cells isolated from spleen as compared with non-targeted mRNA-LNPs. Intravenous injection of CD4-targeted LNPs loaded with Cre recombinase-encoding mRNA provided specific dose-dependent loxP-mediated genetic recombination, resulting in reporter gene expression in about 60% and 40% of CD4+ T cells in spleen and lymph nodes, respectively. T cell phenotyping showed uniform transfection of T cell subpopulations, with no variability in uptake of CD4-targeted mRNA-LNPs in naive, central memory, and effector cells. The specific and efficient targeting and transfection of mRNA to T cells established in this study provides a platform technology for immunotherapy of devastating conditions and HIV cure., Competing Interests: Declaration of interests H.P., I.T., N.P., V.R.M., and D.W. are inventors on a patent filed on some aspects of this work. Those interests have been fully disclosed to the University of Pennsylvania. All other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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18. The key role of NLRP3 and STING in APOL1-associated podocytopathy.
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Wu J, Raman A, Coffey NJ, Sheng X, Wahba J, Seasock MJ, Ma Z, Beckerman P, Laczkó D, Palmer MB, Kopp JB, Kuo JJ, Pullen SS, Boustany-Kari CM, Linkermann A, and Susztak K
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- Animals, Apolipoprotein L1 physiology, Humans, Mice, Apolipoprotein L1 genetics, Kidney Diseases etiology, Membrane Proteins physiology, NLR Family, Pyrin Domain-Containing 3 Protein physiology, Podocytes pathology
- Abstract
Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOL1-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.
- Published
- 2021
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19. A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice.
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Laczkó D, Hogan MJ, Toulmin SA, Hicks P, Lederer K, Gaudette BT, Castaño D, Amanat F, Muramatsu H, Oguin TH 3rd, Ojha A, Zhang L, Mu Z, Parks R, Manzoni TB, Roper B, Strohmeier S, Tombácz I, Arwood L, Nachbagauer R, Karikó K, Greenhouse J, Pessaint L, Porto M, Putman-Taylor T, Strasbaugh A, Campbell TA, Lin PJC, Tam YK, Sempowski GD, Farzan M, Choe H, Saunders KO, Haynes BF, Andersen H, Eisenlohr LC, Weissman D, Krammer F, Bates P, Allman D, Locci M, and Pardi N
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- Animals, B-Lymphocytes drug effects, B-Lymphocytes immunology, B-Lymphocytes virology, Betacoronavirus immunology, Betacoronavirus pathogenicity, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes virology, COVID-19, COVID-19 Vaccines, Coronavirus Infections genetics, Coronavirus Infections immunology, Coronavirus Infections pathology, Disease Models, Animal, Furin genetics, Furin immunology, Humans, Immunity, Humoral drug effects, Immunization methods, Immunogenicity, Vaccine, Immunologic Memory drug effects, Lymphocyte Activation drug effects, Mice, Mice, Inbred BALB C, Nanoparticles administration & dosage, Nanoparticles chemistry, Pneumonia, Viral immunology, Pneumonia, Viral pathology, RNA, Messenger genetics, RNA, Viral genetics, SARS-CoV-2, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus immunology, Vaccines, Synthetic, Viral Vaccines biosynthesis, Viral Vaccines genetics, Antibodies, Neutralizing biosynthesis, Antibodies, Viral biosynthesis, Betacoronavirus drug effects, Coronavirus Infections prevention & control, Pandemics prevention & control, Pneumonia, Viral prevention & control, RNA, Messenger immunology, RNA, Viral immunology, Viral Vaccines administration & dosage
- Abstract
SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding the full-length SARS-CoV-2 spike protein or the spike receptor binding domain in mice. We demonstrate that a single dose of these vaccines induces strong type 1 CD4
+ and CD8+ T cell responses, as well as long-lived plasma and memory B cell responses. Additionally, we detect robust and sustained neutralizing antibody responses and the antibodies elicited by nucleoside-modified mRNA vaccines do not show antibody-dependent enhancement of infection in vitro. Our findings suggest that the nucleoside-modified mRNA-LNP vaccine platform can induce robust immune responses and is a promising candidate to combat COVID-19., Competing Interests: Declaration of Interests In accordance with the University of Pennsylvania policies and procedures and our ethical obligations as researchers, we report that D.W. and K.K. are named on patents that describe the use of nucleoside-modified mRNA as a platform to deliver therapeutic proteins. D.W. and N.P. are also named on a patent describing the use of nucleoside-modified mRNA in lipid nanoparticles as a vaccine platform. We have disclosed those interests fully to the University of Pennsylvania, and we have an approved plan for managing any potential conflicts arising from licensing of our patents in place. K.K. is an employee of BioNTech. P.J.C.L. and Y.K.T. are employees of Acuitas Therapeutics, a company involved in the development of mRNA-LNP therapeutics. Y.K.T. is named on patents that describe lipid nanoparticles for delivery of nucleic acid therapeutics including mRNA and the use of modified mRNA in lipid nanoparticles as a vaccine platform., (Published by Elsevier Inc.)- Published
- 2020
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20. PRRX1 isoforms cooperate with FOXM1 to regulate the DNA damage response in pancreatic cancer cells.
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Marchand B, Pitarresi JR, Reichert M, Suzuki K, Laczkó D, and Rustgi AK
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- Animals, Apoptosis drug effects, Apoptosis genetics, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal genetics, Cell Line, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation genetics, DNA Repair drug effects, DNA Repair genetics, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Epithelial-Mesenchymal Transition, Etoposide pharmacology, HEK293 Cells, Humans, Liver Neoplasms drug therapy, Liver Neoplasms genetics, Mice, Mice, Knockout, Pancreas drug effects, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms pathology, Transcription, Genetic drug effects, Transcription, Genetic genetics, Gemcitabine, DNA Damage genetics, Forkhead Box Protein M1 genetics, Homeodomain Proteins genetics, Pancreatic Neoplasms genetics, Protein Isoforms genetics
- Abstract
PRRX1 is a homeodomain transcriptional factor, which has two isoforms, PRXX1A and PRRX1B. The PRRX1 isoforms have been demonstrated to be important in pancreatic cancer, especially in the regulation of epithelial-to-mesenchymal transition (EMT) in Pancreatic Ductal Adenocarcinoma (PDAC) and of mesenchymal-to-epithelial transition (MET) in liver metastasis. In order to determine the functional underpinnings of PRRX1 and its isoforms, we have unraveled a new interplay between PRRX1 and the FOXM1 transcriptional factors. Our detailed biochemical analysis reveals the direct physical interaction between PRRX1 and FOXM1 proteins that requires the PRRX1A/B 200-222/217 amino acid (aa) region and the FOXM1 Forkhead domain. Additionally, we demonstrate the cooperation between PRRX1 and FOXM1 in the regulation of FOXM1-dependent transcriptional activity. Moreover, we establish FOXM1 as a critical downstream target of PRRX1 in pancreatic cancer cells. We demonstrate a novel role for PRRX1 in the regulation of genes involved in DNA repair pathways. Indeed, we show that expression of PRRX1 isoforms may limit the induction of DNA damage in pancreatic cancer cells. Finally, we demonstrate that targeting FOXM1 with the small molecule inhibitor FDI6 suppress pancreatic cancer cell proliferation and induces their apoptotic cell death. FDI6 sensitizes pancreatic cancer cells to Etoposide and Gemcitabine induced apoptosis. Our data provide new insights into PRRX1's involvement in regulating DNA damage and provide evidence of a possible PRRX1-FOXM1 axis that is critical for PDAC cells.
- Published
- 2019
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21. KLF4 activates NFκB signaling and esophageal epithelial inflammation via the Rho-related GTP-binding protein RHOF.
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Shaverdashvili K, Padlo J, Weinblatt D, Jia Y, Jiang W, Rao D, Laczkó D, Whelan KA, Lynch JP, Muir AB, and Katz JP
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- Animals, Esophageal Mucosa pathology, Esophagitis genetics, Esophagitis pathology, Inflammation genetics, Inflammation metabolism, Inflammation pathology, Keratinocytes pathology, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Mice, Mice, Transgenic, NF-kappa B genetics, rho GTP-Binding Proteins genetics, Esophageal Mucosa metabolism, Esophagitis metabolism, Keratinocytes metabolism, Kruppel-Like Transcription Factors metabolism, NF-kappa B metabolism, Signal Transduction, rho GTP-Binding Proteins metabolism
- Abstract
Understanding the regulatory mechanisms within esophageal epithelia is essential to gain insight into the pathogenesis of esophageal diseases, which are among the leading causes of morbidity and mortality throughout the world. The zinc-finger transcription factor Krüppel-like factor (KLF4) is implicated in a large number of cellular processes, such as proliferation, differentiation, and inflammation in esophageal epithelia. In murine esophageal epithelia, Klf4 overexpression causes chronic inflammation which is mediated by activation of NFκB signaling downstream of KLF4, and this esophageal inflammation produces epithelial hyperplasia and subsequent esophageal squamous cell cancer. Yet, while NFκB activation clearly promotes esophageal inflammation, the mechanisms by which NFκB signaling is activated in esophageal diseases are not well understood. Here, we demonstrate that the Rho-related GTP-binding protein RHOF is activated by KLF4 in esophageal keratinocytes, leading to the induction of NFκB signaling. Moreover, RHOF is required for NFκB activation by KLF4 in esophageal keratinocytes and is also important for esophageal keratinocyte proliferation and migration. Finally, we find that RHOF is upregulated in eosinophilic esophagitis, an important esophageal inflammatory disease in humans. Thus, RHOF activation of NFκB in esophageal keratinocytes provides a potentially important and clinically-relevant mechanism for esophageal inflammation and inflammation-mediated esophageal squamous cell cancer., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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22. Modeling Esophagitis Using Human Three-Dimensional Organotypic Culture System.
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Laczkó D, Wang F, Johnson FB, Jhala N, Rosztóczy A, Ginsberg GG, Falk GW, Rustgi AK, and Lynch JP
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- Cell Line, Esophagitis immunology, Esophagus immunology, Humans, Inflammation immunology, Inflammation pathology, Oxidative Stress physiology, Cell Culture Techniques methods, Esophagitis pathology, Esophagus pathology
- Abstract
Esophagitis, whether caused by acid reflux, allergic responses, graft-versus-host disease, drugs, or infections, is a common condition of the gastrointestinal tract affecting nearly 20% of the US population. The instigating agent typically triggers an inflammatory response. The resulting inflammation is a risk factor for the development of esophageal strictures, Barrett esophagus, and esophageal adenocarcinoma. Research into the pathophysiology of these conditions has been limited by the availability of animal and human model systems. Three-dimensional organotypic tissue culture (OTC) is an innovative three-dimensional multicellular in vitro platform that recapitulates normal esophageal epithelial stratification and differentiation. We hypothesized that this platform can be used to model esophagitis to better understand the interactions between immune cells and the esophageal epithelium. We found that human immune cells remain viable and respond to cytokines when cultured under OTC conditions. The acute inflammatory environment induced in the OTC significantly affected the overlying epithelium, inducing a regenerative response marked by increased cell proliferation and epithelial hyperplasia. Moreover, oxidative stress from the acute inflammation induced DNA damage and strand breaks in epithelial cells, which could be reversed by antioxidant treatment. These findings support the importance of immune cell-mediated esophageal injury in esophagitis and confirms the utility of the OTC platform to characterize the underlying molecular events in esophagitis., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
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23. Autophagy levels are elevated in barrett's esophagus and promote cell survival from acid and oxidative stress.
- Author
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Kong J, Whelan KA, Laczkó D, Dang B, Caro Monroig A, Soroush A, Falcone J, Amaravadi RK, Rustgi AK, Ginsberg GG, Falk GW, Nakagawa H, and Lynch JP
- Subjects
- Adenocarcinoma metabolism, Animals, Autophagy drug effects, Barrett Esophagus metabolism, Cell Line, Cell Survival, Chloroquine pharmacology, Disease Models, Animal, Disease Progression, Esophageal Neoplasms metabolism, Humans, Mice, Oxidative Stress, Acids adverse effects, Adenocarcinoma pathology, Barrett Esophagus pathology, Esophageal Neoplasms pathology, Reactive Oxygen Species metabolism
- Abstract
Autophagy is a highly conserved mechanism that is activated during cellular stress. We hypothesized that autophagy may be induced by acid reflux, which causes injury, and inflammation, and therefore, contributes to the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Currently, the role of autophagy in BE and EAC is poorly studied. We quantitatively define autophagy levels in human BE cell lines, a transgenic mouse model of BE, and human BE, and EAC biopsies. Human non-dysplastic BE had the highest basal number of autophagic vesicles (AVs), while AVs were reduced in normal squamous cells and dysplastic BE cells, and nearly absent in EAC. To demonstrate a functional role for autophagy in BE pathogenesis, normal squamous (STR), non-dysplastic BE (CPA), dysplastic BE (CPD), and EAC (OE19) cell lines were exposed to an acid pulse (pH 3.5) followed by incubation in the presence or absence of chloroquine, an autophagy inhibitor. Acid exposure increased reactive oxygen species (ROS) levels in STR and CPA cells. Chloroquine alone had a small impact on intracellular ROS or cell survival. However, combination of chloroquine with the acid pulse resulted in a significant increase in ROS levels at 6 h in STR and CPA cells, and increased cell death in all cell lines. These findings establish increased numbers of AVs in human BE compared to normal squamous or EAC, and suggest that autophagy functions to improve cell survival after acid reflux injury. Autophagy may thus play a critical role in BE pathogenesis and progression. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
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24. Analysis of Research Activity in Gastroenterology: Pancreatitis Is in Real Danger.
- Author
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Szentesi A, Tóth E, Bálint E, Fanczal J, Madácsy T, Laczkó D, Ignáth I, Balázs A, Pallagi P, Maléth J, Rakonczay Z Jr, Kui B, Illés D, Márta K, Blaskó Á, Demcsák A, Párniczky A, Pár G, Gódi S, Mosztbacher D, Szücs Á, Halász A, Izbéki F, Farkas N, and Hegyi P
- Subjects
- Acute Disease, Clinical Trials as Topic, Gastrointestinal Diseases, Humans, Internationality, Biomedical Research, Pancreatitis therapy
- Abstract
Objective: Biomedical investment trends in 2015 show a huge decrease of investment in gastroenterology. Since academic research usually provides the basis for industrial research and development (R&D), our aim was to understand research trends in the field of gastroenterology over the last 50 years and identify the most endangered areas., Methods: We searched for PubMed hits for gastrointestinal (GI) diseases for the 1965-2015 period. Overall, 1,554,325 articles were analyzed. Since pancreatology was identified as the most endangered field of research within gastroenterology, we carried out a detailed evaluation of research activity in pancreatology., Results: In 1965, among the major benign GI disorders, 51.9% of the research was performed on hepatitis, 25.7% on pancreatitis, 21.7% on upper GI diseases and only 0.7% on the lower GI disorders. Half a century later, in 2015, research on hepatitis and upper GI diseases had not changed significantly; however, studies on pancreatitis had dropped to 10.7%, while work on the lower GI disorders had risen to 23.4%. With regard to the malignant disorders (including liver, gastric, colon, pancreatic and oesophageal cancer), no such large-scale changes were observed in the last 50 years. Detailed analyses revealed that besides the drop in research activity in pancreatitis, there are serious problems with the quality of the studies as well. Only 6.8% of clinical trials on pancreatitis were registered and only 5.5% of these registered trials were multicentre and multinational (more than five centres and nations), i.e., the kind that provides the highest level of impact and evidence level., Conclusions: There has been a clear drop in research activity in pancreatitis. New international networks and far more academic R&D activities should be established in order to find the first therapy specifically for acute pancreatitis., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
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25. Role of ion transporters in the bile acid-induced esophageal injury.
- Author
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Laczkó D, Rosztóczy A, Birkás K, Katona M, Rakonczay Z Jr, Tiszlavicz L, Róka R, Wittmann T, Hegyi P, and Venglovecz V
- Subjects
- Aged, Aged, 80 and over, Barrett Esophagus pathology, Bile Acids and Salts metabolism, Calcium metabolism, Cell Line, Chloride-Bicarbonate Antiporters metabolism, Epithelial Cells metabolism, Epithelial Cells pathology, Esophageal Mucosa metabolism, Esophageal Mucosa pathology, Female, Gene Expression Regulation, Humans, Hydrogen-Ion Concentration, Inositol Phosphates metabolism, Ion Transport, Male, Membrane Transport Proteins genetics, Metaplasia, Middle Aged, Sodium-Bicarbonate Symporters metabolism, Sodium-Hydrogen Exchangers metabolism, Time Factors, Barrett Esophagus metabolism, Bile Acids and Salts toxicity, Epithelial Cells drug effects, Esophageal Mucosa drug effects, Membrane Transport Proteins metabolism
- Abstract
Barrett's esophagus (BE) is considered to be the most severe complication of gastro-esophageal reflux disease (GERD), in which the prolonged, repetitive episodes of combined acidic and biliary reflux result in the replacement of the squamous esophageal lining by columnar epithelium. Therefore, the acid-extruding mechanisms of esophageal epithelial cells (EECs) may play an important role in the defense. Our aim was to identify the presence of acid/base transporters on EECs and to investigate the effect of bile acids on their expressions and functions. Human EEC lines (CP-A and CP-D) were acutely exposed to bile acid cocktail (BAC) and the changes in intracellular pH (pHi) and Ca(2+) concentration ([Ca(2+)]i) were measured by microfluorometry. mRNA and protein expression of ion transporters was investigated by RT-PCR, Western blot, and immunohistochemistry. We have identified the presence of a Na(+)/H(+) exchanger (NHE), Na(+)/HCO3 (-) cotransporter (NBC), and a Cl(-)-dependent HCO3 (-) secretory mechanism in CP-A and CP-D cells. Acute administration of BAC stimulated HCO3 (-) secretion in both cell lines and the NHE activity in CP-D cells by an inositol triphosphate-dependent calcium release. Chronic administration of BAC to EECs increased the expression of ion transporters compared with nontreated cells. A similar expression pattern was observed in biopsy samples from BE compared with normal epithelium. We have shown that acute administration of bile acids differently alters ion transport mechanisms of EECs, whereas chronic exposure to bile acids increases the expression of acid/base transporters. We speculate that these adaptive processes of EECs represent an important mucosal defense against the bile acid-induced epithelial injury., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
- Full Text
- View/download PDF
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