Imperial College London

Professor Kazuhiro Ito

Faculty of MedicineNational Heart & Lung Institute

Principal Research Fellow in Respiratory Molecular Pharmacol
 
 
 
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Contact

 

+44 (0)20 7594 0953k.ito Website

 
 
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Location

 

412Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

258 results found

Ito K, 2021, HDAC6: A Neglected Player in Chronic Obstructive Pulmonary Disease?, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 65, Pages: 569-570, ISSN: 1044-1549

Journal article

Wada H, Nakamura M, Inoue S-I, Kudo A, Hanawa T, Iwakura Y, Kobayashi F, Kamma H, Kamiya S, Ito K, Barnes PJ, Takizawa Het al., 2021, Dual interleukin-17A/F deficiency protects against acute and chronic response to cigarette smoke exposure in mice, SCIENTIFIC REPORTS, Vol: 11, ISSN: 2045-2322

Journal article

Laura G, Liu Y, Fernandes K, Willis-Owen SAG, Ito K, Cookson WO, Moffatt MF, Zhang Yet al., 2021, ORMDL3 regulates poly I:C induced inflammatory responses in airway epithelial cells, BMC Pulmonary Medicine, Vol: 21, ISSN: 1471-2466

Background:Oroscomucoid 3 (ORMDL3) has been linked to susceptibility of childhood asthma and respiratory viral infection. Polyinosinic-polycytidylic acid (poly I:C) is a synthetic analog of viral double-stranded RNA, a toll-like receptor 3 (TLR3) ligand and mimic of viral infection.Methods:To investigate the functional role of ORMDL3 in the poly I:C-induced inflammatory response in airway epithelial cells, ORMDL3 knockdown and over-expression models were established in human A549 epithelial cells and primary normal human bronchial epithelial (NHBE) cells. The cells were stimulated with poly I:C or the Th17 cytokine IL-17A. IL-6 and IL-8 levels in supernatants, mRNA levels of genes in the TLR3 pathway and inflammatory response from cell pellets were measured. ORMDL3 knockdown models in A549 and BEAS-2B epithelial cells were then infected with live human rhinovirus (HRV16) followed by IL-6 and IL-8 measurement.Results:ORMDL3 knockdown and over-expression had little influence on the transcript levels of TLR3 in airway epithelial cells. Time course studies showed that ORMDL3-deficient A549 and NHBE cells had an attenuated IL-6 and IL-8 response to poly I:C stimulation. A549 and NHBE cells over-expressing ORMDL3 released relatively more IL-6 and IL-8 following poly I:C stimulation. IL-17A exhibited a similar inflammatory response in ORMDL3 knockdown and over-expressing cells, but co-stimulation of poly I:C and IL-17A did not significantly enhance the IL-6 and IL-8 response. Transcript abundance of IFNB following poly I:C stimulation was not significantly altered by ORMDL3 knockdown or over-expression. Dampening of the IL-6 response by ORMDL3 knockdown was confirmed in HRV16 infected BEAS-2B and A549 cells.Conclusions:ORMDL3 regulates the viral inflammatory response in airway epithelial cells via mechanisms independent of the TLR3 pathway.

Journal article

Coates M, Alton E, Rapeport W, Davies J, Ito Ket al., 2021, Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway, PLoS One, Vol: 16, ISSN: 1932-6203

Pseudomonas aeruginosa (Pa) infection is a major cause of airway inflammation in immunocompromised and cystic fibrosis (CF) patients. Mitogen-activated protein (MAP) and tyrosine kinases are integral to inflammatory responses and are therefore potential targets for novel anti-inflammatory therapies. We have determined the involvement of specific kinases in Pa-induced inflammation. The effects of kinase inhibitors against p38MAPK, MEK 1/2, JNK 1/2, Syk or c-Src, a combination of a p38MAPK with Syk inhibitor, or a novel narrow spectrum kinase inhibitor (NSKI), were evaluated against the release of the proinflammatory cytokine/chemokine, IL-6 and CXCL8 from BEAS-2B and CFBE41o- epithelial cells by Pa. Effects of a Syk inhibitor against phosphorylation of the MAPKs were also evaluated. IL-6 and CXCL8 release by Pa were significantly inhibited by p38MAPK and Syk inhibitors (p<0.05). Phosphorylation of HSP27, but not ERK or JNK, was significantly inhibited by Syk kinase inhibition. A combination of p38MAPK and Syk inhibitors showed synergy against IL-6 and CXCL8 induction and an NSKI completely inhibited IL-6 and CXCL8 at low concentrations. Pa-induced inflammation is dependent on p38MAPK primarily, and Syk partially, which is upstream of p38MAPK. The NSKI suggests that inhibiting specific combinations of kinases is a potent potential therapy for Pa-induced inflammation.

Journal article

Cass L, Murray A, Davis A, Woodward K, Albayaty M, Ito K, Strong P, Ayrton J, Brindley C, Prosser J, Murray J, French E, Haywood P, Wallis C, Rapeport Get al., 2021, Safety and nonclinical and clinical pharmacokinetics of PC945, a novel inhaled triazole antifungal agent, PHARMACOLOGY RESEARCH & PERSPECTIVES, Vol: 9, ISSN: 2052-1707

Journal article

Kono Y, Colley T, To M, Papaioannou AI, Mercado N, Baker JR, To Y, Abe S, Haruki K, Ito K, Barnes PJet al., 2021, Cigarette smoke-induced impairment of autophagy in macrophages increases galectin-8 and inflammation, SCIENTIFIC REPORTS, Vol: 11, ISSN: 2045-2322

Journal article

Castilho M, de Ruijter M, Beirne S, Villette CC, Ito K, Wallace GG, Malda Jet al., 2020, Multitechnology Biofabrication: A New Approach for the Manufacturing of Functional Tissue Structures?, TRENDS IN BIOTECHNOLOGY, Vol: 38, Pages: 1316-1328, ISSN: 0167-7799

Journal article

Murray A, Cass L, Ito K, Pagani N, Armstrong-James D, Dalal P, Reed A, Strong Pet al., 2020, PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections, JOURNAL OF FUNGI, Vol: 6

Journal article

Rapeport WG, Ito K, Denning DW, 2020, The role of antifungals in the management of patients with severe asthma, Clinical and Translational Allergy, Vol: 10, Pages: 1-15, ISSN: 2045-7022

In patients with asthma, the inhalation of elevated amounts of fungal spores and hyphae may precipitate the onset of asthma or worsen control to the extent of being life-threatening. Sensitisation to fungi, especially Aspergillus fumigatus, is found in 15% to 48% of asthmatics in secondary care and is linked to worse asthma control, hospitalisation, bronchiectasis and fixed airflow obstruction, irrespective of whether allergic bronchopulmonary aspergillosis (ABPA) is diagnosed. ABPA represents a florid response to the presence of Aspergillus spp. but up to 70% of patients with severe asthma exhibit sensitisation to different fungi without meeting the diagnostic criteria for ABPA. The presence of persistent endobronchial colonisation with fungi, especially A. fumigatus, is linked to significantly higher rates of radiological abnormalities, lower post-bronchodilator FEV1 and significantly less reversibility to short acting bronchodilators. The therapeutic benefit for antifungal intervention in severe asthma is based on the assumption that reductions in airway fungal burden may result in improvements in asthma control, lung function and symptoms (especially cough). This contention is supported by several prospective studies which demonstrate the effectiveness of antifungals for the treatment of ABPA. Significantly, these studies confirm lower toxicity of treatment with azoles versus high dose oral corticosteroid dosing regimens for ABPA. Here we review recent evidence for the role of fungi in the progression of severe asthma and provide recommendations for the use of antifungal agents in patients with severe asthma, airways fungal infection (mycosis) and fungal colonisation. Documenting fungal airways colonisation and sensitisation in those with severe asthma opens up alternative therapy options of antifungal therapy, which may be particularly valuable in low resource settings.

Journal article

Abe K, Bronner C, Haga Y, Hayato Y, Ikeda M, Imaizumi S, Ito H, Iyogi K, Kameda J, Kataoka Y, Kato Y, Kishimoto Y, Marti L, Miura M, Moriyama S, Mochizuki T, Nagao Y, Nakahata M, Nakajima Y, Nakajima T, Nakayama S, Okada T, Okamoto K, Orii A, Pronost G, Sekiya H, Shiozawa M, Sonoda Y, Takeda A, Takenaka A, Tanaka H, Tasaka S, Tomura T, Ueno K, Yano T, Yokozawa T, Akutsu R, Han S, Irvine T, Kajita T, Kametani I, Lee KP, McLachlan T, Okumura K, Richard E, Tashiro T, Wang R, Xia J, Bravo-Berguno D, Labarga L, Fernandez P, Blaszczyk FDM, Gustafson J, Kachulis C, Kearns E, Raaf JL, Stone JL, Sulak LR, Sussman S, Wan L, Wester T, Berkman S, Tobayama S, Bian J, Carminati G, Elnimr M, Griskevich NJ, Kropp WR, Locke S, Mine S, Renshaw A, Smy MB, Sobel HW, Takhistov V, Weatherly P, Hartfiel BL, Hill J, Keig WE, Hong N, Kim JY, Lim IT, Park RG, Akiri T, Bodur B, Himmel A, Li Z, O'Sullivan E, Scholberg K, Walter CW, Wongjirad T, Coffani A, Drapier O, El Hedri S, Giampaolo A, Gonin M, Imber J, Mueller TA, Paganini P, Quilain B, Ishizuka T, Nakamura T, Jang JS, Choi K, Learned JG, Matsuno S, Smith SN, Amey J, Anthony LH, Litchfield RP, Sztuc AA, Uchida Y, Wascko MO, Berardi V, Catanesi MG, Intonti RA, Radicioni E, Calabria NF, Machado LN, De Rosa G, Collazuol G, Iacob F, Lamoureux M, Ospina N, Ludovici L, Boschi T, Di Lodovico F, Sedgwick SM, Zsoldos S, Nishimura Y, Cao S, Friend M, Hasegawa T, Ishida T, Ishii T, Kobayashi T, Nakadaira T, Nakamura K, Oyama Y, Sakashita K, Sekiguchi T, Tsukamoto T, Abe K, Hasegawa M, Isobe Y, Miyabe H, Nakano Y, Shiozawa T, Sugimoto T, Suzuki AT, Takeuchi Y, Yamamoto S, Ali A, Ashida Y, Hayashino T, Hiraki T, Hirota S, Huang K, Ieki K, Jiang M, Kikawa T, Mori M, Murakami A, Nakamura KE, Nakaya T, Patel ND, Suzuki K, Takahashi S, Tateishi K, Wendell RA, McCauley N, Mehta P, Pritchard A, Tsui KM, Fukuda Y, Itow Y, Menjo H, Mitsuka G, Murase M, Muto F, Niwa T, Sato K, Suzuki T, Taani M, Tsukada M, Mijakowski P, Frankiewicz K, Hignight J, Jung CK, Liet al., 2020, Indirect search for dark matter from the Galactic Center and halo with the Super-Kamiokande detector, Physical Review D: Particles, Fields, Gravitation and Cosmology, Vol: 102, Pages: 072002 – 1-072002 – 14, ISSN: 1550-2368

We present a search for an excess of neutrino interactions due to dark matter in the form of weakly interacting massive particles (WIMPs) annihilating in the Galactic center or halo based on the data set of Super-Kamiokande-I, -II, -III and -IV taken from 1996 to 2016. We model the neutrino flux, energy, and flavor distributions assuming WIMP self-annihilation is dominant to ν¯ν, μ+μ−, b¯b, or W+W−. The excess is in comparison to atmospheric neutrino interactions which are modeled in detail and fit to data. Limits on the self-annihilation cross section ⟨σAV⟩ are derived for WIMP masses in the range 1 GeV to 10 TeV, reaching as low as 9.6×10−23  cm3 s−1 for 5 GeV WIMPs in b¯b mode and 1.2×10−24  cm3 s−1 for 1 GeV WIMPs in ν¯ν mode. The obtained sensitivity of the Super-Kamiokande detector to WIMP masses below several tens of GeV is the best among similar indirect searches to date.

Journal article

Kimura G, Nishimoto Y, Nakaoki T, Ito K, Kizawa Yet al., 2020, Establishment of Nontypeable Haemophilus influenzae airway infection murine model, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Fukuda Y, Akimoto K, Homma T, Baker JR, Ito K, Barnes PJ, Sagara Het al., 2020, Virus-Induced Asthma Exacerbations: SIRT1 Targeted Approach, JOURNAL OF CLINICAL MEDICINE, Vol: 9

Journal article

Ito K, Zhang Y, 2020, Fighting the common cold: ORMDL3 in the crosshairs?, American Journal of Respiratory Cell and Molecular Biology, Vol: 62, Pages: 676-677, ISSN: 1044-1549

Journal article

Ito K, Wu C-C, Chan KTF, Toumi R, Davis Cet al., 2020, Recent progress in the fundamental understanding of tropical cyclone motion, Journal of the Meteorological Society of Japan, Vol: 98, Pages: 5-17, ISSN: 0026-1165

While the fundamental understanding of tropical cyclone (TC) movement is fairly mature, notable advancements are still being made. This paper summarizes new concepts and updates to the existing fundamental theories on TC movement obtained from simplified barotropic models, full-physics models, and data analysis, particularly since 2014. The scope includes recent works on the interaction between a TC and its environment, and the predictability related to TC movement. Although conventional concepts of steering flow, β-gyre, and diabatic heating remain important, a more complete understanding of TC movement governing mechanisms can provide an important basis for further track forecast improvements.

Journal article

Tsilogianni Z, Baker JR, Papaporfyriou A, Papaioannou AI, Papathanasiou E, Koulouris NG, Daly L, Ito K, Hillas G, Papiris S, Bakakos P, Loukides Set al., 2020, Sirtuin 1: Endocan and Sestrin 2 in Different Biological Samples in Patients with Asthma. Does Severity Make the Difference?, JOURNAL OF CLINICAL MEDICINE, Vol: 9

Journal article

Bittner VA, Szarek M, Aylward PE, Bhatt DL, Diaz R, Edelberg JM, Fras Z, Goodman SG, Halvorsen S, Hanotin C, Harrington RA, Jukema JW, Loizeau V, Moriarty PM, Moryusef A, Pordy R, Roe MT, Sinnaeve P, Tsimikas S, Vogel R, White HD, Zahger D, Zeiher AM, Steg G, Schwartz GG, Aylward PE, Drexel H, Sinnaeve P, Dilic M, Lopes RD, Gotcheva NN, Goodman SG, Prieto J-C, Yong H, Lopez-Jaramillo P, Pecin I, Reiner Z, Ostadal P, Poulsen SH, Viigimaa M, Nieminen MS, Danchin N, Chumburidze V, Marx N, Liberopoulos E, Montenegro Valdovinos PC, Tse H-F, Kiss RG, Xavier D, Zahger D, Valgimigli M, Kimura T, Kim HS, Kim S-H, Erglis A, Laucevicius A, Kedev S, Yusoff K, Ramos Lopez GA, Alings M, Halvorsen S, Correa Flores RM, Sy RG, Budaj A, Morais J, Dorobantu M, Karpov Y, Ristic AD, Chua T, Murin J, Fras Z, Dalby AJ, Tunon J, de Silva HA, Hagstrom E, Muller C, Chiang C-E, Sritara P, Guneri S, Parkhomenko A, Ray KK, Moriarty PM, Vogel R, Chaitman B, Kelsey SF, Olsson AG, Rouleau J-L, Simoons ML, Alexander K, Meloni C, Rosenson R, Sijbrands EJG, Alexander JH, Armaganijan L, Bagai A, Bahit MC, Brennan JM, Clifton S, DeVore AD, Deloatch S, Dickey S, Dombrowski K, Ducrocq G, Eapen Z, Endsley P, Eppinger A, Hess CN, Hlatky MA, Jordan JD, Knowles JW, Kolls BJ, Kong DF, Leonardi S, Lillis L, Lopes RD, Maron DJ, Marcus J, Mathews R, Mehta RH, Mentz RJ, Moreira HG, Patel CB, Pereira SB, Perkins L, Povsic TJ, Puymirat E, Jones WS, Shah BR, Sherwood MW, Stringfellow K, Sujjavanich D, Toma M, Trotter C, van Diepen SFP, Wilson MD, Yan AT-K, Schiavi LB, Garrido M, Alvarisqueta AF, Sassone SA, Bordonava AP, Alves De Lima AE, Schmidberg JM, Duronto EA, Caruso OC, Novaretto LP, Angel Hominal M, Montana OR, Caccavo A, Gomez Vilamajo OA, Lorenzatti AJ, Cartasegna LR, Paterlini GA, Mackinnon IJ, Caime GD, Amuchastegui M, Codutti OR, Jure HO, Bono JOE, Hrabar AD, Vallejos JA, Ahuad Guerrero RA, Novoa F, Patocchi CA, Zaidman CJ, Giuliano ME, Dran RD, Vico ML, Carnero GS, Guzman PN, Medrano Allende JC, Garciaet al., 2020, Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 75, Pages: 133-144, ISSN: 0735-1097

Journal article

Kubo M, Toshikawa J, Kashikawa N, Chiang Y-K, Overzier R, Uchiyama H, Clements DL, Alexander DM, Matsuda Y, Kodama T, Ono Y, Goto T, Cheng T-A, Ito Ket al., 2019, Planck far-infrared detection of hyper suprime-cam protoclusters at z similar to 4: Hidden AGN and star formation activity, The Astrophysical Journal: an international review of astronomy and astronomical physics, Vol: 887, Pages: 1-20, ISSN: 0004-637X

We perform a stacking analysis of Planck, AKARI, Infrared Astronomical Satellite, Wide-field Infrared Survey Explorer, and Herschel images of the largest number of (candidate) protoclusters at z ~ 3.8 selected from the Hyper Suprime-Cam Subaru Strategic Program. Stacking the images of the 179 candidate protoclusters, the combined infrared (IR) emission of the protocluster galaxies in the observed 12–850 μm wavelength range is successfully detected with >5σ significance (at Planck). This is the first time that the average IR spectral energy distribution (SED) of a protocluster has been constrained at z ~ 4. The observed IR SEDs of the protoclusters exhibit significant excess emission in the mid-IR compared to that expected from typical star-forming galaxies (SFGs). They are reproduced well using SED models of intense starburst galaxies with warm/hot dust heated by young stars, or by a population of active galactic nucleus (AGN)/SFG composites. For the pure star-forming model, a total IR (from 8–1000 μm) luminosity of ${19.3}_{-4.2}^{+0.6}\times {10}^{13}\,{L}_{\odot }$ and a star formation rate of ${16.3}_{-7.8}^{+1.0}\times {10}^{3}\,{M}_{\odot }$ yr−1 are found, whereas for the AGN/SFG composite model, ${5.1}_{-2.5}^{+2.5}\times {10}^{13}\,{L}_{\odot }$ and ${2.1}_{-1.7}^{+6.3}\times {10}^{3}\,{M}_{\odot }$ yr−1 are found. Uncertainty remains in the total SFRs; however, the IR luminosities of the most massive protoclusters are likely to continue increasing up to z ~ 4. Meanwhile, no significant IR flux excess is observed around optically selected QSOs at similar redshifts, which confirms previous results. Our results suggest that the z ~ 4 protoclusters trace dense, intensely star-forming environments that may also host obscured AGNs missed by the selection in the optical.

Journal article

Knobloch J, Jungck D, Kronsbein J, Stoelben E, Ito K, Koch Aet al., 2019, LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD, JOURNAL OF CLINICAL MEDICINE, Vol: 8

Journal article

Roe MT, Li QH, Bhatt DL, Bittner VA, Diaz R, Goodman SG, Harrington RA, Jukema JW, Lopez-Jaramillo P, Lopes RD, Louie MJ, Moriarty PM, Szarek M, Vogel R, White HD, Zeiher AM, Baccara-Dinet MT, Steg PG, Schwartz GG, Steg PG, Bhatt DL, Bittner VA, Diaz R, Goodman SG, Harrington RA, Jukema JW, Szarek M, Zeiher AM, Tricoci P, Roe MT, Mahaffey KW, Edelberg JM, Hanotin C, Lecorps G, Moryusef A, Pordy R, Sasiela WJ, Tamby J-F, Aylward PE, Drexel H, Sinnaeve P, Dilic M, Gotcheva NN, Goodman SG, Prieto J-C, Yong H, Lopez-Jaramillo P, Pecin I, Reiner Z, Ostadal P, Poulsen SH, Viigimaa M, Nieminen MS, Danchin N, Chumburidze V, Marx N, Liberopoulos E, Valdovinos PCM, Tse H-F, Kiss RG, Xavier D, Zahger D, Valgimigli M, Kimura T, Kim HS, Kim S-H, Kedev S, Erglis A, Laucevicius A, Yusoff K, Lopez R, Ramos Lopez GA, Alings M, Halvorsen S, Correa Flores RM, Sy RG, Budaj A, Morais J, Dorobantu M, Karpov Y, Ristic AD, Chua T, Murin J, Fras Z, Dalby AJ, Tunon J, de Silva HA, Hagstrom E, Muller C, Chiang C-E, Sritara P, Guneri S, Parkhomenko A, Ray KK, Moriarty PM, Roe MT, Chaitman B, Kelsey SF, Olsson AG, Rouleau J-L, Simoons ML, Alexander K, Meloni C, Rosenson R, Sijbrands EJG, Alexander JH, Armaganijan L, Bagai A, Bahit MC, Brennan JM, Clifton S, DeVore AD, Deloatch S, Dickey S, Dombrowski K, Ducrocq G, Eapen Z, Endsley P, Eppinger A, Harrison RW, Hess CN, Hlatky MA, Jordan JD, Knowles JW, Kolls BJ, Kong DF, Leonardi S, Lillis L, Maron DJ, Marcus J, Mathews R, Mehta RH, Mentz RJ, Moreira HG, Patel CB, Pereira SB, Perkins L, Povsic TJ, Puymirat E, Jones WS, Shah BR, Sherwood MW, Stringfellow K, Sujjavanich D, Toma M, Van Diepen SFP, Wilson MD, Yan AT-K, Lopes RD, Trotter C, Schiavi LB, Garrido M, Alvarisqueta AF, Sassone SA, Bordonava AP, Alves De Lima AE, Schmidberg JM, Duronto EA, Caruso OC, Novaretto LP, Angel Hominal M, Montana OR, Caccavo A, Gomez Vilamajo OA, Lorenzatti AJ, Cartasegna LR, Paterlini GA, Mackinnon IJ, Caime GD, Amuchastegui M, Salomone R, Codutti OR, Jure HO, Bonoet al., 2019, Risk categorization using New American College of Cardiology/American Heart Association guidelines for cholesterol management and its relation to alirocumab treatment following acute coronary syndromes, Circulation, Vol: 140, Pages: 1578-1589, ISSN: 0009-7322

Background:The 2018 US cholesterol management guidelines recommend additional lipid-lowering therapies for secondary prevention in patients with low-density lipoprotein cholesterol ≥70 mg/dL or non−high-density lipoprotein cholesterol ≥100 mg/dL despite maximum tolerated statin therapy. Such patients are considered at very high risk (VHR) based on a history of >1 major atherosclerotic cardiovascular disease (ASCVD) event or a single ASCVD event and multiple high-risk conditions. We investigated the association of US guideline-defined risk categories with the occurrence of ischemic events after acute coronary syndrome and reduction of those events by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.Methods:In the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), patients with recent acute coronary syndrome and residual dyslipidemia despite optimal statin therapy were randomly assigned to alirocumab or placebo. The primary trial outcome (major adverse cardiovascular events, ie, coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) was examined according to American College of Cardiology/American Heart Association risk category.Results:Of 18 924 participants followed for a median of 2.8 years, 11 935 (63.1%) were classified as VHR: 4450 (37.3%) had multiple prior ASCVD events and 7485 (62.7%) had 1 major ASCVD event and multiple high-risk conditions. Major adverse cardiovascular events occurred in 14.4% of placebo-treated patients at VHR versus 5.6% of those not at VHR. In the VHR category, major adverse cardiovascular events occurred in 20.4% with multiple prior ASCVD events versus 10.7% with 1 ASCVD event and multiple high-risk conditions. Alirocumab was associated with consistent relative risk reductions in both risk categories (hazard ratio=0.84 for VHR; hazard rati

Journal article

Szarek M, Steg PG, DiCenso D, Bhatt DL, Bittner VA, Budaj A, Diaz R, Goodman SG, Gotcheva N, Jukema JW, Pordy R, Roe MT, Sourdille T, White HD, Xavier D, Zeiher AM, Schwartz GG, Steg PG, Bhatt DL, Bittner VA, Diaz R, Goodman SG, Harrington RA, Jukema JW, Szarek M, Zeiher AM, Tricoci P, Roe MT, Mahaffey KW, Edelberg JM, Hanotin C, Lecorps G, Moryusef A, Pordy R, Sasiela WJ, Tamby J-F, Aylward PE, Drexel H, Sinnaeve P, Dilic M, Gotcheva NN, Goodman SG, Prieto J-C, Yong H, Lopez-Jaramillo P, Pecin I, Reiner Z, Ostadal P, Poulsen SH, Viigimaa M, Nieminen MS, Danchin N, Chumburidze V, Marx N, Liberopoulos E, Valdovinos PCM, Tse H-F, Kiss RG, Xavier D, Zahger D, Valgimigli M, Kimura T, Kim HS, Kim S-H, Kedev S, Erglis A, Laucevicius A, Yusoff K, Lopez R, Ramos Lopez GA, Alings M, Halvorsen S, Correa Flores RM, Sy RG, Budaj A, Morais J, Dorobantu M, Karpov Y, Ristic AD, Chua T, Murin J, Fras Z, Dalby AJ, Tunon J, de Silva HA, Hagstrom E, Muller C, Chiang C-E, Sritara P, Guneri S, Parkhomenko A, Ray KK, Moriarty PM, Roe MT, Chaitman B, Kelsey SF, Olsson AG, Rouleau J-L, Simoons ML, Alexander K, Meloni C, Rosenson R, Sijbrands EJG, Alexander JH, Armaganijan L, Bagai A, Bahit MC, Brennan JM, Clifton S, DeVore AD, Deloatch S, Dickey S, Dombrowski K, Ducrocq G, Eapen Z, Endsley P, Eppinger A, Harrison RW, Hess CN, Hlatky MA, Jordan JD, Knowles JW, Kolls BJ, Kong DF, Leonardi S, Lillis L, Maron DJ, Marcus J, Mathews R, Mehta RH, Mentz RJ, Moreira HG, Patel CB, Pereira SB, Perkins L, Povsic TJ, Puymirat E, Jones WS, Shah BR, Sherwood MW, Stringfellow K, Sujjavanich D, Toma M, Van Diepen SFP, Wilson MD, Yan AT-K, Lopes RD, Trotter C, Schiavi LB, Garrido M, Alvarisqueta AF, Sassone SA, Bordonava AP, Alves De Lima AE, Schmidberg JM, Duronto EA, Caruso OC, Novaretto LP, Angel Hominal M, Montana OR, Caccavo A, Gomez Vilamajo OA, Lorenzatti AJ, Cartasegna LR, Paterlini GA, Mackinnon IJ, Caime GD, Amuchastegui M, Salomone R, Codutti OR, Jure HO, Bono JOE, Hrabar AD, Vallejos JA, Ahuad Get al., 2019, Alirocumab Reduces Total Hospitalizations and Increases Days Alive and Out of Hospital in the ODYSSEY OUTCOMES Trial, CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES, Vol: 12, ISSN: 1941-7705

Journal article

Colley T, Sharma C, Alanio A, Kimura G, Daly L, Nakaoki T, Nishimoto Y, Bretagne S, Kizawa Y, Strong P, Rapeport G, Ito K, Meis JF, Chowdhary Aet al., 2019, Anti-fungal activity of a novel triazole, PC1244, against emerging azole-resistant Aspergillus fumigatus and other species of Aspergillus, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 74, Pages: 2950-2958, ISSN: 0305-7453

Journal article

Rudramurthy SM, Colley T, Abdolrasouli A, Ashman J, Dhaliwal M, Kaur H, Armstrong-James D, Strong P, Rapeport G, Schelenz S, Ito K, Chakrabarti Aet al., 2019, In vitro antifungal activity of a novel topical triazole PC945 against emerging yeast Candida auris, Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 2943-2949, ISSN: 0305-7453

ObjectivesManagement of Candida auris infection is difficult as this yeast exhibits resistance to different classes of antifungals, necessitating the development of new antifungals. The aim of this study was to investigate the susceptibility of C. auris to a novel antifungal triazole, PC945, optimized for topical delivery.MethodsA collection of 50 clinical isolates was obtained from a tertiary care hospital in North India. Nine isolates from the UK, 10 from a CDC panel (USA) and 3 from the CBS-KNAW culture collection (Japanese and South Korean isolates) were also obtained. MICs (azole endpoint) of PC945 and other triazoles were determined in accordance with CLSI M27 (third edition). Quality control strains were included [Candida parapsilosis (ATCC 22019) and Candida krusei (ATCC 6258)].ResultsSeventy-four percent of isolates tested showed reduced susceptibility to fluconazole (≥64 mg/L). PC945 (geometric mean MIC = 0.058 mg/L) was 7.4-fold and 1.5-fold more potent than voriconazole and posaconazole, respectively (both P < 0.01). PC945 MIC values correlated with those of voriconazole or posaconazole, and only three isolates were found to be cross-resistant between PC945 and other azoles. ERG11 sequence analysis revealed several mutations, but no correlation could be established with the MIC of PC945. Tentative epidemiological cut-off values (ECOFFs) evaluated by CLSI’s ECOFF Finder (at 99%) with 24 h reading of MICs were 1, 4 and 1 mg/L for PC945, voriconazole and posaconazole, respectively. MIC values for quality control strains of all triazoles were in the normal ranges.ConclusionsPC945 was found to be a more potent inhibitor than posaconazole, voriconazole and fluconazole of C. auris isolates collected globally, warranting further laboratory and clinical evaluations.

Journal article

Nishimoto Y, Yasuda H, Masuko K, Usui Y, Ueda K, Kimura G, Ito K, Kizawa Yet al., 2019, The Involvement of Src in Airway Inflammation Induced by Repeated Exposure to Lipopolysaccharide in Mice, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, Vol: 139, Pages: 1211-1217, ISSN: 0031-6903

Journal article

Colley T, Sehra G, Daly L, Kimura G, Nakaoki T, Nishimoto Y, Kizawa Y, Strong P, Rapeport G, Ito Ket al., 2019, Antifungal synergy of a topical triazole, PC945, with a systemic triazole against respiratory Aspergillus fumigatus infection, SCIENTIFIC REPORTS, Vol: 9, ISSN: 2045-2322

Journal article

Nishimoto Y, Iwamoto I, Suzuki A, Ueda K, Kimura G, Ito K, Kizawa Yet al., 2019, TNF-alpha Decreased Corticosteroid Responsiveness in Mice Models of Airway Inflammation Induced by Double Strand RNA and/or Tobacco Smoke Exposure, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, Vol: 139, Pages: 955-961, ISSN: 0031-6903

Journal article

Strong P, Ito K, Murray J, Rapeport Get al., 2018, Current approaches to the discovery of novel inhaled medicines, DRUG DISCOVERY TODAY, Vol: 23, Pages: 1705-1717, ISSN: 1359-6446

Journal article

Tregoning JS, Mallia P, Webber J, Gill SK, Trujillo-Torralbo, Calderazzo MA, Finney L, Bakhsoliani E, Farne H, Singanayagam A, Footitt J, Hewitt R, Kebadze, Aniscenko J, Padmanaban V, Molyneaux PL, Adcock, Barnes PJ, Ito K, Elkin SL, Kon OM, Cookson WO, MOffatt MF, Johnston SLet al., 2018, Role of airway glucose in bacterial infections in chronic obstructive pulmonary disease, Journal of Allergy and Clinical Immunology, Vol: 142, Pages: 815-823.e6, ISSN: 0091-6749

BackgroundPatients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to respiratory tract infection, which contributes to disease progression and mortality, but mechanisms of increased susceptibility to infection remain unclear.ObjectivesThe aim of this study was to determine whether glucose concentrations were increased in airway samples (nasal lavage fluid, sputum, and bronchoalveolar lavage fluid) from patients with stable COPD and to determine the effects of viral infection on sputum glucose concentrations and how airway glucose concentrations relate to bacterial infection.MethodsWe measured glucose concentrations in airway samples collected from patients with stable COPD and smokers and nonsmokers with normal lung function. Glucose concentrations were measured in patients with experimentally induced COPD exacerbations, and these results were validated in patients with naturally acquired COPD exacerbations. Relationships between sputum glucose concentrations, inflammatory markers, and bacterial load were examined.ResultsSputum glucose concentrations were significantly higher in patients with stable COPD compared with those in control subjects without COPD. In both experimental virus-induced and naturally acquired COPD exacerbations, sputum and nasal lavage fluid glucose concentrations were increased over baseline values. There were significant correlations between sputum glucose concentrations and sputum inflammatory markers, viral load, and bacterial load. Airway samples with higher glucose concentrations supported more Pseudomonas aeruginosa growth in vitro.ConclusionsAirway glucose concentrations are increased in patients with stable COPD and further increased during COPD exacerbations. Increased airway glucose concentrations might contribute to bacterial infections in both patients with stable and those with exacerbated COPD. This has important implications for the development of nonantibiotic therapeutic strategies for the prev

Journal article

Maneechotesuwan K, Yao X, Ito K, Jazrawi E, Usmani OS, Adcock IM, Barnes PJet al., 2018, Correction: Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease, PLoS Medicine, Vol: 15, ISSN: 1549-1277

[This corrects the article DOI: 10.1371/journal.pmed.1000076.].

Journal article

Baker J, Vuppusetty C, Colley T, Hassibi S, Fenwick P, Donnelly L, Ito K, Barnes Pet al., 2018, MicroRNA-570 is a novel regulator of cellular senescence and inflammaging, FASEB Journal, ISSN: 0892-6638

Diseases of accelerated aging often occur together (multimorbidity), and their prevalence is increasing, with high societal and health care costs. Chronic obstructive pulmonary disease (COPD) is one such condition, in which one half of patients exhibit ≥4 age-related diseases. Diseases of accelerated aging share common molecular pathways, which lead to the detrimental accumulation of senescent cells. These senescent cells no longer divide but release multiple inflammatory proteins, known as the senescence-associated secretory phenotype, which may perpetuate and speed disease. Here, we show that inhibiting miR-570-3p, which is increased in COPD cells, reverses cellular senescence by restoring the antiaging molecule sirtuin-1. MiR-570-3p is induced by oxidative stress in airway epithelial cells through p38 MAP kinase-c-Jun signaling and drives senescence by inhibiting sirtuin-1. Inhibition of elevated miR-570-3p in COPD small airway epithelial cells, using an antagomir, restores sirtuin-1 and suppresses markers of cellular senescence (p16INK4a, p21Waf1, and p27Kip1), thereby restoring cellular growth by allowing progression through the cell cycle. MiR-570-3p inhibition also suppresses the senescence-associated secretory phenotype (matrix metalloproteinases-2/9, C-X-C motif chemokine ligand 8, IL-1β, and IL-6). Collectively, these data suggest that inhibiting miR-570-3p rejuvenates cells via restoration of sirtuin-1, reducing many of the abnormalities associated with cellular senescence.—Baker, J. R., Vuppusetty, C., Colley, T., Hassibi, S., Fenwick, P. S., Donnelly, L. E., Ito, K., Barnes, P. J. MicroRNA-570 is a novel regulator of cellular senescence and inflammaging.

Journal article

Brookes DW, Coates M, Allen H, Daly L, Constant S, Huang S, Hows M, Davis A, Cass L, Ayrton J, Knowles I, Strong P, Rapeport G, Ito Ket al., 2018, Late therapeutic intervention with a respiratory syncytial virus L-protein polymerase inhibitor, PC786, on respiratory syncytial virus infection in human airway epithelium, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 175, Pages: 2520-2534, ISSN: 0007-1188

Journal article

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