43 results on '"Whitwell, Harry"'
Search Results
2. Maternal PIGF and umbilical Dopplers predict pregnancy outcomes at diagnosis of early-onset fetal growth restriction
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Spencer, Rebecca, Maksym, Kasia, Hecher, Kurt, Marsal, Karel, Figueras, Francesc, Ambler, Gareth, Whitwell, Harry, Nene, Nuno Rocha, Sebire, Neil J., Hansson, Stefan R., Brodszki, Anke DiemerJana, Gratacos, Eduard, Ginsberg, Yuval, Weissbach, Tal, Peebles, Donald M., Zachary, Ian, Marlow, Neil, Huertas-Ceballos, Angela, and David, Anna L.
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Infants -- Patient outcomes ,Medical research -- Analysis -- Health aspects ,Medicine, Experimental -- Analysis -- Health aspects ,Fetus -- Growth ,Mass spectrometry -- Health aspects -- Analysis ,Liquid chromatography -- Health aspects -- Analysis ,Pregnant women -- Prognosis ,Infants (Newborn) -- Prognosis ,Blood proteins -- Health aspects -- Growth -- Analysis ,Company growth ,Health care industry - Abstract
BACKGROUND. Severe, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth. METHODS. Women with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data. RESULTS. The most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94). CONCLUSION. Ultrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians. TRIAL REGISTRATION. ClinicalTrials.gov NCT02097667. FUNDING. The European Union, Rosetrees Trust, Mitchell Charitable Trust., Introduction The survival and growth of a fetus depends on placental provision of nutrients and waste exchange with the mother. When this system is impaired by inadequate transformation of the [...]
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- 2023
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3. Serum biomarker-based early detection of pancreatic ductal adenocarcinomas with ensemble learning
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Nené, Nuno R., Ney, Alexander, Nazarenko, Tatiana, Blyuss, Oleg, Johnston, Harvey E., Whitwell, Harry J., Sedlak, Eva, Gentry-Maharaj, Aleksandra, Apostolidou, Sophia, Costello, Eithne, Greenhalf, William, Jacobs, Ian, Menon, Usha, Hsuan, Justin, Pereira, Stephen P., Zaikin, Alexey, and Timms, John F.
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- 2023
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4. An organ-on-chip model of pulmonary arterial hypertension identifies a BMPR2-SOX17-prostacyclin signalling axis
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Ainscough, Alexander J., Smith, Timothy J., Haensel, Maike, Rhodes, Christopher J., Fellows, Adam, Whitwell, Harry J., Vasilaki, Eleni, Gray, Kelly, Freeman, Adrian, Howard, Luke S., Wharton, John, Dunmore, Benjamin, Upton, Paul D., Wilkins, Martin R., Edel, Joshua B., and Wojciak-Stothard, Beata
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- 2022
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5. FANS Unfixed: Isolation and Proteomic Analysis of Mouse Cell Type-Specific Brain Nuclei.
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Bedwell, Lucy, Mavrotas, Myrto, Demchenko, Nikita, Yaa, Reuben M., Willis, Brittannie, Demianova, Zuzana, Syed, Nelofer, Whitwell, Harry J., and Nott, Alexi
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- 2024
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6. Identification of a serum proteomic biomarker panel using diagnosis specific ensemble learning and symptoms for early pancreatic cancer detection.
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Ney, Alexander, Nené, Nuno R., Sedlak, Eva, Acedo, Pilar, Blyuss, Oleg, Whitwell, Harry J., Costello, Eithne, Gentry-Maharaj, Aleksandra, Williams, Norman R., Menon, Usha, Fusai, Giuseppe K., Zaikin, Alexey, and Pereira, Stephen P.
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EARLY detection of cancer ,BILIARY tract ,PANCREATIC duct ,SYMPTOMS ,BIOMARKERS - Abstract
Background: The grim (<10% 5-year) survival rates for pancreatic ductal adenocarcinoma (PDAC) are attributed to its complex intrinsic biology and most often late-stage detection. The overlap of symptoms with benign gastrointestinal conditions in early stage further complicates timely detection. The suboptimal diagnostic performance of carbohydrate antigen (CA) 19–9 and elevation in benign hyperbilirubinaemia undermine its reliability, leaving a notable absence of accurate diagnostic biomarkers. Using a selected patient cohort with benign pancreatic and biliary tract conditions we aimed to develop a data analysis protocol leading to a biomarker signature capable of distinguishing patients with non-specific yet concerning clinical presentations, from those with PDAC. Methods: 539 patient serum samples collected under the Accelerated Diagnosis of neuro Endocrine and Pancreatic TumourS (ADEPTS) study (benign disease controls and PDACs) and the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS, healthy controls) were screened using the Olink Oncology II panel, supplemented with five in-house markers. 16 specialized base-learner classifiers were stacked to select and enhance biomarker performances and robustness in blinded samples. Each base-learner was constructed through cross-validation and recursive feature elimination in a discovery set comprising approximately two thirds of the ADEPTS and UKCTOCS samples and contrasted specific diagnosis with PDAC. Results: The signature which was developed using diagnosis-specific ensemble learning demonstrated predictive capabilities outperforming CA19-9, the only biomarker currently accepted by the FDA and the National Comprehensive Cancer Network guidelines for pancreatic cancer, and other individual biomarkers and combinations in both discovery and held-out validation sets. An AUC of 0.98 (95% CI 0.98–0.99) and sensitivity of 0.99 (95% CI 0.98–1) at 90% specificity was achieved with the ensemble method, which was significantly larger than the AUC of 0.79 (95% CI 0.66–0.91) and sensitivity 0.67 (95% CI 0.50–0.83), also at 90% specificity, for CA19-9, in the discovery set (p = 0.0016 and p = 0.00050, respectively). During ensemble signature validation in the held-out set, an AUC of 0.95 (95% CI 0.91–0.99), sensitivity 0.86 (95% CI 0.68–1), was attained compared to an AUC of 0.80 (95% CI 0.66–0.93), sensitivity 0.65 (95% CI 0.48–0.56) at 90% specificity for CA19-9 alone (p = 0.0082 and p = 0.024, respectively). When validated only on the benign disease controls and PDACs collected from ADEPTS, the diagnostic-specific signature achieved an AUC of 0.96 (95% CI 0.92–0.99), sensitivity 0.82 (95% CI 0.64–0.95) at 90% specificity, which was still significantly higher than the performance for CA19-9 taken as a single predictor, AUC of 0.79 (95% CI 0.64–0.93) and sensitivity of 0.18 (95% CI 0.03–0.69) (p = 0.013 and p = 0.0055, respectively). Conclusion: Our ensemble modelling technique outperformed CA19-9, individual biomarkers and indices developed with prevailing algorithms in distinguishing patients with non-specific but concerning symptoms from those with PDAC, with implications for improving its early detection in individuals at risk. Author summary: Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates among cancers, primarily due to its complex biology and late-stage diagnosis. Early symptoms often mimic benign gastrointestinal conditions, complicating timely detection. The standard biomarker, carbohydrate antigen (CA) 19–9, is not reliable due to its suboptimal performance and elevation in benign conditions, highlighting the need for better diagnostic tools. In our study, we aimed to develop a biomarker signature to distinguish between benign pancreatic/biliary conditions and PDAC using serum samples from the Accelerated Diagnosis of neuro Endocrine and Pancreatic Tumours and UK Collaborative Trial of Ovarian Cancer Screening studies. We screened 539 patient serum samples with state-of-the-art biomarker panels and developed a robust predictive signature by applying specialized machine learning methods. This new signature significantly outperformed CA19-9 and other panels reported in the literature. Our findings suggest that this new biomarker signature can improve early detection of PDAC in patients with ambiguous clinical symptoms, potentially leading to better outcomes for those at risk. [ABSTRACT FROM AUTHOR]
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- 2024
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7. A time-resolved proteomic and prognostic map of COVID-19
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Kleinschmidt, Malte, Heim, Katrin M., Millet, Belén, Meyer-Arndt, Lil, Hübner, Ralf H., Andermann, Tim, Doehn, Jan M., Opitz, Bastian, Sawitzki, Birgit, Grund, Daniel, Radünzel, Peter, Schürmann, Mariana, Zoller, Thomas, Alius, Florian, Knape, Philipp, Breitbart, Astrid, Li, Yaosi, Bremer, Felix, Pergantis, Panagiotis, Schürmann, Dirk, Temmesfeld-Wollbrück, Bettina, Wendisch, Daniel, Brumhard, Sophia, Haenel, Sascha S., Conrad, Claudia, Georg, Philipp, Eckardt, Kai-Uwe, Lehner, Lukas, Kruse, Jan M., Ferse, Carolin, Körner, Roland, Spies, Claudia, Edel, Andreas, Weber-Carstens, Steffen, Krannich, Alexander, Zvorc, Saskia, Li, Linna, Behrens, Uwe, Schmidt, Sein, Rönnefarth, Maria, Dang-Heine, Chantip, Röhle, Robert, Lieker, Emma, Kretzler, Lucie, Wirsching, Isabelle, Wollboldt, Christian, Wu, Yinan, Schwanitz, Georg, Hillus, David, Kasper, Stefanie, Olk, Nadine, Horn, Alexandra, Briesemeister, Dana, Treue, Denise, Hummel, Michael, Corman, Victor M., Drosten, Christian, von Kalle, Christof, Demichev, Vadim, Tober-Lau, Pinkus, Lemke, Oliver, Nazarenko, Tatiana, Thibeault, Charlotte, Whitwell, Harry, Röhl, Annika, Freiwald, Anja, Szyrwiel, Lukasz, Ludwig, Daniela, Correia-Melo, Clara, Aulakh, Simran Kaur, Helbig, Elisa T., Stubbemann, Paula, Lippert, Lena J., Grüning, Nana-Maria, Blyuss, Oleg, Vernardis, Spyros, White, Matthew, Messner, Christoph B., Joannidis, Michael, Sonnweber, Thomas, Klein, Sebastian J., Pizzini, Alex, Wohlfarter, Yvonne, Sahanic, Sabina, Hilbe, Richard, Schaefer, Benedikt, Wagner, Sonja, Mittermaier, Mirja, Machleidt, Felix, Garcia, Carmen, Ruwwe-Glösenkamp, Christoph, Lingscheid, Tilman, Bosquillon de Jarcy, Laure, Stegemann, Miriam S., Pfeiffer, Moritz, Jürgens, Linda, Denker, Sophy, Zickler, Daniel, Enghard, Philipp, Zelezniak, Aleksej, Campbell, Archie, Hayward, Caroline, Porteous, David J., Marioni, Riccardo E., Uhrig, Alexander, Müller-Redetzky, Holger, Zoller, Heinz, Löffler-Ragg, Judith, Keller, Markus A., Tancevski, Ivan, Timms, John F., Zaikin, Alexey, Hippenstiel, Stefan, Ramharter, Michael, Witzenrath, Martin, Suttorp, Norbert, Lilley, Kathryn, Mülleder, Michael, Sander, Leif Erik, Ralser, Markus, and Kurth, Florian
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- 2021
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8. Nanoparticles, their protein corona and impact on the immune function of human lung cells
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Whitwell, Harry James, Madsen, Jens, Clark, Howard, and Warner, Jane
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616.2 - Abstract
Particles with a single dimension smaller than 100 nm are called nanoparticles (NPs). There is a large amount of epidemiology that anthropogenic particles cause increased mortality, increased risk of asthma and increased incidence of lung adenocarcinoma. Inhaled NPs can reach the lung terminus, interacting with a lipid lining at the air-liquid interface (pulmonary surfactant (PSf)) and with an aqueous hydrophase beneath. Studies in serum have shown that upon contact with blood, proteins very rapidly adsorb to the particle surface, thus the particle accrues a biological identity. However, no such interaction studies have been performed in the pulmonary system, where there is a complex interplay of proteins and lipids. The interaction of NPs with PSf is poorly understood. Prior to reaching the lung epithelium, NPs must translocate through this layer. The aims of this thesis are to firstly explore the interactions of NPs with proteins and lipids in the lung and secondly investigate the toxicity and effect on the immunological action of lung cells. NPs were incubated with pulmonary lavage fluid and adsorbed proteins were analysed using state-of-the-art, high resolution, quantitative mass spectrometry. To investigate the interactions of NPs with PSf, particles were incubated with a porcine surfactant. The bound lipids were analysed by qualitative mass spectrometry. The effect of NPs and the NP-protein-corona was investigated in cell lines by a number of techniques. Unique proteins were observed on each particle type, however the main contributors contribution was from a few key proteins. There was no biophysical property of these bound proteins that could predict their affinity to a particle. Surfactant associated protein A, B and D (SP-A, B, D) were observed to be bound to the particle surface. SP-A was bound with high abundance, suggesting it is likely these particles may interfere with PSf in vivo. All particles retained lipids on their surface through binding mediated by electrostatic interactions. Aminated-polystyrene and titanium dioxide NPs were capable of interfering with PSf in vitro. There was little observed effect of the particles to induce inflammation. The key findings suggest that the protein corona does not predict particle toxicity. Any observed effect is due to the core particle chemistry, not an acquired bio-identity. The toxicity of particles observed through epidemiological surveys could be caused from the inhibition of pulmonary surfactant, not from direct toxicity of the particles themselves.
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- 2016
9. Generation of novel trimeric fragments of human SP-A and SP-D after recombinant soluble expression in E. coli
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Watson, Alastair, Sørensen, Grith L., Holmskov, Uffe, Whitwell, Harry J., Madsen, Jens, and Clark, Howard
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- 2020
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10. Improved early detection of ovarian cancer using longitudinal multimarker models
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Whitwell, Harry J., Worthington, Jenny, Blyuss, Oleg, Gentry-Maharaj, Aleksandra, Ryan, Andy, Gunu, Richard, Kalsi, Jatinderpal, Menon, Usha, Jacobs, Ian, Zaikin, Alexey, and Timms, John F.
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- 2020
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11. Characterization of emergent toxigenic M1UK Streptococcus pyogenes and associated sublineages
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Li, Ho Kwong, primary, Zhi, Xiangyun, additional, Vieira, Ana, additional, Whitwell, Harry J., additional, Schricker, Amelia, additional, Jauneikaite, Elita, additional, Li, Hanqi, additional, Yosef, Ahmed, additional, Andrew, Ivan, additional, Game, Laurence, additional, Turner, Claire E., additional, Lamagni, Theresa, additional, Coelho, Juliana, additional, and Sriskandan, Shiranee, additional
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- 2023
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12. Commentary on “The road to reliable peptide assays is paved with good guidelines”
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Kowalka, Anna M., primary, Alexiadou, Kleopatra, additional, Cuenco, Joyceline, additional, Clarke, Rosemary E., additional, Camuzeaux, Stephane, additional, Minnion, James, additional, Williams, Emma L., additional, Bech, Paul, additional, Purkayastha, Sanjay, additional, Ahmed, Ahmed R., additional, Takats, Zoltan, additional, Khoo, Bernard, additional, Whitwell, Harry J., additional, Romero, Maria G., additional, Bloom, Stephen R., additional, Lewis, Matthew R., additional, and Tan, Tricia M.‐M., additional
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- 2023
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13. The postprandial secretion of peptide YY1‐36 and 3‐36 in obesity is differentially increased after gastric bypass versus sleeve gastrectomy.
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Kowalka, Anna M., Alexiadou, Kleopatra, Cuenco, Joyceline, Clarke, Rosemary E., Minnion, James, Williams, Emma L., Bech, Paul, Purkayastha, Sanjay, Ahmed, Ahmed R., Takats, Zoltan, Whitwell, Harry J., Romero, Maria Gomez, Bloom, Stephen R., Camuzeaux, Stephane, Lewis, Matthew R., Khoo, Bernard, and Tan, Tricia M.‐M.
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GASTRIC bypass ,SLEEVE gastrectomy ,PEPTIDES ,LIQUID chromatography-mass spectrometry ,SECRETION ,APPETITE stimulants - Abstract
Objectives: Peptide tyrosine tyrosine (PYY) exists as two species, PYY1‐36 and PYY3‐36, with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY1‐36 and PYY3‐36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux‐en‐Y gastric bypass (RYGB) on fasting and postprandial PYY1‐36 and PYY3‐36 secretion using a newly developed liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) assay. Design and Subjects: Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY1‐36 and PYY3‐36 concentrations. Results: Presurgery, the fasting and postprandial levels of PYY1‐36 and PYY3‐36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY1‐36 and PYY3‐36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG. Conclusions: There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY1‐36 and PYY3‐36, which may account for long‐term differences in efficacy and adverse effects between the two types of surgery. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Ultrasound and biochemical predictors of pregnancy outcome at diagnosis of early-onset fetal growth restriction
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Spencer, Rebecca, primary, Maksym, Kasia, additional, Hecher, Kurt, additional, Maršál, Karel, additional, Figueras, Francesc, additional, Ambler, Gareth, additional, Whitwell, Harry, additional, Nené, Nuno Rocha, additional, Sebire, Neil J., additional, Hansson, Stefan R., additional, Diemert, Anke, additional, Brodszki, Jana, additional, Gratacós, Eduard, additional, Ginsberg, Yuval, additional, Weissbach, Tal, additional, Peebles, Donald M, additional, Zachary, Ian, additional, Marlow, Neil, additional, Huertas-Ceballos, Angela, additional, and David, Anna L., additional
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- 2023
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15. Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension
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Alzaydi, Mai M., primary, Abdul-Salam, Vahitha B., additional, Whitwell, Harry J., additional, Russomanno, Giusy, additional, Glynos, Angelos, additional, Capece, Daria, additional, Szabadkai, Gyorgy, additional, Wilkins, Martin R., additional, and Wojciak-Stothard, Beata, additional
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- 2023
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16. Characterisation of emergent toxigenic M1UKStreptococcus pyogenesand associated sublineages
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Li, Ho Kwong, primary, Zhi, Xiangyun, additional, Vieira, Ana, additional, Whitwell, Harry J, additional, Schricker, Amelia, additional, Jauneikaite, Elita, additional, Li, Hanqi, additional, Yosef, Ahmed, additional, Andrew, Ivan, additional, Game, Laurence, additional, Turner, Claire E., additional, Lamagni, Theresa, additional, Coelho, Juliana, additional, and Sriskandan, Shiranee, additional
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- 2022
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17. The postprandial secretion of peptide YY 1‐36 and 3‐36 in obesity is differentially increased after gastric bypass versus sleeve gastrectomy
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Kowalka, Anna M., primary, Alexiadou, Kleopatra, additional, Cuenco, Joyceline, additional, Clarke, Rosemary E., additional, Minnion, James, additional, Williams, Emma L., additional, Bech, Paul, additional, Purkayastha, Sanjay, additional, Ahmed, Ahmed R., additional, Takats, Zoltan, additional, Whitwell, Harry J., additional, Romero, Maria Gomez, additional, Bloom, Stephen R., additional, Camuzeaux, Stephane, additional, Lewis, Matthew R., additional, Khoo, Bernard, additional, and Tan, Tricia M.‐M., additional
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- 2022
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18. Nanoparticle growth and surface chemistry changes in cell-conditioned culture medium
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Kendall, Michaela, Hodges, Nikolas J., Whitwell, Harry, Tyrrell, Jess, and Cangul, Hakan
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- 2015
19. A proteomic survival predictor for COVID-19 patients in intensive care
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Demichev, Vadim, Tober-Lau, Pinkus, Nazarenko, Tatiana, Lemke, Oliver, Kaur Aulakh, Simran, Whitwell, Harry J, Röhl, Annika, Freiwald, Anja, Mittermaier, Mirja, Szyrwiel, Lukasz, Ludwig, Daniela, Correia-Melo, Clara, Lippert, Lena J, Helbig, Elisa T, Stubbemann, Paula, Olk, Nadine, Thibeault, Charlotte, Grüning, Nana-Maria, Blyuss, Oleg, Vernardis, Spyros, White, Matthew, Messner, Christoph B, Joannidis, Michael, Sonnweber, Thomas, Klein, Sebastian J, Pizzini, Alex, Wohlfarter, Yvonne, Sahanic, Sabina, Hilbe, Richard, Schaefer, Benedikt, Wagner, Sonja, Machleidt, Felix, Garcia, Carmen, Ruwwe-Glösenkamp, Christoph, Lingscheid, Tilman, Bosquillon De Jarcy, Laure, Stegemann, Miriam S, Pfeiffer, Moritz, Jürgens, Linda, Denker, Sophy, Zickler, Daniel, Spies, Claudia, Edel, Andreas, Müller, Nils B, Enghard, Philipp, Zelezniak, Aleksej, Bellmann-Weiler, Rosa, Weiss, Günter, Campbell, Archie, Hayward, Caroline, Porteous, David J, Marioni, Riccardo E, Uhrig, Alexander, Zoller, Heinz, Löffler-Ragg, Judith, Keller, Markus A, Tancevski, Ivan, Timms, John F, Zaikin, Alexey, Hippenstiel, Stefan, Ramharter, Michael, Müller-Redetzky, Holger, Witzenrath, Martin, Suttorp, Norbert, Lilley, Kathryn, Mülleder, Michael, Sander, Leif Erik, PA-COVID-19 Study Group, Kurth, Florian, Ralser, Markus, Demichev, Vadim [0000-0002-2424-9412], Nazarenko, Tatiana [0000-0002-4245-7346], Kaur Aulakh, Simran [0000-0002-1580-7144], Whitwell, Harry J [0000-0001-8987-4158], Röhl, Annika [0000-0003-3924-6422], Mittermaier, Mirja [0000-0003-0678-6676], Szyrwiel, Lukasz [0000-0003-1983-2950], Correia-Melo, Clara [0000-0001-6062-1472], Lippert, Lena J [0000-0002-8337-1311], Helbig, Elisa T [0000-0003-4276-7974], Thibeault, Charlotte [0000-0002-8979-9386], Grüning, Nana-Maria [0000-0002-1528-6625], Blyuss, Oleg [0000-0002-0194-6389], Vernardis, Spyros [0000-0002-3946-1686], White, Matthew [0000-0003-0923-974X], Pizzini, Alex [0000-0003-3699-1822], Wohlfarter, Yvonne [0000-0002-0988-9411], Hilbe, Richard [0000-0001-9987-109X], Schaefer, Benedikt [0000-0001-8690-2774], Wagner, Sonja [0000-0003-2319-2722], Machleidt, Felix [0000-0002-6108-5269], Garcia, Carmen [0000-0002-6859-1084], Ruwwe-Glösenkamp, Christoph [0000-0001-5077-829X], Lingscheid, Tilman [0000-0001-5377-3152], Stegemann, Miriam S [0000-0002-7968-0429], Denker, Sophy [0000-0002-0736-6019], Edel, Andreas [0000-0002-9951-7223], Müller, Nils B [0000-0001-8918-857X], Zelezniak, Aleksej [0000-0002-3098-9441], Bellmann-Weiler, Rosa [0000-0002-5584-111X], Campbell, Archie [0000-0003-0198-5078], Hayward, Caroline [0000-0002-9405-9550], Porteous, David J [0000-0003-1249-6106], Uhrig, Alexander [0000-0001-7474-6743], Zoller, Heinz [0000-0003-1794-422X], Keller, Markus A [0000-0002-8654-9920], Tancevski, Ivan [0000-0001-5116-8960], Zaikin, Alexey [0000-0001-7540-1130], Ramharter, Michael [0000-0002-9259-1885], Witzenrath, Martin [0000-0002-9787-5633], Mülleder, Michael [0000-0001-9792-3861], Sander, Leif Erik [0000-0002-0476-9947], Kurth, Florian [0000-0002-3807-473X], and Apollo - University of Cambridge Repository
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Chemical Biology & High Throughput ,PA-COVID-19 Study group ,Metabolism ,Ecology,Evolution & Ethology ,Synthetic Biology ,Computational & Systems Biology - Abstract
Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Additional tools are also needed to monitor treatment, including experimental therapies in clinical trials. Comprehensively capturing human physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index, and APACHE II score showed limited performance in predicting the COVID-19 outcome. Instead, the quantification of 321 plasma protein groups at 349 timepoints in 50 critically ill patients receiving invasive mechanical ventilation revealed 14 proteins that showed trajectories different between survivors and non-survivors. A predictor trained on proteomic measurements obtained at the first time point at maximum treatment level (i.e. WHO grade 7), which was weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81). We tested the established predictor on an independent validation cohort (AUROC 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that plasma proteomics can give rise to prognostic predictors substantially outperforming current prognostic markers in intensive care.
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- 2022
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20. Early detection of pancreatic ductal adenocarcinomas with an ensemble learning model based on a panel of protein serum biomarkers
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Nene, Nuno Rocha, primary, Ney, Alexander, additional, Nazarenko, Tatiana, additional, Blyuss, Oleg, additional, Johnston, Harvey, additional, Whitwell, Harry, additional, Sedlak, Eva, additional, Gentry-Maharaj, Aleksandra, additional, Costello, Eithne, additional, Greenhalf, William, additional, Jacobs, Ian, additional, Menon, Usha, additional, Hsuan, Justin, additional, Pereira, Stephen, additional, Zaikin, Alexey, additional, and Timms, John, additional
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- 2021
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21. A time-resolved proteomic and prognostic map of COVID-19
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Demichev, Vadim, Tober-Lau, Pinkus, Lemke, Oliver, Nazarenko, Tatiana, Thibeault, Charlotte, Whitwell, Harry, Röhl, Annika, Freiwald, Anja, Szyrwiel, Lukasz, Ludwig, Daniela, Correia-Melo, Clara, Aulakh, Simran Kaur, Helbig, Elisa T, Stubbemann, Paula, Lippert, Lena J, Grüning, Nana-Maria, Blyuss, Oleg, Vernardis, Spyros, White, Matthew, Messner, Christoph B, Joannidis, Michael, Sonnweber, Thomas, Klein, Sebastian J, Pizzini, Alex, Wohlfarter, Yvonne, Sahanic, Sabina, Hilbe, Richard, Schaefer, Benedikt, Wagner, Sonja, Mittermaier, Mirja, Machleidt, Felix, Garcia, Carmen, Ruwwe-Glösenkamp, Christoph, Lingscheid, Tilman, Bosquillon De Jarcy, Laure, Stegemann, Miriam S, Pfeiffer, Moritz, Jürgens, Linda, Denker, Sophy, Zickler, Daniel, Enghard, Philipp, Zelezniak, Aleksej, Campbell, Archie, Hayward, Caroline, Porteous, David J, Marioni, Riccardo E, Uhrig, Alexander, Müller-Redetzky, Holger, Zoller, Heinz, Löffler-Ragg, Judith, Keller, Markus A, Tancevski, Ivan, Timms, John F, Zaikin, Alexey, Hippenstiel, Stefan, Ramharter, Michael, Witzenrath, Martin, Suttorp, Norbert, Lilley, Kathryn, Mülleder, Michael, Sander, Leif Erik, PA-COVID-19 Study Group, Ralser, Markus, Kurth, Florian, Lilley, Kathryn [0000-0003-0594-6543], and Apollo - University of Cambridge Repository
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Chemical Biology & High Throughput ,Inflammation ,Proteomics ,Proteome ,clinical disease progression ,SARS-CoV-2 ,Age Factors ,COVID-19 ,biomarkers ,Prognosis ,disease prognosis ,Blood Cell Count ,Enzyme Activation ,Machine Learning ,Metabolism ,Ecology,Evolution & Ethology ,physiological parameters ,Disease Progression ,Humans ,Synthetic Biology ,Blood Gas Analysis ,longitudinal profiling ,patient trajectories ,Computational & Systems Biology - Abstract
COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.
- Published
- 2021
22. Ensemble of correlation, parenclitic and synolitic graphs as a tool to detect universal changes in complex biological systems: Comment on “Dynamic and thermodynamic models of adaptation” by A.N. Gorban et al.
- Author
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Nazarenko, Tatiana, Blyuss, Oleg, Whitwell, Harry, and Zaikin, Alexey
- Published
- 2021
- Full Text
- View/download PDF
23. Parenclitic and Synolytic Networks Revisited
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Nazarenko, Tatiana, primary, Whitwell, Harry J., additional, Blyuss, Oleg, additional, and Zaikin, Alexey, additional
- Published
- 2021
- Full Text
- View/download PDF
24. A time-resolved proteomic and prognostic map of COVID-19
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Demichev, Vadim, primary, Tober-Lau, Pinkus, additional, Lemke, Oliver, additional, Nazarenko, Tatiana, additional, Thibeault, Charlotte, additional, Whitwell, Harry, additional, Röhl, Annika, additional, Freiwald, Anja, additional, Szyrwiel, Lukasz, additional, Ludwig, Daniela, additional, Correia-Melo, Clara, additional, Aulakh, Simran Kaur, additional, Helbig, Elisa T., additional, Stubbemann, Paula, additional, Lippert, Lena J., additional, Grüning, Nana-Maria, additional, Blyuss, Oleg, additional, Vernardis, Spyros, additional, White, Matthew, additional, Messner, Christoph B., additional, Joannidis, Michael, additional, Sonnweber, Thomas, additional, Klein, Sebastian J., additional, Pizzini, Alex, additional, Wohlfarter, Yvonne, additional, Sahanic, Sabina, additional, Hilbe, Richard, additional, Schaefer, Benedikt, additional, Wagner, Sonja, additional, Mittermaier, Mirja, additional, Machleidt, Felix, additional, Garcia, Carmen, additional, Ruwwe-Glösenkamp, Christoph, additional, Lingscheid, Tilman, additional, Bosquillon de Jarcy, Laure, additional, Stegemann, Miriam S., additional, Pfeiffer, Moritz, additional, Jürgens, Linda, additional, Denker, Sophy, additional, Zickler, Daniel, additional, Enghard, Philipp, additional, Zelezniak, Aleksej, additional, Campbell, Archie, additional, Hayward, Caroline, additional, Porteous, David J., additional, Marioni, Riccardo E., additional, Uhrig, Alexander, additional, Müller-Redetzky, Holger, additional, Zoller, Heinz, additional, Löffler-Ragg, Judith, additional, Keller, Markus A., additional, Tancevski, Ivan, additional, Timms, John F., additional, Zaikin, Alexey, additional, Hippenstiel, Stefan, additional, Ramharter, Michael, additional, Witzenrath, Martin, additional, Suttorp, Norbert, additional, Lilley, Kathryn, additional, Mülleder, Michael, additional, Sander, Leif Erik, additional, Ralser, Markus, additional, Kurth, Florian, additional, Kleinschmidt, Malte, additional, Heim, Katrin M., additional, Millet, Belén, additional, Meyer-Arndt, Lil, additional, Hübner, Ralf H., additional, Andermann, Tim, additional, Doehn, Jan M., additional, Opitz, Bastian, additional, Sawitzki, Birgit, additional, Grund, Daniel, additional, Radünzel, Peter, additional, Schürmann, Mariana, additional, Zoller, Thomas, additional, Alius, Florian, additional, Knape, Philipp, additional, Breitbart, Astrid, additional, Li, Yaosi, additional, Bremer, Felix, additional, Pergantis, Panagiotis, additional, Schürmann, Dirk, additional, Temmesfeld-Wollbrück, Bettina, additional, Wendisch, Daniel, additional, Brumhard, Sophia, additional, Haenel, Sascha S., additional, Conrad, Claudia, additional, Georg, Philipp, additional, Eckardt, Kai-Uwe, additional, Lehner, Lukas, additional, Kruse, Jan M., additional, Ferse, Carolin, additional, Körner, Roland, additional, Spies, Claudia, additional, Edel, Andreas, additional, Weber-Carstens, Steffen, additional, Krannich, Alexander, additional, Zvorc, Saskia, additional, Li, Linna, additional, Behrens, Uwe, additional, Schmidt, Sein, additional, Rönnefarth, Maria, additional, Dang-Heine, Chantip, additional, Röhle, Robert, additional, Lieker, Emma, additional, Kretzler, Lucie, additional, Wirsching, Isabelle, additional, Wollboldt, Christian, additional, Wu, Yinan, additional, Schwanitz, Georg, additional, Hillus, David, additional, Kasper, Stefanie, additional, Olk, Nadine, additional, Horn, Alexandra, additional, Briesemeister, Dana, additional, Treue, Denise, additional, Hummel, Michael, additional, Corman, Victor M., additional, Drosten, Christian, additional, and von Kalle, Christof, additional
- Published
- 2021
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25. Impact of modular mitochondrial epistatic interactions on the evolution of human subpopulations
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Shinde, Pramod, primary, Whitwell, Harry J., additional, Verma, Rahul Kumar, additional, Ivanchenko, Mikhail, additional, Zaikin, Alexey, additional, and Jalan, Sarika, additional
- Published
- 2021
- Full Text
- View/download PDF
26. Identification of a serum biomarker panel for the differential diagnosis of cholangiocarcinoma and primary sclerosing cholangitis
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Cuenco, Joy, Wehnert, Natascha, Blyuss, Oleg, Kazarian, Anna, Whitwell, Harry J., Menon, Usha, Dawnay, Anne, Manns, Michael P., Pereira, Stephen P., and Timms, John F.
- Subjects
biliary tract cancer ,serum biomarker ,differential diagnosis ,primary sclerosing cholangitis ,cholangiocarcinoma ,Research Paper - Abstract
The non-invasive differentiation of malignant and benign biliary disease is a clinical challenge. Carbohydrate antigen 19-9 (CA19-9), leucine-rich α2-glycoprotein (LRG1), interleukin 6 (IL6), pyruvate kinase M2 (PKM2), cytokeratin 19 fragment (CYFRA21.1) and mucin 5AC (MUC5AC) have reported utility for differentiating cholangiocarcinoma (CCA) from benign biliary disease. Herein, serum levels of these markers were tested in 66 cases of CCA and 62 cases of primary sclerosing cholangitis (PSC) and compared with markers of liver function and inflammation. Markers panels were assessed for their ability to discriminate malignant and benign disease. Several of the markers were also assessed in pre-diagnosis biliary tract cancer (BTC) samples with performances evaluated at different times prior to diagnosis. We show that LRG1 and IL6 were unable to accurately distinguish CCA from PSC, whereas CA19-9, PKM2, CYFRA21.1 and MUC5AC were significantly elevated in malignancy. Area under the receiver operating characteristic curves for these individual markers ranged from 0.73-0.84, with the best single marker (PKM2) providing 61% sensitivity at 90% specificity. A panel combining PKM2, CYFRA21.1 and MUC5AC gave 76% sensitivity at 90% specificity, which increased to 82% sensitivity by adding gamma-glutamyltransferase (GGT). In the pre-diagnosis setting, LRG1, IL6 and PKM2 were poor predictors of BTC, whilst CA19-9 and C-reactive protein were elevated up to 2 years before diagnosis. In conclusion, LRG1, IL6 and PKM2 were not useful for early detection of BTC, whilst a model combining PKM2, CYFRA21.1, MUC5AC and GGT was beneficial in differentiating malignant from benign biliary disease, warranting validation in a prospective trial.
- Published
- 2018
27. The Human Body as a Super Network: Digital Methods to Analyze the Propagation of Aging
- Author
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Whitwell, Harry J., primary, Bacalini, Maria Giulia, additional, Blyuss, Oleg, additional, Chen, Shangbin, additional, Garagnani, Paolo, additional, Gordleeva, Susan Yu, additional, Jalan, Sarika, additional, Ivanchenko, Mikhail, additional, Kanakov, Oleg, additional, Kustikova, Valentina, additional, Mariño, Ines P., additional, Meyerov, Iosif, additional, Ullner, Ekkehard, additional, Franceschi, Claudio, additional, and Zaikin, Alexey, additional
- Published
- 2020
- Full Text
- View/download PDF
28. HiLight-PTM: an online application to aid matching peptide pairs with isotopically labelled PTMs
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Whitwell, Harry J, primary and DiMaggio, Peter, additional
- Published
- 2019
- Full Text
- View/download PDF
29. Impact of modular mitochondrial epistatic interactions on the evolution of human subpopulations
- Author
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Shinde, Pramod, primary, Whitwell, Harry J., additional, Verma, Rahul Kumar, additional, Ivanchenko, Mikhail, additional, Zaikin, Alexey, additional, and Jalan, Sarika, additional
- Published
- 2018
- Full Text
- View/download PDF
30. Evidence against Stable Protein S-Nitrosylation as a Widespread Mechanism of Post-translational Regulation
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Wolhuter, Kathryn, Whitwell, Harry J, Switzer, Christopher H, Burgoyne, Joseph R, Timms, John F, and Eaton, Philip
- Subjects
Proteomics ,Biochemistry & Molecular Biology ,PTEN ,Nitrosation ,OXIDATION ,Nitric Oxide ,Article ,Humans ,Cysteine ,Disulfides ,Sulfhydryl Compounds ,NITRIC-OXIDE SYNTHASE ,Science & Technology ,S-Nitrosothiols ,thiol ,Proteins ,Cell Biology ,11 Medical And Health Sciences ,S-nitrosation ,06 Biological Sciences ,NITROSOHEMOGLOBIN ,S-nitrosylation ,NITROSOTHIOLS ,redox ,Proteolysis ,OXYR ,protein ,signaling ,Life Sciences & Biomedicine ,Oxidation-Reduction ,Protein Processing, Post-Translational ,SYSTEM ,disulfide ,Developmental Biology - Abstract
Summary S-nitrosation, commonly referred to as S-nitrosylation, is widely regarded as a ubiquitous, stable post-translational modification that directly regulates many proteins. Such a widespread role would appear to be incompatible with the inherent lability of the S-nitroso bond, especially its propensity to rapidly react with thiols to generate disulfide bonds. As anticipated, we observed robust and widespread protein S-nitrosation after exposing cells to nitrosocysteine or lipopolysaccharide. Proteins detected using the ascorbate-dependent biotin switch method are typically interpreted to be directly regulated by S-nitrosation. However, these S-nitrosated proteins are shown to predominantly comprise transient intermediates leading to disulfide bond formation. These disulfides are likely to be the dominant end effectors resulting from elevations in nitrosating cellular nitric oxide species. We propose that S-nitrosation primarily serves as a transient intermediate leading to disulfide formation. Overall, we conclude that the current widely held perception that stable S-nitrosation directly regulates the function of many proteins is significantly incorrect., Graphical Abstract, Highlights • Protein S-nitrosation is commonly regarded as a stable, regulatory modification • However, S-nitrosothiols are labile and rapidly react with thiols to form disulfides • Here disulfides are shown to be the dominant end effectors of nitrosative signaling • Protein S-nitrosation as a regulatory end effector may occur, but this may be rare, Nitric oxide-related molecules post-translationally modify protein thiols, resulting in functional changes. Such S-nitrosothiols are widely thought to be regulatory end effector modifications. However, Wolhuter et al. show that S-nitrosation predominantly serves as a transient intermediate in the formation of disulfide bonds. This furthers our understanding of how nitric oxide regulates signaling.
- Published
- 2017
31. Parenclitic networks for predicting ovarian cancer
- Author
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Whitwell, Harry J., primary, Blyuss, Oleg, additional, Menon, Usha, additional, Timms, John F., additional, and Zaikin, Alexey, additional
- Published
- 2018
- Full Text
- View/download PDF
32. Evidence against Stable Protein S-Nitrosylation as a Widespread Mechanism of Post-translational Regulation
- Author
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Wolhuter, Kathryn, primary, Whitwell, Harry J., additional, Switzer, Christopher H., additional, Burgoyne, Joseph R., additional, Timms, John F., additional, and Eaton, Philip, additional
- Published
- 2018
- Full Text
- View/download PDF
33. Evidence of Altered Glycosylation of Serum Proteins Prior to Pancreatic Cancer Diagnosis
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Krishnan, Shibu, primary, Whitwell, Harry, additional, Cuenco, Joy, additional, Gentry-Maharaj, Aleksandra, additional, Menon, Usha, additional, Pereira, Stephen, additional, Gaspari, Marco, additional, and Timms, John, additional
- Published
- 2017
- Full Text
- View/download PDF
34. Nanoparticles, Their protein corona and impact on the immune function of human lung cells
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Whitwell, Harry James. and Whitwell, Harry James.
- Abstract
Particles with a single dimension smaller than 100 nm are called nanoparticles (NPs). There is a large amount of epidemiology that anthropogenic particles cause increased mortality, increased risk of asthma and increased incidence of lung adenocarcinoma. Inhaled NPs can reach the lung terminus, interacting with a lipid lining at the air-liquid interface (pulmonary surfactant (PSf)) and with an aqueous hydrophase beneath. Studies in serum have shown that upon contact with blood, proteins very rapidly adsorb to the particle surface, thus the particle accrues a biological identity. However, no such interaction studies have been performed in the pulmonary system, where there is a complex interplay of proteins and lipids. The interaction of NPs with PSf is poorly understood. Prior to reaching the lung epithelium, NPs must translocate through this layer. The aims of this thesis are to firstly explore the interactions of NPs with proteins and lipids in the lung and secondly investigate the toxicity and effect on the immunological action of lung cells. NPs were incubated with pulmonary lavage fluid and adsorbed proteins were analysed using state-of-the-art, high resolution, quantitative mass spectrometry. To investigate the interactions of NPs with PSf, particles were incubated with a porcine surfactant. The bound lipids were analysed by qualitative mass spectrometry. The effect of NPs and the NP-protein-corona was investigated in cell lines by a number of techniques. Unique proteins were observed on each particle type, however the main contributors contribution was from a few key proteins. There was no biophysical property of these bound proteins that could predict their affinity to a particle. Surfactant associated protein A, B and D (SP-A, B, D) were observed to be bound to the particle surface. SP-A was bound with high abundance, suggesting it is likely these particles may interfere with PSf in vivo. All particles retained lipids on t
- Published
- 2016
35. Nanoparticles in the lung and their protein corona: the few proteins that count
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Whitwell, Harry, primary, Mackay, Rose-Marie, additional, Elgy, Christine, additional, Morgan, Cliff, additional, Griffiths, Mark, additional, Clark, Howard, additional, Skipp, Paul, additional, and Madsen, Jens, additional
- Published
- 2016
- Full Text
- View/download PDF
36. Surfactant Protein-D Is Essential for Immunity to Helminth Infection
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Thawer, Sumaiyya, primary, Auret, Jennifer, additional, Schnoeller, Corinna, additional, Chetty, Alisha, additional, Smith, Katherine, additional, Darby, Matthew, additional, Roberts, Luke, additional, Mackay, Rosie-Marie, additional, Whitwell, Harry J., additional, Timms, John F., additional, Madsen, Jens, additional, Selkirk, Murray E., additional, Brombacher, Frank, additional, Clark, Howard William, additional, and Horsnell, William G. C., additional
- Published
- 2016
- Full Text
- View/download PDF
37. Surfactant protein A (SP-A) inhibits agglomeration and macrophage uptake of toxic amine modified nanoparticles
- Author
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McKenzie, Zofi, primary, Kendall, Michaela, additional, Mackay, Rose-Marie, additional, Whitwell, Harry, additional, Elgy, Christine, additional, Ding, Ping, additional, Mahajan, Sumeet, additional, Morgan, Cliff, additional, Griffiths, Mark, additional, Clark, Howard, additional, and Madsen, Jens, additional
- Published
- 2015
- Full Text
- View/download PDF
38. HiLight-PTM: an online application to aid matching peptide pairs with isotopically labelled PTMs.
- Author
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Whitwell, Harry J and DiMaggio, Peter
- Subjects
- *
INTERNET servers , *DATABASE searching - Abstract
Motivation Database searching of isotopically labelled PTMs can be problematic and we frequently find that only one, or neither in a heavy/light pair are assigned. In such cases, having a pair of MS/MS spectra that differ due to an isotopic label can assist in identifying the relevant m / z values that support the correct peptide annotation or can be used for de novo sequencing. Results We have developed an online application that identifies matching peaks and peaks differing by the appropriate mass shift (difference between heavy and light PTM) between two MS/MS spectra. Furthermore, the application predicts, from the exact-match peaks, the mass of their complementary ions and highlights these as high confidence matches between the two spectra. The result is a tool to visually compare two spectra, and downloadable peaks lists that can be used to support de novo sequencing. Availability and implementation HiLight-PTM is released using shinyapps.io by RStudio, and can be accessed from any internet browser at https://harrywhitwell.shinyapps.io/hilight-ptm/. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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39. Non-Histone Protein Methylation: Biological Significance and Bioengineering Potential
- Author
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Di Blasi, Roberto, Blyuss, Oleg, Timms, John F., Conole, Daniel, Ceroni, Francesca, and Whitwell, Harry J.
- Abstract
Protein methylation is a key post-translational modification whose effects on gene expression have been intensively studied over the last two decades. Recently, renewed interest in non-histone protein methylation has gained momentum for its role in regulating important cellular processes and the activity of many proteins, including transcription factors, enzymes, and structural complexes. The extensive and dynamic role that protein methylation plays within the cell also highlights its potential for bioengineering applications. Indeed, while synthetic histone protein methylation has been extensively used to engineer gene expression, engineering of non-histone protein methylation has not been fully explored yet. Here, we report the latest findings, highlighting how non-histone protein methylation is fundamental for certain cellular functions and is implicated in disease, and review recent efforts in the engineering of protein methylation.
- Published
- 2021
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40. The postprandial secretion of peptide YY 1-36 and 3-36 in obesity is differentially increased after gastric bypass versus sleeve gastrectomy.
- Author
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Kowalka AM, Alexiadou K, Cuenco J, Clarke RE, Minnion J, Williams EL, Bech P, Purkayastha S, Ahmed AR, Takats Z, Whitwell HJ, Romero MG, Bloom SR, Camuzeaux S, Lewis MR, Khoo B, and Tan TM
- Subjects
- Humans, Peptide YY, Chromatography, Liquid, Blood Glucose, Tandem Mass Spectrometry, Obesity surgery, Gastrectomy, Tyrosine, Gastric Bypass methods
- Abstract
Objectives: Peptide tyrosine tyrosine (PYY) exists as two species, PYY
1-36 and PYY3-36 , with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY1-36 and PYY3-36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on fasting and postprandial PYY1-36 and PYY3-36 secretion using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay., Design and Subjects: Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY1-36 and PYY3-36 concentrations., Results: Presurgery, the fasting and postprandial levels of PYY1-36 and PYY3-36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY1-36 and PYY3-36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG., Conclusions: There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY1-36 and PYY3-36 , which may account for long-term differences in efficacy and adverse effects between the two types of surgery., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)- Published
- 2023
- Full Text
- View/download PDF
41. Characterization of emergent toxigenic M1 UK Streptococcus pyogenes and associated sublineages.
- Author
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Li HK, Zhi X, Vieira A, Whitwell HJ, Schricker A, Jauneikaite E, Li H, Yosef A, Andrew I, Game L, Turner CE, Lamagni T, Coelho J, and Sriskandan S
- Subjects
- Phylogeny, Antigens, Bacterial genetics, England, Streptococcus pyogenes genetics, Proteomics
- Abstract
Streptococcus pyogenes genotype emm 1 is a successful, globally distributed epidemic clone that is regarded as inherently virulent. An emm 1 sublineage, M1
UK , that produces increased levels of SpeA toxin was associated with increased scarlet fever and invasive infections in England in 2015/2016. Defined by 27 SNPs in the core genome, M1UK is now dominant in England. To more fully characterize M1UK , we undertook comparative transcriptomic and proteomic analyses of M1UK and contemporary non-M1UK emm 1 strains (M1global ). Just seven genes were differentially expressed by M1UK compared with contemporary M1global strains. In addition to speA , five genes in the operon that includes glycerol dehydrogenase were upregulated in M1UK ( gldA, mipB/talC, pflD , and phosphotransferase system IIC and IIB components), while aquaporin ( glpF2 ) was downregulated. M1UK strains have a stop codon in gldA . Deletion of gldA in M1global abrogated glycerol dehydrogenase activity, and recapitulated upregulation of gene expression within the operon that includes gldA , consistent with a feedback effect. Phylogenetic analysis identified two intermediate emm 1 sublineages in England comprising 13/27 (M113SNPs ) and 23/27 SNPs (M123SNPs ), respectively, that had failed to expand in the population. Proteomic analysis of invasive strains from the four phylogenetic emm 1 groups highlighted sublineage-specific changes in carbohydrate metabolism, protein synthesis and protein processing; upregulation of SpeA was not observed in chemically defined medium. In rich broth, however, expression of SpeA was upregulated ~10-fold in both M123SNPs and M1UK sublineages, compared with M113SNPs and M1global . We conclude that stepwise accumulation of SNPs led to the emergence of M1UK . While increased expression of SpeA is a key indicator of M1UK and undoubtedly important, M1UK strains have outcompeted M123SNPs and other emm types that produce similar or more superantigen toxin. We speculate that an accumulation of adaptive SNPs has contributed to a wider fitness advantage in M1UK on an inherently successful emm 1 streptococcal background.- Published
- 2023
- Full Text
- View/download PDF
42. A proteomic survival predictor for COVID-19 patients in intensive care.
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Demichev V, Tober-Lau P, Nazarenko T, Lemke O, Kaur Aulakh S, Whitwell HJ, Röhl A, Freiwald A, Mittermaier M, Szyrwiel L, Ludwig D, Correia-Melo C, Lippert LJ, Helbig ET, Stubbemann P, Olk N, Thibeault C, Grüning NM, Blyuss O, Vernardis S, White M, Messner CB, Joannidis M, Sonnweber T, Klein SJ, Pizzini A, Wohlfarter Y, Sahanic S, Hilbe R, Schaefer B, Wagner S, Machleidt F, Garcia C, Ruwwe-Glösenkamp C, Lingscheid T, Bosquillon de Jarcy L, Stegemann MS, Pfeiffer M, Jürgens L, Denker S, Zickler D, Spies C, Edel A, Müller NB, Enghard P, Zelezniak A, Bellmann-Weiler R, Weiss G, Campbell A, Hayward C, Porteous DJ, Marioni RE, Uhrig A, Zoller H, Löffler-Ragg J, Keller MA, Tancevski I, Timms JF, Zaikin A, Hippenstiel S, Ramharter M, Müller-Redetzky H, Witzenrath M, Suttorp N, Lilley K, Mülleder M, Sander LE, Kurth F, and Ralser M
- Abstract
Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Additional tools are also needed to monitor treatment, including experimental therapies in clinical trials. Comprehensively capturing human physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index, and APACHE II score showed limited performance in predicting the COVID-19 outcome. Instead, the quantification of 321 plasma protein groups at 349 timepoints in 50 critically ill patients receiving invasive mechanical ventilation revealed 14 proteins that showed trajectories different between survivors and non-survivors. A predictor trained on proteomic measurements obtained at the first time point at maximum treatment level (i.e. WHO grade 7), which was weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81). We tested the established predictor on an independent validation cohort (AUROC 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that plasma proteomics can give rise to prognostic predictors substantially outperforming current prognostic markers in intensive care., Competing Interests: The authors declare no competing interests. Author John F. Timms was unable to confirm their authorship contributions. On their behalf, the corresponding author has reported their contributions to the best of their knowledge., (Copyright: © 2022 Demichev 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.)
- Published
- 2022
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43. Nanoparticle growth and surface chemistry changes in cell-conditioned culture medium.
- Author
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Kendall M, Hodges NJ, Whitwell H, Tyrrell J, and Cangul H
- Subjects
- Cell Line, Tumor, Humans, Mass Spectrometry methods, Peptides chemistry, Polystyrenes, Protein Binding, Culture Media, Conditioned chemistry, Nanoparticles chemistry
- Abstract
When biomolecules attach to engineered nanoparticle (ENP) surfaces, they confer the particles with a new biological identity. Physical format may also radically alter, changing ENP stability and agglomeration state within seconds. In order to measure which biomolecules are associated with early ENP growth, we studied ENPs in conditioned medium from A549 cell culture, using dynamic light scattering (DLS) and linear trap quadrupole electron transfer dissociation mass spectrometry. Two types of 100 nm polystyrene particles (one uncoated and one with an amine functionalized surface) were used to measure the influence of surface type. In identically prepared conditioned medium, agglomeration was visible in all samples after 1 h, but was variable, indicating inter-sample variability in secretion rates and extracellular medium conditions. In samples conditioned for 1 h or more, ENP agglomeration rates varied significantly. Agglomerate size measured by DLS was well correlated with surface sequestered peptide number for uncoated but not for amine coated polystyrene ENPs. Amine-coated ENPs grew much faster and into larger agglomerates associated with fewer sequestered peptides, but including significant sequestered lactose dehydrogenase. We conclude that interference with extracellular peptide balance and oxidoreductase activity via sequestration is worthy of further study, as increased oxidative stress via this new mechanism may be important for cell toxicity., (© 2014 The Author(s) Published by the Royal Society. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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