34 results on '"Abis G"'
Search Results
2. The effect of selective decontamination on the intestinal microbiota as measured with IS-pro: a taxonomic classification tool applicable for direct evaluation of intestinal microbiota in clinical routine
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van Doorn-Schepens, M. L. M., Abis, G. S. A., Oosterling, S. J., van Egmond, M., Poort, L., Stockmann, H. B. A. C., Bonjer, H. J., Savelkoul, P. H. M., and Budding, A. E.
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- 2022
- Full Text
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3. Multi-criteria decision analysis to redesign an Italian Clinical Engineering Service under specific needs and regulation requirements
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Lasorsa, I., Abis, G., Podda, B., Accardo, A., MAGJAREVIC, Ratko, Editor-in-chief, Ladyzynsk, Piotr, Series editor, Ibrahim, Fatimah, Series editor, Lacković, Igor, Series editor, Rock, Emilio Sacristan, Series editor, and Jaffray, David A., editor
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- 2015
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4. Supplement to: A randomized trial of laparoscopic versus open surgery for rectal cancer.
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Bonjer, H J, Deijen, C L, and Abis, G A
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- 2015
5. EAES Consensus Development Conference on endoscopic repair of groin hernias
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Poelman, M. M., van den Heuvel, B., Deelder, J. D., Abis, G. S. A., Beudeker, N., Bittner, R. R., Campanelli, G., van Dam, D., Dwars, B. J., Eker, H. H., Fingerhut, A., Khatkov, I., Koeckerling, F., Kukleta, J. F., Miserez, M., Montgomery, A., Munoz Brands, R. M., Morales Conde, S., Muysoms, F. E., Soltes, M., Tromp, W., Yavuz, Y., and Bonjer, H. J.
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- 2013
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6. Randomized clinical trial of selective decontamination of the digestive tract in elective colorectal cancer surgery (SELECT trial)
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Abis, G. S. A., Stockmann, H. B. A. C., Bonjer, H. J., van Veenendaal, N., van Doorn-Schepens, M. L. M., Budding, A. E., Wilschut, J. A., van Egmond, M., Oosterling, S. J., de Lange, E. S. M., Tuynman, J. B., e. Vandenbroucke-Grauls, C. M. J., C. Stockmann, H. B. A., van der Bij, G. J., de Korte, N., Acherman, Y. I. Z., den Boer, F. C., Sonneveld, D. J. A., Poort, L., e Vandenbroucke-Grauls, C. M. J., C Stockmann, H. B. A., VU University medical center, CCA - Cancer Treatment and quality of life, APH - Quality of Care, APH - Global Health, Surgery, Medical Microbiology and Infection Prevention, AGEM - Digestive immunity, AII - Infectious diseases, Epidemiology and Data Science, Molecular cell biology and Immunology, AGEM - Re-generation and cancer of the digestive system, CCA - Cancer biology and immunology, and ACS - Microcirculation
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Male ,musculoskeletal diseases ,medicine.medical_specialty ,Colectomies ,Colorectal cancer ,Cefazolin ,030230 surgery ,Anastomosis ,Risk Assessment ,law.invention ,Hospitals, University ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Reference Values ,Preoperative Care ,medicine ,Humans ,Surgical Wound Infection ,Antibiotic prophylaxis ,Colectomy ,Decontamination ,Aged ,Netherlands ,Academic Medical Centers ,Analysis of Variance ,business.industry ,Anastomosis, Surgical ,Perioperative ,Antibiotic Prophylaxis ,Middle Aged ,Interim analysis ,medicine.disease ,Surgery ,Treatment Outcome ,Elective Surgical Procedures ,Multivariate Analysis ,Tobramycin ,030211 gastroenterology & hepatology ,Female ,business ,Colorectal Neoplasms ,medicine.drug ,Follow-Up Studies - Abstract
Background Infectious complications and anastomotic leakage affect approximately 30 per cent of patients after colorectal cancer surgery. The aim of this multicentre randomized trial was to investigate whether selective decontamination of the digestive tract (SDD) reduces these complications of elective colorectal cancer surgery. Methods The effectiveness of SDD was evaluated in a multicentre, open-label RCT in six centres in the Netherlands. Patients with colorectal cancer scheduled for elective curative surgery with a primary anastomosis were eligible. Oral colistin, tobramycin and amphotericin B were administered to patients in the SDD group to decontaminate the digestive tract. Both treatment and control group received intravenous cefazolin and metronidazole for perioperative prophylaxis. Mechanical bowel preparation was given for left-sided colectomies, sigmoid and anterior resections. Anastomotic leakage was the primary outcome; infectious complications and mortality were secondary outcomes. Results The outcomes for 228 patients randomized to the SDD group and 227 randomized to the control group were analysed. The trial was stopped after interim analysis demonstrated that superiority was no longer attainable. Effective SDD was confirmed by interspace DNA profiling analysis of rectal swabs. Anastomotic leakage was observed in 14 patients (6·1 per cent) in the SDD group and in 22 patients (9·7 per cent) in the control group (odds ratio (OR) 0·61, 95 per cent c.i. 0·30 to 1·22). Fewer patients in the SDD group had one or more infectious complications than patients in the control group (14·9 versus 26·9 per cent respectively; OR 0·48, 0·30 to 0·76). Multivariable analysis indicated that SDD reduced the rate of infectious complications (OR 0·47, 0·29 to 0·76). Conclusion SDD reduces infectious complications after colorectal cancer resection but did not significantly reduce anastomotic leakage in this trial. Registration number: NCT01740947 (https://www.clinicaltrials.gov).
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- 2019
7. Peri-Operative Bowel Perforation in Early Stage Colon Cancer is Associated with an Adverse Oncological Outcome
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Belt, E. J. T., Stockmann, H. B. A. C., Abis, G. S. A., de Boer, J. M., de Lange-de Klerk, E. S. M., van Egmond, M., Meijer, G. A., and Oosterling, S. J.
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- 2012
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8. Patient-reported genitourinary dysfunction after laparoscopic and open rectal cancer surgery in a randomized trial (COLOR II)
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Andersson, J., Abis, G., Gellerstedt, M., Angenete, E., Angerås, U., Cuesta, M. A., Jess, P., Rosenberg, J., Bonjer, H. J., and Haglind, E.
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- 2014
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9. AN OBJECTIVE ASSESSMENT OF PALMAR SWEATING AFTER ROBOT-ASSISTED HIGHLY SELECTIVE DORSAL SYMPATHECTOMY: (S085)
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Coveliers, H. M. E., Abis, G. S. A., and Wisselink, W.
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- 2011
10. 15-deoxy-Δ12,14-Prostaglandin J2 inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism
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Abis, G, Charles, RL, Kopec, J, Yue, WW, Atkinson, RA, Bui, TTT, Lynham, S, Popova, S, Sun, Y-B, Fraternali, F, Eaton, P, Conte, MR, King‘s College London, and University of Oxford [Oxford]
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[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics ,lcsh:Biology (General) ,lcsh:QH301-705.5 ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] - Abstract
Human soluble epoxide hydrolase (hsEH) is an enzyme responsible for the inactivation of bioactive epoxy fatty acids, and its inhibition is emerging as a promising therapeutical strategy to target hypertension, cardiovascular disease, pain and insulin sensitivity. Here, we uncover the molecular bases of hsEH inhibition mediated by the endogenous 15-deoxy-Δ 12,14-Prostaglandin J 2 (15d-PGJ 2). Our data reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15d-PGJ 2 in the catalytic pocket, as well as by covalent locking of the same compound onto cysteine residues C423 and C522, remote to the active site. Biophysical characterisations allied with in silico investigations indicate that the covalent modification of the reactive cysteines may be part of a hitherto undiscovered allosteric regulatory mechanism of the enzyme. This study provides insights into the molecular modes of inhibition of hsEH epoxy-hydrolytic activity and paves the way for the development of new allosteric inhibitors.
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- 2019
11. PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation
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Chelban, V., Wilson, M. P., Warman Chardon, J., Vandrovcova, J., Zanetti, M. N., Zamba-Papanicolaou, E., Efthymiou, S., Pope, S., Conte, M. R., Abis, G., Liu, Y. -T., Tribollet, E., Haridy, N. A., Botia, J. A., Ryten, M., Nicolaou, P., Minaidou, A., Christodoulou, K., Kernohan, K. D., Eaton, A., Osmond, M., Ito, Y., Bourque, P., Jepson, J. E. C., Bello, O., Bremner, F., Cordivari, C., Reilly, M. M., Foiani, M., Heslegrave, A., Zetterberg, H., Heales, S. J. R., Wood, N. W., Rothman, J. E., Boycott, K. M., Mills, P. B., Clayton, P. T., Houlden, H., Kriouile, Y., Khorassani, M. E., Aguennouz, M., Groppa, S., Marinova Karashova, B., Van Maldergem, L., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Di Rosa, G., Goraya, J. S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Giunti, P., Salpietro, V., Oconnor, E., Kullmann, D., Kaiyrzhanov, R., Sullivan, R., Khan, A. M., Yau, W. Y., Hostettler, I., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Lim, S. -Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Torti, E., Zollo, M., Heimer, G., Dauvilliers, Y. A., Striano, P., Al-Khawaja, I., Al-Mutairi, F., Alkuraya, F. S., Sherifa, H., Rizig, M., Okubadejo, N. U., Ojo, O. O., Oshinaike, O. O., Wahab, K., Bello, A. H., Abubakar, S., Obiabo, Y., Nwazor, E., Ekenze, O., Williams, U., Iyagba, A., Taiwo, L., Komolafe, M., Oguntunde, O., Pchelina, S., Senkevich, K., Shashkin, C., Zharkynbekova, N., Koneyev, K., Manizha, G., Isrofilov, M., Guliyeva, U., Salayev, K., Khachatryan, S., Rossi, S., Silvestri, Gabriella, Bourinaris, T., Xiromerisiou, G., Fidani, L., Spanaki, C., Tucci, A., Silvestri G. (ORCID:0000-0002-1950-1468), Chelban, V., Wilson, M. P., Warman Chardon, J., Vandrovcova, J., Zanetti, M. N., Zamba-Papanicolaou, E., Efthymiou, S., Pope, S., Conte, M. R., Abis, G., Liu, Y. -T., Tribollet, E., Haridy, N. A., Botia, J. A., Ryten, M., Nicolaou, P., Minaidou, A., Christodoulou, K., Kernohan, K. D., Eaton, A., Osmond, M., Ito, Y., Bourque, P., Jepson, J. E. C., Bello, O., Bremner, F., Cordivari, C., Reilly, M. M., Foiani, M., Heslegrave, A., Zetterberg, H., Heales, S. J. R., Wood, N. W., Rothman, J. E., Boycott, K. M., Mills, P. B., Clayton, P. T., Houlden, H., Kriouile, Y., Khorassani, M. E., Aguennouz, M., Groppa, S., Marinova Karashova, B., Van Maldergem, L., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Di Rosa, G., Goraya, J. S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Giunti, P., Salpietro, V., Oconnor, E., Kullmann, D., Kaiyrzhanov, R., Sullivan, R., Khan, A. M., Yau, W. Y., Hostettler, I., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Lim, S. -Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Torti, E., Zollo, M., Heimer, G., Dauvilliers, Y. A., Striano, P., Al-Khawaja, I., Al-Mutairi, F., Alkuraya, F. S., Sherifa, H., Rizig, M., Okubadejo, N. U., Ojo, O. O., Oshinaike, O. O., Wahab, K., Bello, A. H., Abubakar, S., Obiabo, Y., Nwazor, E., Ekenze, O., Williams, U., Iyagba, A., Taiwo, L., Komolafe, M., Oguntunde, O., Pchelina, S., Senkevich, K., Shashkin, C., Zharkynbekova, N., Koneyev, K., Manizha, G., Isrofilov, M., Guliyeva, U., Salayev, K., Khachatryan, S., Rossi, S., Silvestri, Gabriella, Bourinaris, T., Xiromerisiou, G., Fidani, L., Spanaki, C., Tucci, A., and Silvestri G. (ORCID:0000-0002-1950-1468)
- Abstract
Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240.
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- 2019
12. X-ray structure of human soluble Epoxide Hydrolase C-terminal Domain (hsEH CTD)in complex with 15d-PGJ2
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Abis, G., primary, Kopec, J., additional, Yue, W.W., additional, and Conte, M.R., additional
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- 2019
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13. X-ray structure of apo human soluble Epoxide Hydrolase C-terminal Domain (hsEH CTD)
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Abis, G., primary, Kopec, J., additional, Yue, W.W., additional, and Conte, M.R., additional
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- 2019
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14. Patient-reported genitourinary dysfunction after laparoscopic and open rectal cancer surgery in a randomized trial (COLOR II)
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Andersson, J, primary, Abis, G, additional, Gellerstedt, M, additional, Angenete, E, additional, Angerås, U, additional, Cuesta, M A, additional, Jess, P, additional, Rosenberg, J, additional, Bonjer, H J, additional, and Haglind, E, additional
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- 2016
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15. Patient-reported genitourinary dysfunction after laparoscopic and open rectal cancer surgery in a randomized trial (COLOR II)
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Andersson, John, Abis, G, Gellerstedt, Martin, Angenete, Eva, Angerås, Ulf, Cuesta, M. A., Jess, P, Rosenberg, Jakob, Bonjer, H. J., Haglind, Eva, Andersson, John, Abis, G, Gellerstedt, Martin, Angenete, Eva, Angerås, Ulf, Cuesta, M. A., Jess, P, Rosenberg, Jakob, Bonjer, H. J., and Haglind, Eva
- Abstract
BACKGROUND: This article reports on patient-reported sexual dysfunction and micturition symptoms following a randomized trial of laparoscopic and open surgery for rectal cancer. METHODS: Patients in the COLOR II randomized trial, comparing laparoscopic and open surgery for rectal cancer, completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CR38 questionnaire before surgery, and after 4 weeks, 6, 12 and 24 months. Adjusted mean differences on a 100-point scale were calculated using changes from baseline value at the various time points in the domains of sexual functioning, sexual enjoyment, male and female sexual problems, and micturition symptoms. RESULTS: Of 617 randomized patients, 385 completed this phase of the trial. Their mean age was 67·1 years. Surgery caused an anticipated reduction in genitourinary function after 4 weeks, with no significant differences between laparoscopic and open approaches. An improvement in sexual dysfunction was seen in the first year, but some male sexual problems persisted. Before operation 64·5 per cent of men in the laparoscopic group and 55·6 per cent in the open group reported some degree of erectile dysfunction. This increased to 81·1 and 80·5 per cent respectively 4 weeks after surgery, and 76·3 versus 75·5 per cent at 12 months, with no significant differences between groups. Micturition symptoms were less affected than sexual function and gradually improved to preoperative levels by 6 months. Adjusting for confounders, including radiotherapy, did not change these results. CONCLUSION: Sexual dysfunction is common in patients with rectal cancer, and treatment (including surgery) increases the proportion of patients affected. A laparoscopic approach does not change this., CC BY NC-NDA correction has been published in: British Journal of Surgery, Volume 103, Issue 12, November 2016, Page 1746, https://doi.org/10.1002/bjs.10279
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- 2014
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16. Patient-reported genitourinary dysfunction after laparoscopic and open rectal cancer surgery in a randomized trial (COLOR II)
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Andersson, J, Abis, G, Gellerstedt, M, Angenete, E, Angerås, U, Cuesta, M A, Jess, P, Rosenberg, J, Bonjer, H J, Haglind, E, Andersson, J, Abis, G, Gellerstedt, M, Angenete, E, Angerås, U, Cuesta, M A, Jess, P, Rosenberg, J, Bonjer, H J, and Haglind, E
- Abstract
BACKGROUND: This article reports on patient-reported sexual dysfunction and micturition symptoms following a randomized trial of laparoscopic and open surgery for rectal cancer.METHODS: Patients in the COLOR II randomized trial, comparing laparoscopic and open surgery for rectal cancer, completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CR38 questionnaire before surgery, and after 4 weeks, 6, 12 and 24 months. Adjusted mean differences on a 100-point scale were calculated using changes from baseline value at the various time points in the domains of sexual functioning, sexual enjoyment, male and female sexual problems, and micturition symptoms.RESULTS: Of 617 randomized patients, 385 completed this phase of the trial. Their mean age was 67·1 years. Surgery caused an anticipated reduction in genitourinary function after 4 weeks, with no significant differences between laparoscopic and open approaches. An improvement in sexual dysfunction was seen in the first year, but some male sexual problems persisted. Before operation 64·5 per cent of men in the laparoscopic group and 55·6 per cent in the open group reported some degree of erectile dysfunction. This increased to 81·1 and 80·5 per cent respectively 4 weeks after surgery, and 76·3 versus 75·5 per cent at 12 months, with no significant differences between groups. Micturition symptoms were less affected than sexual function and gradually improved to preoperative levels by 6 months. Adjusting for confounders, including radiotherapy, did not change these results.CONCLUSION: Sexual dysfunction is common in patients with rectal cancer, and treatment (including surgery) increases the proportion of patients affected. A laparoscopic approach does not change this.REGISTRATION NUMBER: NCT0029779 (http://www.clinicaltrials.gov).
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- 2014
17. Carbon-13 CP/MAS solid state NMR and FT/IR spectroscopy of wood cell wall biodegradation
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Gilardi, Gianfranco, Abis, G., Cass, L., and A. E. G.
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- 1995
18. Wideline solid state NMR of wood. Proton relaxation time measurements on cell walls biodegraded by white-rot and brown-rot fungi
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Gilardi, Gianfranco, Abis, G., Cass, L., and A. E. G.
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- 1994
19. Multi-criteria decision analysis to redesign an Italian Clinical Engineering Service under specific needs and regulation requirement
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A. Accardo, B. Podda, G. Abis, I. Lasorsa, David A. Jaffray, Lasorsa, Irene, Abis, G., Podda, Barbara, and Accardo, Agostino
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Service (business) ,Engineering ,medicine.medical_specialty ,Knowledge management ,business.industry ,PAPRIKA ,healthcare decision-making ,Clinical Engineering Service ,Hospital management ,Reengineering ,Business process reengineering ,Local health authority ,Multiple-criteria decision analysis ,humanities ,Engineering management ,Health care ,otorhinolaryngologic diseases ,medicine ,Needs analysis ,business ,Clinical engineering - Abstract
The aim of this study is to fulfill the need of reengineering the Clinical Engineering Service in an Italian ASL (Local Health Authority) located in Sardinia, in accordance with the Italian regulations for healthcare. Even if methods for processes redesigning in healthcare organizations are available in the literature, there are no recent evidences of their application in Clinical Engineering Services. Among the multi-criteria techniques, in this work PAPRIKA was used, since it is an easy-to-use and intuitive method for multi- criteria decision making, based on decision-makers’ preferences. We identified the decision makers’ criteria to be fulfilled and four different preference levels for each criterion, as inputs of the method. Moreover four different scenarios were identified and, for each scenario and criterion, the decision makers selected the most suitable level. In order to reduce the number of pairwise comparisons among the preference levels associated to the identified criteria, the online software 1000minds, implementing the PAPRIKA method, was used. After 460 steps, the software allowed to rank the four possible scenarios. The application of the method allowed choosing the best solution for the ASL and it represents a good way for decision making, even though the number of questions is still high.
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- 2015
20. PDXK mutations cause polyneuropathy responsive to pyridoxal 5′‐phosphate supplementation
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Chelban, Viorica, Wilson, Matthew P., Warman Chardon, Jodi, Vandrovcova, Jana, Zanetti, M. Natalia, Zamba‐Papanicolaou, Eleni, Efthymiou, Stephanie, Pope, Simon, Conte, Maria R., Abis, Giancarlo, Liu, Yo‐Tsen, Tribollet, Eloise, Haridy, Nourelhoda A., Botía, Juan A., Ryten, Mina, Nicolaou, Paschalis, Minaidou, Anna, Christodoulou, Kyproula, Kernohan, Kristin D., Eaton, Alison, Osmond, Matthew, Ito, Yoko, Bourque, Pierre, Jepson, James E. C., Bello, Oscar, Bremner, Fion, Cordivari, Carla, Reilly, Mary M., Foiani, Martha, Heslegrave, Amanda, Zetterberg, Henrik, Heales, Simon J. R., Wood, Nicholas W., Rothman, James E., Boycott, Kym M., Mills, Philippa B., Clayton, Peter T., Houlden, Henry, Kriouile, Yamna, Khorassani, Mohamed El, Aguennouz, Mhammed, Groppa, Stanislav, Marinova Karashova, Blagovesta, Van Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Arning, Larissa, Timmann, Dagmar, Cormand, Bru, Pérez‐Dueñas, Belen, Di Rosa, Gabriella, Goraya, Jatinder S., Sultan, Tipu, Mine, Jun, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Banu, Selina, Pineda‐Marfa, Mercedes, Veggiotti, Pierangelo, Ferrari, Michel D., van den Maagdenberg, Arn M J M, Verrotti, Alberto, Marseglia, Giangluigi, Savasta, Salvatore, García‐Silva, Mayte, Ruiz, Alfons Macaya, Garavaglia, Barbara, Borgione, Eugenia, Portaro, Simona, Sanchez, Benigno Monteagudo, Boles, Richard, Papacostas, Savvas, Vikelis, Michail, Rothman, James, Giunti, Paola, Salpietro, Vincenzo, Oconnor, Emer, Kullmann, Dimitri, Kaiyrzhanov, Rauan, Sullivan, Roisin, Khan, Alaa Matooq, Yau, Wai Yan, Hostettler, Isabel, Papanicolaou, Eleni Zamba, Dardiotis, Efthymios, Maqbool, Shazia, Ibrahim, Shahnaz, Kirmani, Salman, Rana, Nuzhat Noureen, Atawneh, Osama, Lim, Shen‐Yang, Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Mangano, Salvatore, Scuderi, Carmela, Morello, Giovanna, Stojkovic, Tanya, Torti, Erin, Zollo, Massimi, Heimer, Gali, Dauvilliers, Yves A., Striano, Pasquale, Al‐Khawaja, Issam, Al‐Mutairi, Fuad, Alkuraya, Fowzan S, Sherifa, Hamed, Rizig, Mie, Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Oguntunde, Olapeju, Pchelina, Sofya, Senkevich, Konstantin, Haridy, Nourelhoda, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Bourinaris, Thomas, Xiromerisiou, Georgia, Fidani, Liana, Spanaki, Cleanthe, Tucci, Arianna, University College London Hospitals (UCLH), Université d'Ottawa [Ontario] (uOttawa), King‘s College London, University College of London [London] (UCL), University of Cyprus [Nicosia], UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, Institute of Psychiatry, Psychology & Neuroscience, King's College London, National Yang Ming University (NYMU), Department of Information and Communications Engineering [Murcia], Universidad de Murcia, Guy's Hospital [London], Cyprus Institute of Neurology and Genetics, University of Ottawa [Ottawa], The Ottawa Hospital, University of British Columbia (UBC), Ottawa Hospital Research Institute [Ottawa] (OHRI), Institute of Neurology, Queen Square, London, Sahlgrenska University Hospital, Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Department of Human Genetics, Ruhr University Bochum (RUB), Universitat de Barcelona (UB), Department of Medical and Surgical Pediatrics, University Hospital, Fondazione, Departments of Human Genetics & Neurology, Leiden University Medical Center (LUMC), University of Laquila, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Yale University School of Medicine, Department of Microbiology, Università degli studi di Catania [Catania], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gene Dx, Partenaires INRAE, Tel Aviv University Sackler School of Medicine [Tel Aviv, Israël], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universita degli studi di Genova, Fondazione 'Policlinico Universitario A. Gemelli' [Rome], UCL Institute of neurology, UCL Institute of Neurology, Chelban V., Wilson M.P., Warman Chardon J., Vandrovcova J., Zanetti M.N., Zamba-Papanicolaou E., Efthymiou S., Pope S., Conte M.R., Abis G., Liu Y.-T., Tribollet E., Haridy N.A., Botia J.A., Ryten M., Nicolaou P., Minaidou A., Christodoulou K., Kernohan K.D., Eaton A., Osmond M., Ito Y., Bourque P., Jepson J.E.C., Bello O., Bremner F., Cordivari C., Reilly M.M., Foiani M., Heslegrave A., Zetterberg H., Heales S.J.R., Wood N.W., Rothman J.E., Boycott K.M., Mills P.B., Clayton P.T., Houlden H., Kriouile Y., Khorassani M.E., Aguennouz M., Groppa S., Marinova Karashova B., Van Maldergem L., Nachbauer W., Boesch S., Arning L., Timmann D., Cormand B., Perez-Duenas B., Di Rosa G., Goraya J.S., Sultan T., Mine J., Avdjieva D., Kathom H., Tincheva R., Banu S., Pineda-Marfa M., Veggiotti P., Ferrari M.D., van den Maagdenberg A.M.J.M., Verrotti A., Marseglia G., Savasta S., Garcia-Silva M., Ruiz A.M., Garavaglia B., Borgione E., Portaro S., Sanchez B.M., Boles R., Papacostas S., Vikelis M., Rothman J., Giunti P., Salpietro V., Oconnor E., Kullmann D., Kaiyrzhanov R., Sullivan R., Khan A.M., Yau W.Y., Hostettler I., Papanicolaou E.Z., Dardiotis E., Maqbool S., Ibrahim S., Kirmani S., Rana N.N., Atawneh O., Lim S.-Y., Shaikh F., Koutsis G., Breza M., Mangano S., Scuderi C., Morello G., Stojkovic T., Torti E., Zollo M., Heimer G., Dauvilliers Y.A., Striano P., Al-Khawaja I., Al-Mutairi F., Alkuraya F.S., Sherifa H., Rizig M., Okubadejo N.U., Ojo O.O., Oshinaike O.O., Wahab K., Bello A.H., Abubakar S., Obiabo Y., Nwazor E., Ekenze O., Williams U., Iyagba A., Taiwo L., Komolafe M., Oguntunde O., Pchelina S., Senkevich K., Haridy N., Shashkin C., Zharkynbekova N., Koneyev K., Manizha G., Isrofilov M., Guliyeva U., Salayev K., Khachatryan S., Rossi S., Silvestri G., Bourinaris T., Xiromerisiou G., Fidani L., Spanaki C., and Tucci A.
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0301 basic medicine ,Male ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,LOCAL TRANSLATION ,Medizin ,medicine.disease_cause ,DISEASE ,chemistry.chemical_compound ,0302 clinical medicine ,polineuropathy ,Cinètica enzimàtica ,Gene Regulatory Networks ,Pyridoxal phosphate ,Child ,Pyridoxal Kinase ,Adenosine triphosphate (ATP) ,Research Articles ,Aged, 80 and over ,Mutation ,Gene Regulatory Network ,PLASMA ,Autosomal recessive axonal polyneuropathy ,Disease gene identification ,Pyridoxal kinase ,3. Good health ,Settore MED/26 - NEUROLOGIA ,Neuropaties perifèriques ,Treatment Outcome ,Polyneuropathie ,Neurology ,Child, Preschool ,Pyridoxal Phosphate ,RELIABILITY ,Vitamin B Complex ,Female ,Life Sciences & Biomedicine ,Polyneuropathy ,Human ,Research Article ,Adult ,Adolescent ,PDXK ,Clinical Neurology ,CHARCOT-MARIE-TOOTH ,CHARCOT-MARIE-TOOTH, CMT NEUROPATHY SCORE, LOCAL TRANSLATION, DISEASE, RELIABILITY ,MECHANISMS, DISCOVERY, FRAMEWORK, KINASE, PLASMA ,MECHANISMS ,03 medical and health sciences ,Polyneuropathies ,Atrophy ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,KINASE ,medicine ,Humans ,CMT NEUROPATHY SCORE ,PDXK mutations ,Pyridoxal ,Dietary Supplement ,Aged ,Peripheral neuropathies ,Science & Technology ,[SCCO.NEUR]Cognitive science/Neuroscience ,Enzyme kinetics ,Neurosciences ,FRAMEWORK ,medicine.disease ,Molecular biology ,030104 developmental biology ,chemistry ,DISCOVERY ,Dietary Supplements ,Neurosciences & Neurology ,Neurology (clinical) ,Adenosine triphosphate ,030217 neurology & neurosurgery - Abstract
OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240. ispartof: ANNALS OF NEUROLOGY vol:86 issue:2 pages:225-240 ispartof: location:United States status: published
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21. Development of a specific and potent IGF2BP1 inhibitor: A promising therapeutic agent for IGF2BP1-expressing cancers.
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Singh A, Singh V, Wallis N, Abis G, Oberman F, Wood T, Dhamdhere M, Gershon T, Ramos A, Yisraeli J, Spiegelman VS, and Sharma AK
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- Animals, Cell Movement, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Neoplasms drug therapy, Neoplasms genetics
- Abstract
IGF2BP1 is a protein that controls the stability, localization, and translation of various mRNA targets. Poor clinical outcomes in numerous cancer types have been associated with its overexpression. As it has been demonstrated to impede tumor growth and metastasis in animal models, inhibiting IGF2BP1 function is a promising strategy for combating cancer. A lead chemical, 7773, which specifically decreased IGF2BP1 RNA binding and cellular activities, was previously identified in a high-throughput screen for effective IGF2BP1 inhibitors. Additional optimization of 7773 described in this manuscript led to the discovery of six compounds that performed equally well or better than 7773. In cell lines with high levels of endogenous IGF2BP1, one of 7773 derivatives, AVJ16, was found to be most efficient at preventing cell migration. Further, AVJ16 was found to be IGF2BP1-specific because it had no effect on cell lines that expressed little or no IGF2BP1 protein. The direct binding of AVJ16 to IGF2BP1 was validated by binding tests, with a 12-fold increase in binding efficiency over the lead compound. AVJ16 was shown to bind to a hydrophobic region at the protein's KH34 di-domain interface between the KH3 and KH4 domains. Overall, the findings imply that AVJ16 is a potent and specific inhibitor of IGF2BP1 activity., Competing Interests: Declaration of competing interest The authors declare no competing financial interests or personal relationships that could inappropriately influence the reported work., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
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- 2024
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22. Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation.
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Knight H, Abis G, Kaur M, Green HLH, Krasemann S, Hartmann K, Lynham S, Clark J, Zhao L, Ruppert C, Weiss A, Schermuly RT, Eaton P, and Rudyk O
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- Humans, Mice, Animals, Cysteine metabolism, Endothelial Cells metabolism, Cell Proliferation, Pulmonary Artery metabolism, Phosphorylation, Cell Cycle Checkpoints, Cyclin D metabolism, Cells, Cultured, Cyclin-Dependent Kinase 4 genetics, Cyclin-Dependent Kinase 4 metabolism, Cyclins metabolism, Pulmonary Arterial Hypertension metabolism
- Abstract
Background: Pulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and a perturbed cellular redox and metabolic balance. Oxidants induce cell cycle arrest to halt proliferation; however, little is known about the redox-regulated effector proteins that mediate these processes. Here, we report a novel kinase-inhibitory disulfide bond in cyclin D-CDK4 (cyclin-dependent kinase 4) and investigate its role in cell proliferation and PH., Methods: Oxidative modifications of cyclin D-CDK4 were detected in human pulmonary arterial smooth muscle cells and human pulmonary arterial endothelial cells. Site-directed mutagenesis, tandem mass-spectrometry, cell-based experiments, in vitro kinase activity assays, in silico structural modeling, and a novel redox-dead constitutive knock-in mouse were utilized to investigate the nature and definitively establish the importance of CDK4 cysteine modification in pulmonary vascular cell proliferation. Furthermore, the cyclin D-CDK4 oxidation was assessed in vivo in the pulmonary arteries and isolated human pulmonary arterial smooth muscle cells of patients with pulmonary arterial hypertension and in 3 preclinical models of PH., Results: Cyclin D-CDK4 forms a reversible oxidant-induced heterodimeric disulfide dimer between C7/8 and C135, respectively, in cells in vitro and in pulmonary arteries in vivo to inhibit cyclin D-CDK4 kinase activity, decrease Rb (retinoblastoma) protein phosphorylation, and induce cell cycle arrest. Mutation of CDK4 C135 causes a kinase-impaired phenotype, which decreases cell proliferation rate and alleviates disease phenotype in an experimental mouse PH model, suggesting this cysteine is indispensable for cyclin D-CDK4 kinase activity. Pulmonary arteries and human pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension display a decreased level of CDK4 disulfide, consistent with CDK4 being hyperactive in human pulmonary arterial hypertension. Furthermore, auranofin treatment, which induces the cyclin D-CDK4 disulfide, attenuates disease severity in experimental PH models by mitigating pulmonary vascular remodeling., Conclusions: A novel disulfide bond in cyclin D-CDK4 acts as a rapid switch to inhibit kinase activity and halt cell proliferation. This oxidative modification forms at a critical cysteine residue, which is unique to CDK4, offering the potential for the design of a selective covalent inhibitor predicted to be beneficial in PH., Competing Interests: Disclosures None.
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- 2023
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23. Cost-effectiveness of selective decontamination of the digestive tract to decrease infectious complications in colorectal cancer surgery: An analysis of the SELECT trial.
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Reuvers JRD, Gaikhorst E, Ben ÂJ, Scholten J, van Egmond M, Bosmans JE, Stockmann HBAC, Kazemier G, Tuynman JB, Abis GSA, and Oosterling SJ
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- Humans, Cost-Benefit Analysis, Decontamination, Postoperative Complications epidemiology, Postoperative Complications prevention & control, Anti-Bacterial Agents therapeutic use, Colorectal Neoplasms surgery, Colorectal Neoplasms drug therapy
- Abstract
Introduction: Selective decontamination of the digestive tract (SDD) is effective in reducing infectious complications in elective colorectal cancer (CRC) surgery. However, it is unclear whether SDD is cost-effective compared to standard antibiotic prophylaxis., Material & Methods: Economic evaluation alongside multicenter randomized controlled trial, the SELECT-trial, from a healthcare perspective. Patients included underwent elective surgery for non-metastatic CRC. The intervention group received oral non-absorbable colistin, tobramycin and amphotericin B (SDD) next to standard antibiotic prophylaxis. Both groups received a single shot intravenous cefazolin and metronidazole preoperatively as standard prophylaxis. Occurrence of postoperative infectious complication in the first 30 postoperative days was extracted from medical records, Quality-Adjusted Life-Years (QALYs) based on the ED-5D-3L, and healthcare costs collected from the hospital's financial administration., Results: Of the 455 patients, 228 were randomly assigned to intervention group and 227 patients to the control group. SDD significantly reduced the number of infectious complications compared to control (difference = -0.13, 95 % CI -0.05 to -0.20). No difference was found for QALYs (difference = 0.002, 95 % CI -0.002 to 0.005). Healthcare costs were statistically significantly lower in the intervention group (difference = -€1258, 95 % CI -2751 to -166). The ICER was -9872 €/infectious complication prevented and -820,380 €/QALY gained. For all willingness-to-pay thresholds, the probability that prophylactic SDD was cost-effective compared to standard prophylactic practice alone was 1.0., Conclusion: The addition of SDD to the standard preoperative intravenous antibiotic prophylaxis is cost-effective compared to standard prophylactic practice from a healthcare perspective and should be considered as the standard of care., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)
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- 2023
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24. Direct m6A recognition by IMP1 underlays an alternative model of target selection for non-canonical methyl-readers.
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Nicastro G, Abis G, Klein P, Esteban-Serna S, Gallagher C, Chaves-Arquero B, Cai Y, Figueiredo AM, Martin SR, Patani R, Taylor IA, and Ramos A
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- Adenosine metabolism, Methylation, Protein Processing, Post-Translational, Proteins genetics, RNA genetics, RNA metabolism, Animals, Chickens, Avian Proteins metabolism, RNA-Binding Proteins metabolism
- Abstract
m6A methylation provides an essential layer of regulation in organismal development, and is aberrant in a range of cancers and neuro-pathologies. The information encoded by m6A methylation is integrated into existing RNA regulatory networks by RNA binding proteins that recognise methylated sites, the m6A readers. m6A readers include a well-characterised class of dedicated proteins, the YTH proteins, as well as a broader group of multi-functional regulators where recognition of m6A is only partially understood. Molecular insight in this recognition is essential to build a mechanistic understanding of global m6A regulation. In this study, we show that the reader IMP1 recognises the m6A using a dedicated hydrophobic platform that assembles on the methyl moiety, creating a stable high-affinity interaction. This recognition is conserved across evolution and independent from the underlying sequence context but is layered upon the strong sequence specificity of IMP1 for GGAC RNA. This leads us to propose a concept for m6A regulation where methylation plays a context-dependent role in the recognition of selected IMP1 targets that is dependent on the cellular concentration of available IMP1, differing from that observed for the YTH proteins., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2023
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25. Affinity-enhanced RNA-binding domains as tools to understand RNA recognition.
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Chaves-Arquero B, Collins KM, Abis G, Kelly G, Christodoulou E, Taylor IA, and Ramos A
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- Proteins genetics, Mutation, RNA-Binding Motifs genetics, RNA genetics, Fragile X Mental Retardation Protein genetics
- Abstract
Understanding how the RNA-binding domains of a protein regulator are used to recognize its RNA targets is a key problem in RNA biology, but RNA-binding domains with very low affinity do not perform well in the methods currently available to characterize protein-RNA interactions. Here, we propose to use conservative mutations that enhance the affinity of RNA-binding domains to overcome this limitation. As a proof of principle, we have designed and validated an affinity-enhanced K-homology (KH) domain mutant of the fragile X syndrome protein FMRP, a key regulator of neuronal development, and used this mutant to determine the domain's sequence preference and to explain FMRP recognition of specific RNA motifs in the cell. Our results validate our concept and our nuclear magnetic resonance (NMR)-based workflow. While effective mutant design requires an understanding of the underlying principles of RNA recognition by the relevant domain type, we expect the method will be used effectively in many RNA-binding domains., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)
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- 2023
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26. Allosteric Regulation of the Soluble Epoxide Hydrolase by Nitro Fatty Acids: a Combined Experimental and Computational Approach.
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Qiu Q, Abis G, Mattingly-Peck F, Lynham S, Fraternali F, and Conte MR
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- Allosteric Regulation drug effects, Cysteine metabolism, Humans, Epoxide Hydrolases antagonists & inhibitors, Epoxide Hydrolases chemistry, Epoxide Hydrolases metabolism, Linoleic Acids chemistry, Linoleic Acids pharmacology, Nitro Compounds chemistry, Nitro Compounds pharmacology
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The human soluble epoxide hydrolase (hsEH) is a key regulator of epoxy fatty acid (EpFA) metabolism. Inhibition of sEH can maintain endogenous levels of beneficial EpFAs and reduce the levels of their corresponding diol products, thus ameliorating a variety of pathological conditions including cardiovascular, central nervous system and metabolic diseases. The quest for orthosteric drugs that bind directly to the catalytic crevice of hsEH has been prolonged and sustained over the past decades, but the disappointing outcome of clinical trials to date warrants alternative pharmacological approaches. Previously, we have shown that hsEH can be allosterically inhibited by the endogenous electrophilic lipid 15-deoxy-Δ
12,14 -Prostaglandin-J2 , via covalent adduction to two cysteines, C423 and C522. In this study, we explore the properties and behaviour of three electrophilic lipids belonging to the class of the nitro fatty acids, namely 9- and 10-nitrooleate and 10-nitrolinoleate. Biochemical and biophysical investigations revealed that, in addition to C423 and C522, nitro fatty acids can covalently bind to additional nucleophilic residues in hsEH C-terminal domain (CTD), two of which predicted in this study to be latent allosteric sites. Systematic mapping of the protein mutational space and evaluation of possible propagation pathways delineated selected residues, both in the allosteric patches and in other regions of the enzyme, envisaged to play a role in allosteric signalling. The responses elicited by the ligands on the covalent adduction sites supports future fragment-based design studies of new allosteric effectors for hsEH with increased efficacy and selectivity., Competing Interests: Declaration of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2022
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27. Small molecule inhibitor of Igf2bp1 represses Kras and a pro-oncogenic phenotype in cancer cells.
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Wallis N, Oberman F, Shurrush K, Germain N, Greenwald G, Gershon T, Pearl T, Abis G, Singh V, Singh A, Sharma AK, Barr HM, Ramos A, Spiegelman VS, and Yisraeli JK
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- Cell Line, Tumor, Drug Screening Assays, Antitumor, High-Throughput Screening Assays, Humans, Protein Binding drug effects, RNA-Binding Proteins metabolism, Signal Transduction drug effects, Antineoplastic Agents pharmacology, Carcinogenesis drug effects, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors, RNA-Binding Proteins antagonists & inhibitors
- Abstract
Igf2bp1 is an oncofetal RNA binding protein whose expression in numerous types of cancers is associated with upregulation of key pro-oncogenic RNAs, poor prognosis, and reduced survival. Importantly, Igf2bp1 synergizes with mutations in Kras to enhance signalling and oncogenic activity, suggesting that molecules inhibiting Igf2bp1 could have therapeutic potential. Here, we isolate a small molecule that interacts with a hydrophobic surface at the boundary of Igf2bp1 KH3 and KH4 domains, and inhibits binding to Kras RNA. In cells, the compound reduces the level of Kras and other Igf2bp1 mRNA targets, lowers Kras protein, and inhibits downstream signalling, wound healing, and growth in soft agar, all in the absence of any toxicity. This work presents an avenue for improving the prognosis of Igf2bp1-expressing tumours in lung, and potentially other, cancer(s).
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- 2022
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28. A thiol redox sensor in soluble epoxide hydrolase enables oxidative activation by intra-protein disulfide bond formation.
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Charles RL, Abis G, Fernandez BF, Guttzeit S, Buccafusca R, Conte MR, and Eaton P
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- Animals, Disulfides, Hydrogen Peroxide, Mice, Oxidation-Reduction, Oxidative Stress, Epoxide Hydrolases genetics, Epoxide Hydrolases metabolism, Sulfhydryl Compounds
- Abstract
Soluble epoxide hydrolase (sEH), an enzyme that broadly regulates the cardiovascular system, hydrolyses epoxyeicosatrienoic acids (EETs) to their corresponding dihydroxyeicosatrienoic acids (DHETs). We previously showed that endogenous lipid electrophiles adduct within the catalytic domain, inhibiting sEH to lower blood pressure in angiotensin II-induced hypertensive mice. As angiotensin II increases vascular H
2 O2 , we explored sEH redox regulation by this oxidant and how this integrates with inhibition by lipid electrophiles to regulate vasotone. Kinetics analyses revealed that H2 O2 not only increased the specific activity of sEH but increased its affinity for substrate and increased its catalytic efficiency. This oxidative activation was mediated by formation of an intra-disulfide bond between C262 and C264, as determined by mass spectrometry and substantiated by biotin-phenylarsinate and thioredoxin-trapping mutant assays. C262S/264S sEH mutants were resistant to peroxide-induced activation, corroborating the disulfide-activation mechanism. The physiological impact of sEH redox state was determined in isolated arteries and the effect of the pro-oxidant vasopressor angiotensin II on arterial sEH redox state and vasodilatory EETs indexed in mice. Angiotensin II induced the activating intra-disulfide in sEH, causing a decrease in plasma EET/DHET ratios that is consistent with the pressor response to this hormone. Although sEH C262-C264 disulfide formation enhances hydrolysis of vasodilatory EETs, this modification also sensitized sEH to inhibition by lipid electrophiles. This explains why angiotensin II decreases EETs and increases blood pressure, but when lipid electrophiles are also present, that EETs are increased and blood pressure lowered., (Copyright © 2021 Queen Mary University of London. Published by Elsevier B.V. All rights reserved.)- Published
- 2021
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29. Author Correction: Two precious lessons from the HIV-1 RT structure.
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Abis G
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- 2021
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30. Two precious lessons from the HIV-1 RT structure.
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Abis G
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- 2021
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31. Isothermal Titration Calorimetry Enables Rapid Characterization of Enzyme Kinetics and Inhibition for the Human Soluble Epoxide Hydrolase.
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Abis G, Pacheco-Gómez R, Bui TTT, and Conte MR
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- Adamantane analogs & derivatives, Adamantane chemistry, Biocatalysis, Epoxide Hydrolases antagonists & inhibitors, Epoxide Hydrolases metabolism, Epoxy Compounds metabolism, Fatty Acids metabolism, Flow Injection Analysis methods, Humans, Hydrolysis, Kinetics, Lauric Acids chemistry, Lipid Metabolism, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Solutions, Substrate Specificity, Calorimetry methods, Enzyme Assays, Epoxide Hydrolases chemistry, Epoxy Compounds chemistry, Fatty Acids chemistry
- Abstract
Isothermal titration calorimetry (ITC) is conventionally used to acquire thermodynamic data for biological interactions. In recent years, ITC has emerged as a powerful tool to characterize enzyme kinetics. In this study, we have adapted a single-injection method (SIM) to study the kinetics of human soluble epoxide hydrolase (hsEH), an enzyme involved in cardiovascular homeostasis, hypertension, nociception, and insulin sensitivity through the metabolism of epoxy-fatty acids (EpFAs). In the SIM method, the rate of reaction is determined by monitoring the thermal power, while the substrate is being depleted, overcoming the need for synthetic substrates and reducing postreaction processing. Our results show that ITC enables the detailed, rapid, and reproducible characterization of the hsEH-mediated hydrolysis of several natural EpFA substrates. Furthermore, we have applied a variant of the single-injection ITC method for the detailed description of enzyme inhibition, proving the power of this approach in the rapid screening and discovery of new hsEH inhibitors using the enzyme's physiological substrates. The methods described herein will enable further studies on EpFAs' metabolism and biology, as well as drug discovery investigations to identify and characterize hsEH inhibitors. This also promises to provide a general approach for the characterization of lipid catalysis, given the challenges that lipid metabolism studies pose to traditional spectroscopic techniques.
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- 2019
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32. PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.
- Author
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Chelban V, Wilson MP, Warman Chardon J, Vandrovcova J, Zanetti MN, Zamba-Papanicolaou E, Efthymiou S, Pope S, Conte MR, Abis G, Liu YT, Tribollet E, Haridy NA, Botía JA, Ryten M, Nicolaou P, Minaidou A, Christodoulou K, Kernohan KD, Eaton A, Osmond M, Ito Y, Bourque P, Jepson JEC, Bello O, Bremner F, Cordivari C, Reilly MM, Foiani M, Heslegrave A, Zetterberg H, Heales SJR, Wood NW, Rothman JE, Boycott KM, Mills PB, Clayton PT, and Houlden H
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Dietary Supplements, Female, Gene Regulatory Networks genetics, Humans, Male, Treatment Outcome, Mutation genetics, Polyneuropathies drug therapy, Polyneuropathies genetics, Pyridoxal Kinase genetics, Pyridoxal Phosphate administration & dosage, Vitamin B Complex administration & dosage
- Abstract
Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy., Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification., Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization., Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B
6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)- Published
- 2019
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33. 15-deoxy-Δ 12,14 -Prostaglandin J 2 inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism.
- Author
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Abis G, Charles RL, Kopec J, Yue WW, Atkinson RA, Bui TTT, Lynham S, Popova S, Sun YB, Fraternali F, Eaton P, and Conte MR
- Subjects
- Allosteric Regulation, Amino Acid Sequence, Amino Acid Substitution, Catalytic Domain genetics, Crystallography, X-Ray, Cysteine chemistry, Enzyme Inhibitors pharmacology, Enzyme Stability drug effects, Epoxide Hydrolases chemistry, Epoxide Hydrolases genetics, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Mutagenesis, Site-Directed, Prostaglandin D2 pharmacology, Protein Domains, Sequence Alignment, Solubility, Epoxide Hydrolases antagonists & inhibitors, Prostaglandin D2 analogs & derivatives
- Abstract
Human soluble epoxide hydrolase (hsEH) is an enzyme responsible for the inactivation of bioactive epoxy fatty acids, and its inhibition is emerging as a promising therapeutical strategy to target hypertension, cardiovascular disease, pain and insulin sensitivity. Here, we uncover the molecular bases of hsEH inhibition mediated by the endogenous 15-deoxy-Δ
12,14 -Prostaglandin J2 (15d-PGJ2 ). Our data reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15d-PGJ2 in the catalytic pocket, as well as by covalent locking of the same compound onto cysteine residues C423 and C522, remote to the active site. Biophysical characterisations allied with in silico investigations indicate that the covalent modification of the reactive cysteines may be part of a hitherto undiscovered allosteric regulatory mechanism of the enzyme. This study provides insights into the molecular modes of inhibition of hsEH epoxy-hydrolytic activity and paves the way for the development of new allosteric inhibitors., Competing Interests: Competing interestsThe authors declare no competing interests.- Published
- 2019
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34. Expression, purification, and characterisation of human soluble Epoxide Hydrolase (hsEH) and of its functional C-terminal domain.
- Author
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Abis G, Charles RL, Eaton P, and Conte MR
- Subjects
- Chromatography, Affinity, Enzyme Assays, Epoxide Hydrolases chemistry, Epoxide Hydrolases isolation & purification, Epoxide Hydrolases metabolism, Escherichia coli genetics, Escherichia coli metabolism, Gene Expression, Genetic Vectors chemistry, Genetic Vectors metabolism, HEK293 Cells, Humans, Hydrolysis, Protein Domains, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins isolation & purification, Recombinant Proteins metabolism, Solubility, Spectrometry, Mass, Electrospray Ionization, 8,11,14-Eicosatrienoic Acid analogs & derivatives, Cloning, Molecular methods, Epoxide Hydrolases genetics
- Abstract
The human soluble Epoxide Hydrolase (hsEH) is an enzyme involved in the hydrolysis of endogenous anti-inflammatory and cardio-protective signalling mediators known as epoxyeicosatrienoic acids (EETs). EETs' conversion into the corresponding diols by hsEH generates non-bioactive molecules, thereby the enzyme inhibition would be expected to enhance the EETs bioavailability, and their beneficial properties. Numerous inhibitors have been developed to target the enzyme, some of which are showing promising antihypertensive and anti-inflammatory properties in vivo. Thus far, the preparation of the recombinant enzyme for enzymatic and structural in vitro studies has been performed mainly using a baculovirus expression system. More recently, it was reported that the enzyme could be exogenously expressed and isolated from E. coli, although limited amounts of active protein were obtained. We herein describe two novel methods to yield pure recombinant enzyme. The first describes the expression and purification of the full-length enzyme from eukaryotic cells HEK293-F, whilst the second concerns the C-terminal domain of hsEH obtained from the cost-effective and rapid E. coli prokaryotic system. The two methods successfully generated satisfactory amounts of functional enzyme, with virtually identical enzymatic activity. Overall, the protocols described in this paper can be employed for the recombinant expression and purification of active hsEH, to be used in future biomedical investigations and for high-throughput screening of inhibitors for potential use in the treatment of cardiovascular disease., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
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