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1. Body Temperature of the Loggerhead Sea Turtle Caretta Caretta and the Leatherback Sea Turtle Dermochelys Coriacea During Nesting

Author

Sapsford, CW and Hughes, GR

Abstract

Body temperatures of loggerhead and leatherback turtles recorded during nesting excursions were found to be greater than sea temperatures. Leatherback turtles exhibited greater temperature differentials (5,3 - 6,25°C) than loggerhead turtles (1,9 - 3,22°C).The possibility that leatherback turtles may have a preferred temperature range (30 - 32°C) as is the case in terrestrial chelonians is discussed. Recordings of exhaled air temperatures suggest that leather-back turtles may employ a countercurrent heat exchange system in the nares in order to conserve body heat.

Published
2017

3. MORBIDITY AND MORTALITY IN THE ANTIPHOSPHOLIPID SYNDROME DURING A 5-YEAR PERIOD: A MULTICENTER PROSPECTIVE STUDY OF 1,000 PATIENTS

Author

Cervera, R, Khamashta, Ma, Shoenfeld, Y, Camps, Mt, Jacobsen, S, Kiss, E, Zeher, Mm, Tincani, Angela, KONTOPOULOU GRIVA, I, Galeazzi, M, Bellisai, F, Meroni, Pl, Derksen, Rh, DE GROOT PG, GROMNICA IHLE, E, Baleva, M, Mosca, M, Bombardieri, S, Houssiau, F, Gris, Jc, Quéré, I, Hachulla, E, Vasconcelos, C, Roch, B, FERNANDEZ NEBRO, A, Piette, Jc, Espinosa, G, Bucciarelli, S, Pisoni, Cn, Bertolaccini, Ml, Boffa, Mc, and Hughes, Gr

Published
2009

4. Euro-Phospholipid Project Group (European Forum on Antiphospholipid Antibodies). Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients

Author

Cervera, R, Khamashta, Ma, Shoenfeld, Y, Camps, Mt, Jacobsen, S, Kiss, E, Zeher, Mm, Tincani, A, KONTOPOULOU GRIVA, I, Galeazzi, M, Bellisai, F, Meroni, Pl, Derksen, Rh, Groot, Pg, GROMNICA IHLE, E, Baleva, M, Mosca, Marta, Bombardieri, S, Houssiau, F, Gris, Jc, Quéré, I, Hachulla, E, Vasconcelos, C, Roch, B, FERNÁNDEZ NEBRO, A, Piette, Jc, Espinosa, G, Bucciarelli, S, Pisoni, Cn, Bertolaccini, Ml, Boffa, Mc, and Hughes, Gr

Published
2009

5. European Working Party on Systemic Lupus Erythematosus. Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the 'Euro-Lupus Project'

Author

Cervera, R, ABARCA COSTALAGO, M, Abramovicz, D, Allegri, F, Annunziata, P, Aydintug, Ao, Bacarelli, Mr, Bellisai, F, Bernardino, I, BIERNAT KALUZA, E, Blockmans, D, Boki, K, Bracci, L, Campanella, V, Camps, Mt, Carcassi, C, Cattaneo, Roberto, Cauli, A, CHWALINSKA SADOWSKA, H, Contu, L, Cosyns, Jp, Danieli, Mg, Dcruz, D, Depresseux, G, Direskeneli, H, Domènech, I, Espinosa, G, FERNÁNDEZ NEBRO, A, Ferrara, Gb, Font, J, Frutos, Ma, Galeazzi, M, GARCÌA CARRASCO, M, GARCÍA IGLESIAS MF, GARCÍA TOBARUELA, A, George, J, Gil, A, GONZÁLEZ SANTOS, P, Grana, M, Gül, A, Haga, Hj, DE HARO LIGER, M, Houssiau, F, Hughes, Gr, Ingelmo, M, JEDRYKA GÓRAL, A, Khamashta, Ma, Lavilla, P, Levi, Y, LÓPEZ DULPA, M, LÓPEZ SOTO, A, Maldykowa, H, Marcolongo, R, Mathieu, A, Morozzi, G, Nicolopoulou, N, Papasteriades, C, Passiu, G, Perelló, I, Petera, P, Petrovic, R, Piette, Jc, Pintado, V, DE PITA, O, Popovic, R, Pucci, G, Puddu, P, DE RAMÓN, E, RAMOS CASALS, M, RODRÍGUEZ ANDREU, J, RUIZ IRASTORZA, G, SANCHEZ LORA, J, Sanna, G, Scorza, R, Sebastiani, Gd, Sherer, Y, Shoenfeld, Y, Simpatico, A, Sinico, Ra, Smolen, J, Tincani, Angela, Tokgöz, G, URBANO MÁRQUEZ, A, Vasconcelos, C, Vázquez, Jj, Veronesi, J, Vianna, J, and Vivancos, J.

Published
2006

6. Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the 'Euro-Lupus Project'

Author

Cervera, R, ABARCA-COSTALAGO, M, Abramovicz, D, Allegri, F, Annunziata, P, Aydintug, Ao, Bacarelli, Mr, Bellisai, F, Bernardino, I, BIERNAT-KALUZA, E, Blockmans, D, Boki, K, Bracci, L, Campanella, V, Camps, Mt, Carcassi, C, Cattaneo, R, Cauli, A, CHWALINSKA-SADOWSKA, H, Contu, L, Cosyns, Jp, Danieli, Mg, Dcruz, D, Depresseux, G, Direskeneli, H, Domenech, I, Espinosa, G, FERNANDEZ-NEBRO, A, Ferrara, Gb, Font, J, Frutos, Ma, Galeazzi, M., GARCIA-CARRASCO, M, GARCIA IGLESIAS MF, GARCIA-TOBARUELA, A, George, J, Gil, A, GONZALEZ-SANTOS, P, Grana, M, Gul, A, Haga, Hj, DE HARO-LIGER, M, Houssiau, F, Hughes, Gr, Ingelmo, M, JEDRYKA-GORAL, A, Khamashta, Ma, Lavilla, P, Levi, Y, LOPEZ-DULPA, M, LOPEZ-SOTO, A, Maldykowa, H, Marcolongo, R, Mathieu, A, Morozzi, G, Nicolopoulou, N, Papasteriades, C, Passiu, G, Perello, I, Petera, P, Petrovic, R, Piette, Jc, Pintado, V, DE PITA, O, Popovic, R, Pucci, G, Puddu, P, DE RAMON, E, RAMOS-CASALS, M, RODRIGUEZ-ANDREU, J, RUIZ-IRASTORZA, G, SANCHEZ-LORA, J, Sanna, G, Scorza, R, Sebastiani, Gd, Sherer, Y, Shoenfeld, Y, Simpatico, A, Sinico, Ra, Smolen, J, Tincani, A, Tokgoz, G, URBANO-MARQUEZ, A, Vasconcelos, C, Vazquez, Jj, Veronesi, J, Vianna, J, Vivancos, J, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Service de rhumatologie, UCL - MD/MNOP - Département de morphologie normale et pathologique, UCL - (SLuc) Service d'anatomie pathologique, Cervera, R, Abarca Costalago, M, Abramovicz, D, Allegri, F, Annunziata, P, Aydintug, A, Bacarelli, M, Bellisai, F, Bernardino, I, Biernat Kaluza, E, Blockmans, D, Boki, K, Bracci, L, Campanella, V, Camps, M, Carcassi, C, Cattaneo, R, Cauli, A, Chwalinska Sadowska, H, Contu, L, Cosyns, J, Danieli, M, D́cruz, D, Depresseux, G, Direskeneli, H, Domènech, I, Espinosa, G, Fernández Nebro, A, Ferrara, G, Font, J, Frutos, M, Galeazzi, M, García Carrasco, M, García Iglesias, M, García Tobaruela, A, George, J, Gil, A, González Santos, P, Grana, M, Gül, A, Haga, H, de Haro Liger, M, Houssiau, F, Hughes, G, Ingelmo, M, Jedryka Góral, A, Khamashta, M, Lavilla, P, Levi, Y, López Dupla, M, López Soto, A, Maldykowa, H, Marcolongo, R, Mathieu, A, Morozzi, G, Nicolopoulou, N, Papasteriades, C, Passiu, G, Perelló, I, Petera, P, Petrovic, R, Piette, J, Pintado, V, de Pita, O, Popovic, R, Pucci, G, Puddu, P, de Ramón, E, Ramos Casals, M, Rodríguez Andreu, J, Ruiz Irastorza, G, Sánchez Lora, J, Sanna, G, Scorza, R, Sebastiani, G, Sherer, Y, Shoenfeld, Y, Simpatico, A, Sinico, R, Smolen, J, Tincani, A, Tokgöz, G, Urbano Márquez, A, Vasconcelos, C, Vázquez, J, Veronesi, M, Vianna, J, and Vivancos, J

Subjects
Male, medicine.medical_specialty, Prognosi, Epidemiology, Immunology, Systemic lupus erythematosu, Disease, Prognostic factors, Autoimmune Disease, Follow-Up Studie, Autoimmune Diseases, Cohort Studies, Systemic lupus erythematosus, immune system diseases, medicine, Immunology and Allergy, Humans, Lupus Erythematosus, Systemic, Prospective Studies, Age of Onset, Mortality, Prospective cohort study, skin and connective tissue diseases, Survival rate, Prognostic factor, business.industry, medicine.disease, Prognosis, Europe, Survival Rate, Prospective Studie, Family medicine, Antibodies, Antinuclear, Cohort, Female, Cohort Studie, Age of onset, Morbidity, business, Human, Cohort study, Follow-Up Studies
Abstract

The "Euro-Lupus Cohort" is composed by 1000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium-the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors. © 2005 Elsevier B.V. All rights reserved.

Published
2006

7. Features associated with epilepsy in the antiphospholipid syndrome

Author

Shoenfeld, Y, Lev, S, Blatt, I, Blank, M, Font, J, von Landenberg, P, Lev, N, Zaech, J, Cervera, R, Piette, Jc, Bertolaccini, Ml, Hughes, Gr, Youinou, P, Meroni, Pl, Pengo, V, Alves, Jd, Tincani, Angela, Szegedi, G, Lakos, G, Sturfelt, G, Jonsen, A, Koike, T, Sanmarco, M, Ruffatti, A, Ulcova Gallova, Z, Praprotnik, S, Rozman, B, Lorber, M, Chapman, J, van Breda Vriezman PJ, and Damoiseaux, J.

Published
2004

8. Prevalence and clinical correlations of antibodies against six beta2-Glycoprotein-I related peptides in the antiphospholipid syndrome

Author

Shoenfeld, Y, Krause, I, Kvapil, F, Sulkes, J, Lev, S, VON LANDENBERG, P, Font, J, Zaech, J, Cervera, R, Piette, Jc, Boffa, Mc, Khamashta, Ma, Bertolaccini, Ml, Hughes, Gr, Youinou, P, Meroni, Pl, Pengo, Vittorio, Alves, Jd, Tincani, A, Szegedi, G, Lakos, G, Sturfelt, G, Jonsen, A, Koike, T, Sanmarco, M, Ruffatti, Amelia, ULCOVA GALLOVA, Z, Praprotnik, S, Rozman, B, Lorber, M, Vriezman, Vb, and Blank, M.

Published
2003

9. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients

Author

Cervera, R, Piette, Jc, Font, J, Khamashta, Ma, Shoenfeld, Y, Camps, Mt, Jacobsen, S, Lakos, G, Tincani, Angela, Kontopoulou Griva, I, Galeazzi, M, Meroni, Pl, Derksen, Rh, de Groot PG, Gromnica Ihle, E, Baleva, M, Mosca, M, Bombardieri, S, Houssiau, F, Gris, Jc, Quere, I, Hachulla, E, Vasconcelos, C, Roch, B, Fernandez Nebro, A, Boffa, Mc, Hughes, Gr, and Ingelmo, M.

Subjects
Adult, Aged, 80 and over, Male, Adolescent, Lupus Vasculitis, Central Nervous System, Infant, Newborn, Infant, Middle Aged, Antiphospholipid Syndrome, Cohort Studies, Diagnosis, Differential, Age Distribution, Child, Preschool, Prevalence, Humans, Female, Sex Distribution, Child, Aged, Autoantibodies
Abstract

To analyze the clinical and immunologic manifestations of antiphospholipid syndrome (APS) in a large cohort of patients and to define patterns of disease expression.The clinical and serologic features of APS (Sapporo preliminary criteria) in 1,000 patients from 13 European countries were analyzed using a computerized database.The cohort consisted of 820 female patients (82.0%) and 180 male patients (18.0%) with a mean +/- SD age of 42 +/- 14 years at study entry. "Primary" APS was present in 53.1% of the patients; APS was associated with systemic lupus erythematosus (SLE) in 36.2%, with lupus-like syndrome in 5.0%, and with other diseases in 5.9%. A variety of thrombotic manifestations affecting the majority of organs were recorded. A catastrophic APS occurred in 0.8% of the patients. Patients with APS associated with SLE had more episodes of arthritis and livedo reticularis, and more frequently exhibited thrombocytopenia and leukopenia. Female patients had a higher frequency of arthritis, livedo reticularis, and migraine. Male patients had a higher frequency of myocardial infarction, epilepsy, and arterial thrombosis in the lower legs and feet. In 28 patients (2.8%), disease onset occurred before age 15; these patients had more episodes of chorea and jugular vein thrombosis than the remaining patients. In 127 patients (12.7%), disease onset occurred after age 50; most of these patients were men. These patients had a higher frequency of stroke and angina pectoris, but a lower frequency of livedo reticularis, than the remaining patients.APS may affect any organ of the body and display a broad spectrum of manifestations. An association with SLE, the patient's sex, and the patient's age at disease onset can modify the disease expression and define specific subsets of APS.

Published
2002

10. European Working Party on Systemic Lupus Erythematosus. Lessons from the 'Euro-Lupus Cohort'

Author

Cervera, R, ABARCA COSTALAGO, M, Abramovicz, D, Allegri, F, Annunziata, P, Aydintug, Ao, Bacarelli, Mr, Bellisai, F, Bernardino, I, BIERNAT KALUZA, E, Blockmans, D, Boki, K, Bracci, L, Campanella, V, Camps, Mt, Carcassi, C, Cattaneo, Roberto, Cauli, A, CHWALINSKA SADOWSKA, H, Contu, L, Cosyns, Jp, Danieli, Mg, D'Cruz, D, Depresseux, G, Direskeneli, H, Domènech, I, Espinosa, G, FERNÁNDEZ NEBRO, A, Ferrara, Gb, Font, J, Frutos, Ma, Galeazzi, M, GARCÍA CARRASCO, M, GARCÍA IGLESIAS MF, GARCÍA TOBARUELA, A, George, J, Gil, A, GONZÁLEZ SANTOS, P, Grana, M, Gül, A, Haga, Hj, DE HARO LIGER, M, Houssiau, F, Hughes, Gr, Ingelmo, M, JEDRYKA GÓRAL, A, Khamashta, Ma, Lavilla, P, Levi, Y, LÓPEZ DUPLA, M, LÓPEZ SOTO, A, Maldykowa, H, Marcolongo, R, Mathieu, A, Morozzi, G, Nicolopoulou, N, Papasteriades, C, Passiu, G, Perelló, I, Petera, P, Petrovic, R, Piette, Jc, Pintado, V, DE PITA, O, Popovic, R, Pucci, G, Puddu, P, DE RAMÓN, E, RAMOS CASALS, M, RODRÍGUEZ ANDREU, J, RUIZ IRASTROZA, G, SÁNCHEZ LORA, J, Sanna, G, Scorza, R, Sebastini, Gd, Sherer, Y, Shoenfeld, Y, Simpatico, A, Sinico, Ra, Smolen, J, Tincani, Angela, Tokgöz, G, URBANO MÁRQUEZ, A, Vasconcelos, C, Vázquez, Jj, Veronesi, M, Vianni, J, and Vivancos, J.

Published
2002

11. Lessons from the 'Euro-Lupus Cohort'

Author

Cervera, R., Abarca Costalago, M., Abramovicz, D., Allegri, F., PASQUALE ANNUNZIATA, Aydintug, Ao, Bacarelli, Mr, Bellisai, F., Bernardino, I., Biernat Kaluza, E., Blockmans, D., Boki, K., LUISA BRACCI, Campanella, V., Camps, Mt, Carcassi, C., Cattaneo, R., Cauli, A., Chwalinska Sadowska, H., Contu, L., Cosyns, Jp, Danieli, Mg, D Cruz, D., Depresseux, G., Direskeneli, H., Domènech, I., Espinosa, G., Fernández Nebro, A., Ferrara, Gb, Font, J., Frutos, Ma, MAURO GALEAZZI, García Carrasco, M., GARCÍA IGLESIAS MF, García Tobaruela, A., George, J., Gil, A., González Santos, P., Grana, M., Gül, A., Haga, Hj, Haro Liger, M., Houssiau, F., Hughes, Gr, Ingelmo, M., Jedryka Góral, A., Khamashta, Ma, Lavilla, P., Levi, Y., López Dupla, M., López Soto, A., Maldykowa, H., Marcolongo, R., Mathieu, A., GABRIELLA MOROZZI, Nicolopoulou, N., Papasteriades, C., Passiu, G., Perelló, I., Petera, P., Petrovic, R., Piette, Jc, Pintado, V., Pita, O., Popovic, R., Pucci, G., Puddu, P., Ramón, E., Ramos Casals, M., Rodríguez Andreu, J., Ruiz Irastroza, G., Sánchez Lora, J., Sanna, G., Scorza, R., Sebastini, Gd, Sherer, Y., Shoenfeld, Y., Simpatico, A., Sinico, Ra, Smolen, J., Tincani, A., Tokgöz, G., Urbano Márquez, A., Vasconcelos, C., Vázquez, Jj, Veronesi, M., Vianni, J., Vivancos, J., EUROPEAN WORKING PARTY ON SYSTEMIC LUPUS ERYTHEMATOSUS, Cervera, R, Abarca Costalago, M, Abramovicz, D, Allegri, F, Annunziata, P, Aydintug, A, Bacarelli, M, Bellisai, F, Bernardino, I, Biernat Kaluza, E, Blockmans, D, Boki, K, Bracci, L, Campanella, V, Camps, M, Carcassi, C, Cattaneo, R, Cauli, A, Chwalinska Sadowska, H, Contu, L, Cosyns, J, Danieli, M, D'Cruz, D, Depresseux, G, Direskeneli, H, Domènech, I, Espinosa, G, Fernández Nebro, A, Ferrara, G, Font, J, Frutos, M, Galeazzi, M, García Carrasco, M, García Iglesias, M, García Tobaruela, A, George, J, Gil, A, González Santos, P, Grana, M, Gül, A, Haga, H, de Haro Liger, M, Houssiau, F, Hughes, G, Ingelmo, M, Jedryka Góral, A, Khamashta, M, Lavilla, P, Levi, Y, López Dupla, M, López Soto, A, Maldykowa, H, Marcolongo, R, Mathieu, A, Morozzi, G, Nicolopoulou, N, Papasteriades, C, Passiu, G, Perelló, I, Petera, P, Petrovic, R, Piette, J, Pintado, V, de Pita, O, Popovic, R, Pucci, G, Puddu, P, de Ramón, E, Ramos Casals, M, Rodríguez Andreu, J, Ruiz Irastroza, G, Sánchez Lora, J, Sanna, G, Scorza, R, Sebastini, G, Sherer, Y, Shoenfeld, Y, Simpatico, A, Sinico, R, Smolen, J, Tincani, A, Tokgöz, G, Urbano Márquez, A, Vasconcelos, C, Vázquez, J, Veronesi, M, Vianni, J, and Vivancos, J

Subjects
Adult, Male, Adolescent, Prognosi, Middle Aged, Prognosis, Cohort Studies, Europe, Survival Rate, Prospective Studie, Antibodies, Antinuclear, Humans, Lupus Erythematosus, Systemic, Female, Prospective Studies, Cohort Studie, Age of Onset, Human
Abstract

The "Euro-Lupus Cohort" is composed by 1,000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium - the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.

Published
2002

14. Letters

Author

Jerome, Lawrence E., Bok, Bart J., Cousins, Harold, Bearden, Romare H., Shields, Allan, Benyon, Margaret, Linderman, Earl W., Khatchadourian, Haig, Brook, Donald, Wenninger, Magnus J., Kramer, Jack, Panting, John, and Hughes, Graham

Published
2017

15. Polymyositis-dermatomyositis: a clinical review

Author

H. Gonzalez-Buritica, Khamashta Ma, K. W. Strauss, and Hughes Gr

Subjects
Pathology, medicine.medical_specialty, Proximal muscle weakness, Polymyositis, Dermatomyositis, Neoplasms, medicine, Humans, Creatine Kinase, Myositis, Muscle biopsy, biology, medicine.diagnostic_test, business.industry, Skeletal muscle, General Medicine, Prognosis, medicine.disease, Rash, medicine.anatomical_structure, biology.protein, Creatine kinase, medicine.symptom, business, Research Article
Abstract

Polymyositis (PM) and dermatomyositis (DM) are characterized by chronic inflammation of skeletal muscle and are manifested, in their classic presentation, by proximal muscle weakness accompanied by elevations of the serum creatine kinase (CK) typical electromyography (EMG) changes with polyphasic potentials and muscle biopsy findings of a necrotizing, inflammatory process.' DM is distinguished from PM by a typical rash, usually red, scaly and plaque-like, over the knuckles, wrists, elbows, knees and ankle malleoli and violaceous lesions in the periorbital and trunk area.2 Most authors, however, consider DM and PM together since the disease course and muscle lesions are the same, whether skin lesions are present or not.3 These diseases are of unknown aetiology and reltively rare but have been associated with a host of inciting agents, from infections4 to vaccines5 to malignancies' and involve a multitude of immunological abnormalities.7 The classification scheme popularized by Bohan et al.8'9 and modified by Whitaker4 appears in Table I. This review concentrates on types I, II, III and V.

Published
1989
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41. Systemic lupus erythematosus.

Author

D'Cruz DP, Khamashta MA, Hughes GR, D'Cruz, David P, Khamashta, Munther A, and Hughes, Graham R V

Abstract

Systemic lupus erythematosus is an autoimmune connective-tissue disorder with a wide range of clinical features, which predominantly affects women, especially from certain ethnic groups. Diagnosis is based on clinical assessment supported by investigations, including the finding of autoantibodies. Treatments range from antimalarial agents to corticosteroids and immunosuppressive agents. This Seminar draws attention to advances in the epidemiology, genetics, cardiovascular risks, lupus nephritis, CNS disease, the antiphospholipid syndrome, assessment of disease activity and damage, and pregnancy related and quality of life issues. New therapeutic approaches, such as biological agents and mycophenolate mofetil, will also be discussed. [ABSTRACT FROM AUTHOR]

Published
2007
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43. Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.

Author

Dudey AP, Rigby JM, Hughes GR, Stephenson GR, Storr TE, Chantry A, and Hemmings AM

Subjects
Humans, Structure-Activity Relationship, Molecular Structure, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis, Ubiquitin-Protein Ligases antagonists & inhibitors, Ubiquitin-Protein Ligases metabolism, Dose-Response Relationship, Drug, Molecular Docking Simulation
Abstract

The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC 50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC 50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5- b ]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.

Published
2024
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44. Enzymatic Fluoromethylation as a Tool for ATP-Independent Ligation.

Author

Peng J, Hughes GR, Müller MM, and Seebeck FP

Abstract

S -adenosylmethionine-dependent methyltransferases are involved in countless biological processes, including signal transduction, epigenetics, natural product biosynthesis, and detoxification. Only a handful of carboxylate methyltransferases have evolved to participate in amide bond formation. In this report we show that enzyme-catalyzed F-methylation of carboxylate substrates produces F-methyl esters that readily react with N - or S -nucleophiles under physiological conditions. We demonstrate the applicability of this approach to the synthesis of small amides, hydroxamates, and thioesters, as well as to site-specific protein modification and native chemical ligation., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Angewandte Chemie published by Wiley-VCH GmbH.)

Published
2024
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45. Delivering manual cardiopulmonary resuscitation (CPR) in a diving bell: an analysis of head-to-chest and knee-to-chest compression techniques.

Author

Johnson G, Bryson P, Tilbury N, McGregor B, Wesson A, Hughes GD, Hughes GR, and Tabner A

Subjects
Humans, Diving, Cardiopulmonary Resuscitation
Abstract

Introduction: Chest compression often cannot be administered using conventional techniques in a diving bell. Multiple alternative techniques are taught, including head-to-chest and both prone and seated knee-to-chest compressions, but there are no supporting efficacy data. This study evaluated the efficacy, safety and sustainability of these techniques., Methods: Chest compressions were delivered by a team of expert cardiopulmonary resuscitation (CPR) providers. The primary outcome was proportion of chest compressions delivered to target depth compared to conventional CPR. Techniques found to be safe and potentially effective by the study team were further trialled by 20 emergency department staff members., Results: Expert providers delivered a median of 98% (interquartile range [IQR] 1.5%) of chest compressions to the target depth using conventional CPR. Only 32% (IQR 60.8%) of head-to-chest compressions were delivered to depth; evaluation of the technique was abandoned due to adverse effects. No study team member could register sustained compression outputs using prone knee-to-chest compressions. Seated knee-to-chest were delivered to depth 12% (IQR 49%) of the time; some compression providers delivered > 90% of compressions to depth., Conclusions: Head-to-chest compressions have limited efficacy and cause harm to providers; they should not be taught or used. Prone knee-to-chest compressions are ineffective. Seated knee-to-chest compressions have poor overall efficacy but some providers deliver them well. Further research is required to establish whether this technique is feasible, effective and sustainable in a diving bell setting, and whether it can be taught and improved with practise., (Copyright: This article is the copyright of the authors who grant Diving and Hyperbaric Medicine a non-exclusive licence to publish the article in electronic and other forms.)

Published
2023
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46. An evaluation of the NUI Compact Chest Compression Device (NCCD), a mechanical CPR device suitable for use in the saturation diving environment.

Author

Tabner A, Bryson P, Tilbury N, McGregor B, Wesson A, Hughes GD, Hughes GR, and Johnson G

Subjects
Humans, Diving, Cardiopulmonary Resuscitation
Abstract

Introduction: Provision of manual chest compressions in a diving bell using a conventional technique is often impossible, and alternative techniques are poorly evidenced in terms of efficacy and sustainability. The first mechanical cardiopulmonary resuscitation (CPR) device suitable for use in this environment, the NUI Compact Chest Compression Device (NCCD), has recently been designed and manufactured. This study assessed both the efficacy of the device in delivering chest compressions to both prone and seated manikins, and the ability of novice users to apply and operate it., Methods: Compression efficacy was assessed using a Resusi Anne QCPR intelligent manikin, and the primary outcome was the proportion of compressions delivered to target depth (50-60 mm). The gold standard was that achieved by expert CPR providers delivering manual CPR; the LUCAS 3 mCPR device was a further comparator., Results: The NCCD delivered 100% of compressions to target depth compared to 98% for the gold standard (interquartile range 1.5%) and 98% for the LUCAS 3 when applied to both supine and seated manikins. The NCCD sometimes became dislodged and had to be reapplied when used with a seated manikin., Conclusions: The NCCD can deliver chest compressions at target rate and depth to both supine and seated manikins with efficacy equivalent to manual CPR and the LUCAS 3. It can become dislodged when applied to a seated manikin; its design has now been altered to prevent this. New users can be trained in use of the NCCD quickly, but practise is required to ensure effective use., (Copyright: This article is the copyright of the authors who grant Diving and Hyperbaric Medicine a non-exclusive licence to publish the article in electronic and other forms.)

Published
2023
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47. Timing and Dose of Upper Limb Motor Intervention After Stroke: A Systematic Review.

Author

Hayward KS, Kramer SF, Dalton EJ, Hughes GR, Brodtmann A, Churilov L, Cloud G, Corbett D, Jolliffe L, Kaffenberger T, Rethnam V, Thijs V, Ward N, Lannin N, and Bernhardt J

Subjects
Humans, Upper Extremity, Recovery of Function, Stroke Rehabilitation methods, Time-to-Treatment
Abstract

This systematic review aimed to investigate timing, dose, and efficacy of upper limb intervention during the first 6 months poststroke. Three online databases were searched up to July 2020. Titles/abstracts/full-text were reviewed independently by 2 authors. Randomized and nonrandomized studies that enrolled people within the first 6 months poststroke, aimed to improve upper limb recovery, and completed preintervention and postintervention assessments were included. Risk of bias was assessed using Cochrane reporting tools. Studies were examined by timing (recovery epoch), dose, and intervention type. Two hundred and sixty-one studies were included, representing 228 (n=9704 participants) unique data sets. The number of studies completed increased from one (n=37 participants) between 1980 and 1984 to 91 (n=4417 participants) between 2015 and 2019. Timing of intervention start has not changed (median 38 days, interquartile range [IQR], 22-66) and study sample size remains small (median n=30, IQR 20-48). Most studies were rated high risk of bias (62%). Study participants were enrolled at different recovery epochs: 1 hyperacute (<24 hours), 13 acute (1-7 days), 176 early subacute (8-90 days), 34 late subacute (91-180 days), and 4 were unable to be classified to an epoch. For both the intervention and control groups, the median dose was 45 (IQR, 600-1430) min/session, 1 (IQR, 1-1) session/d, 5 (IQR, 5-5) d/wk for 4 (IQR, 3-5) weeks. The most common interventions tested were electromechanical (n=55 studies), electrical stimulation (n=38 studies), and constraint-induced movement (n=28 studies) therapies. Despite a large and growing body of research, intervention dose and sample size of included studies were often too small to detect clinically important effects. Furthermore, interventions remain focused on subacute stroke recovery with little change in recent decades. A united research agenda that establishes a clear biological understanding of timing, dose, and intervention type is needed to progress stroke recovery research. Prospective Register of Systematic Reviews ID: CRD42018019367/CRD42018111629.

Published
2021
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48. Frontiers in PROTACs.

Author

Hughes GR, Dudey AP, Hemmings AM, and Chantry A

Subjects
Drug Discovery methods, Humans, Proteasome Endopeptidase Complex metabolism, Proteolysis, Drug Development methods, Molecular Targeted Therapy, Proteins metabolism
Abstract

Targeting protein-protein interactions (PPI) is a key focus in the development of new and emerging small-molecule therapeutics. Shallow interacting surfaces can render PPI targeting notoriously difficult. This leaves many therapeutically captivating targets 'undruggable'. Despite these challenges, there has been extraordinary progress circumventing this issue by hijacking the ubiquitin proteasome system (UPS) to target selected substrates for destruction using target-based degradation (TBD) strategies, including bifunctional molecules known as proteolysis-targeting chimeras (PROTACs). In this review, we discuss some of the most recent innovative concepts emerging from PROTAC research and related technologies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Published
2021
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49. Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors.

Author

Watt JE, Hughes GR, Walpole S, Monaco S, Stephenson GR, Bulman Page PC, Hemmings AM, Angulo J, and Chantry A

Subjects
Binding Sites, Drug Discovery, Enzyme Inhibitors metabolism, Humans, Inhibitory Concentration 50, Ligands, Molecular Docking Simulation, Nuclear Magnetic Resonance, Biomolecular, PTEN Phosphohydrolase metabolism, Protein Structure, Tertiary, Small Molecule Libraries metabolism, Solubility, Ubiquitin-Protein Ligases metabolism, Enzyme Inhibitors chemistry, Small Molecule Libraries chemistry, Ubiquitin-Protein Ligases antagonists & inhibitors
Abstract

We have screened small molecule libraries specifically for inhibitors that target WWP2, an E3 ubiquitin ligase associated with tumour outgrowth and spread. Selected hits demonstrated dose-dependent WWP2 inhibition, low micromolar IC50 values, and inhibition of PTEN substrate-specific ubiquitination. Binding to WWP2 was confirmed by ligand-based NMR spectroscopy. Furthermore, we used a combination of STD NMR, the recently developed DEEP-STD NMR approach, and docking calculations, to propose for the first time an NMR-validated 3D molecular model of a WWP2-inhibitor complex. These first generation WWP2 inhibitors provide a molecular framework for informing organic synthetic approaches to improve activity and selectivity., (© 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Published
2018
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