119 results on '"Polus F"'
Search Results
2. Non-invasive candidate protein signature predicts hepatic venous pressure gradient reduction in cirrhotic patients after sustained virologic response.
- Author
-
Richards SM, Guo F, Zou H, Nigsch F, Baiges A, Pachori A, Zhang Y, Lens S, Pitts R, Finkel N, Loureiro J, Mongeon D, Ma S, Watkins M, Polus F, Albillos A, Tellez L, Martinez-González J, Bañares R, Turon F, Ferrusquía-Acosta J, Perez-Campuzano V, Magaz M, Forns X, Badman M, Sailer AW, Ukomadu C, Hernández-Gea V, and Garcia-Pagán JC
- Subjects
- Humans, Sustained Virologic Response, Proteomics, Liver Cirrhosis, Hepacivirus, Portal Pressure, Venous Pressure, Hypertension, Portal drug therapy, Hypertension, Portal etiology, Hepatitis C
- Abstract
Background and Aims: A reduction in hepatic venous pressure gradient (HVPG) is the most accurate marker for assessing the severity of portal hypertension and the effectiveness of intervention treatments. This study aimed to evaluate the prognostic potential of blood-based proteomic biomarkers in predicting HVPG response amongst cirrhotic patients with portal hypertension due to Hepatitis C virus (HCV) and had achieved sustained virologic response (SVR)., Methods: The study comprised 59 patients from two cohorts. Patients underwent paired HVPG (pretreatment and after SVR), liver stiffness (LSM), and enhanced liver fibrosis scores (ELF) measurements, as well as proteomics-based profiling on serum samples using SomaScan® at baseline (BL) and after SVR (EOS). Machine learning with feature selection (Caret, Random Forest and RPART) methods were performed to determine the proteins capable of classifying HVPG responders. Model performance was evaluated using AUROC (pROC R package)., Results: Patients were stratified by a change in HVPG (EOS vs. BL) into responders (greater than 20% decline in HVPG from BL, or <10 mmHg at EOS with >10 mmHg at BL) and non-responders. LSM and ELF decreased markedly after SVR but did not correlate with HVPG response. SomaScan (SomaLogic, Inc., Boulder, CO) analysis revealed a substantial shift in the peripheral proteome composition, reflected by 82 significantly differentially abundant proteins. Twelve proteins accurately distinguished responders from non-responders, with an AUROC of .86, sensitivity of 83%, specificity of 83%, accuracy of 83%, PPV of 83%, and NPV of 83%., Conclusions: A combined non-invasive soluble protein signature was identified, capable of accurately predicting HVPG response in HCV liver cirrhosis patients after achieving SVR., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
3. First-in-human trial results of LNA043, a novel cartilage regenerative treatment for osteoarthritis
- Author
-
Scotti, C., primary, Gimbel, J., additional, Laurent, D., additional, Madar, A., additional, Peters, T., additional, Zhang, Y., additional, Polus, F., additional, Beste, M., additional, Vostiar, I., additional, Choudhury, S., additional, Gerwin, N., additional, Goldhahn, J., additional, Schieker, M., additional, and Roubenoff, R., additional
- Published
- 2021
- Full Text
- View/download PDF
4. Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial.
- Author
-
Gerwin N, Scotti C, Halleux C, Fornaro M, Elliott J, Zhang Y, Johnson K, Shi J, Walter S, Li Y, Jacobi C, Laplanche N, Belaud M, Paul J, Glowacki G, Peters T, Wharton KA Jr, Vostiar I, Polus F, Kramer I, Guth S, Seroutou A, Choudhury S, Laurent D, Gimbel J, Goldhahn J, Schieker M, Brachat S, Roubenoff R, and Kneissel M
- Subjects
- Humans, Chondrocytes, Signal Transduction, Angiopoietins metabolism, Angiopoietins pharmacology, Angiopoietins therapeutic use, Angiopoietin-Like Protein 3, Osteoarthritis, Knee drug therapy, Cartilage, Articular
- Abstract
Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043-a derivative of angiopoietin-like 3 (ANGPTL3)-as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo. LNA043 exerts at least part of these effects through binding to the fibronectin receptor, integrin α
5 β1 on mesenchymal stem cells and chondrocytes. In a first-in-human (phase 1), randomized, double-blinded, placebo-controlled, single ascending dose, single-center trial ( NCT02491281 ; sponsored by Novartis Pharmaceuticals), 28 patients with knee OA were injected intra-articularly with LNA043 or placebo (3:1 ratio) either 2 h, 7 d or 21 d before total knee replacement. LNA043 met its primary safety endpoint and showed short serum pharmacokinetics, cartilage penetration and a lack of immunogenicity (secondary endpoints). Post-hoc transcriptomics profiling of cartilage revealed that a single LNA043 injection reverses the OA transcriptome signature over at least 21 d, inducing the expression of hyaline cartilage matrix components and anabolic signaling pathways, while suppressing mediators of OA progression. LNA043 is a novel disease-modifying OA drug candidate that is currently in a phase 2b trial ( NCT04864392 ) in patients with knee OA., (© 2022. The Author(s).)- Published
- 2022
- Full Text
- View/download PDF
5. Evaluation of a comprehensive pre-procedural screening protocol for COVID-19 in times of a high SARS CoV-2 prevalence: a prospective cross-sectional study.
- Author
-
Stessel B, Callebaut I, Polus F, Geebelen L, Evers S, Ory JP, Magerman K, Souverijns G, Braeken G, Ramaekers D, and Cox J
- Subjects
- Adult, Aged, COVID-19 epidemiology, Cross-Sectional Studies, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Sensitivity and Specificity, Tomography, X-Ray Computed, COVID-19 diagnosis, COVID-19 Testing methods, Mass Screening methods, Patient Admission
- Abstract
Background: To minimise the risk of COVID-19 transmission, an ambulant screening protocol for COVID-19 in patients before admission to the hospital was implemented, combining the SARS CoV-2 reverse-transcriptase polymerase chain reaction (RT-PCR) on a nasopharyngeal swab, a chest computed tomography (CT) and assessment of clinical symptoms. The aim of this study was to evaluatethe diagnostic yield and the proportionality of this pre-procedural screeningprotocol., Methods: In this mono-centre, prospective, cross-sectional study, all patients admitted to the hospital between 22nd April 2020 until 14th May 2020 for semi-urgent surgery, haematological or oncological treatment, or electrophysiological investigationunderwent a COVID-19 screening 2 days before their procedure. At a 2-week follow-up, the presence of clinical symptoms was evaluated by telephone as a post-hoc evaluation of the screening approach.Combined positive RT-PCR assay and/or positive chest CT was used as gold standard. Post-procedural outcomes of all patients diagnosed positive for COVID-19 were assessed., Results: In total,528 patients were included of which 20 (3.8%) were diagnosed as COVID-19 positive and 508 (96.2%) as COVID-19 negative. 11 (55.0%) of COVID-19 positive patients had only a positive RT-PCR assay, 3 (15.0%) had only a positive chest CT and 6 (30%) had both a positive RT-PCR assay and chest CT. 10 out of 20 (50.0%) COVID-19 positive patients reported no single clinical symptom at the screening. At 2 week follow-up, 50% of these patients were still asymptomatic. 37.5% of all COVID-19 negative patients were symptomatic at screening. In the COVID-19 negative group without symptoms at screening, 78 (29.3%) patients developed clinical symptoms at a 2-week follow-up., Conclusion: This study suggests that routine chest CT and assessment of self-reported symptoms have limited value in the preprocedural COVID-19 screening due to low sensitivity and/or specificity.
- Published
- 2021
- Full Text
- View/download PDF
6. A new viewpoint on endoscopic CABG: technique description and clinical experience.
- Author
-
Yilmaz A, Robic B, Starinieri P, Polus F, Stinkens R, and Stessel B
- Subjects
- Aged, Coronary Artery Disease mortality, Diabetes Mellitus mortality, Diabetes Mellitus surgery, Female, Graft Rejection, Humans, Length of Stay, Male, Middle Aged, Obesity mortality, Obesity surgery, Reoperation, Sternotomy, Coronary Artery Bypass methods, Coronary Artery Disease surgery, Endoscopy methods
- Abstract
Background: The aim of this paper is to describe a newly developed endoscopic coronary artery bypass graft (Endo-CABG) technique to treat patients with single- and multi-vessel disease and discuss the short-term clinical results in a large patient cohort. This technique avoids a median sternotomy by combining a thoracoscopic technique via three ∼5 mm thoracic ports and a mini-thoracotomy utility 3-4 cm port through the intercostal space., Methods: From January 2016 to January 2018, data from consecutive patients undergoing an elective Endo-CABG were prospectively entered into a customized database and retrospectively reviewed. Patients scheduled for a combined hybrid intervention were excluded. Conversion rate to sternotomy, incidence of surgical revision and postoperative graft failure, one-month survival, morbidity, and length of stay (LOS) were investigated. Subgroup analyses were performed., Results: A total of 342 patients undergoing an Endo-CABG with one (n = 53) or multiple (n = 289) bypasses were included. No conversion to sternotomy occurred and incidence of surgical revision, graft failure, and 30-day mortality was 7.3%, 1.5%, and 1.8%, respectively. Adverse neurological outcomes were rare: cerebrovascular accident, transient ischemic attack, epilepsy, and postoperative delirium were observed in 0.6%, 0.3%, 0.3%, and 5.3% of patients, respectively. Median intensive care unit and hospital LOS were 2.75 (IQR 1.8 to 3.8) and 8.0 days (IQR 7.0 to 10.0), respectively. Thirty-day mortality in obese patients, diabetics, and octogenarians was 0%, 3.6%, and 5.6%, respectively. EuroSCORE II > 5% was associated with a high 30-day mortality (25%)., Conclusions: Endo-CABG can be considered a safe and effective procedure to treat single- and multi-vessel coronary artery disease. Individual patient selection seems not necessary to apply this technique., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
7. β-Defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis.
- Author
-
Kolbinger F, Loesche C, Valentin MA, Jiang X, Cheng Y, Jarvis P, Peters T, Calonder C, Bruin G, Polus F, Aigner B, Lee DM, Bodenlenz M, Sinner F, Pieber TR, and Patel DD
- Subjects
- Adult, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Autoimmune Diseases blood, Biomarkers blood, Female, Humans, Male, Psoriasis drug therapy, Psoriasis immunology, Skin immunology, Skin pathology, Interleukin-17 blood, Psoriasis blood, beta-Defensins blood
- Abstract
Background: IL-17A is a key driver of human autoimmune diseases, particularly psoriasis., Objective: We sought to determine the role of IL-17A in psoriasis pathogenesis and to identify a robust and measurable biomarker of IL-17A-driven pathology., Methods: We studied 8 healthy subjects and 8 patients with psoriasis before and after administration of secukinumab, a fully human anti-IL-17A mAb, and used a combination of classical techniques and a novel skin microperfusion assay to evaluate the expression of 170 proteins in blood, nonlesional skin, and lesional skin. For validation, we also tested stored sera from 601 patients with a variety of autoimmune diseases., Results: IL-17A was specifically expressed in lesional compared with nonlesional psoriatic skin (9.8 vs 0.8 pg/mL, P < .001). Proteomic and gene transcription analyses revealed dysregulated antimicrobial peptides, proinflammatory cytokines, and neutrophil chemoattractants, levels of which returned to normal after treatment with secukinumab. β-Defensin 2 (BD-2) was identified as a biomarker of IL-17A-driven pathology by comparing protein expression in patients with psoriasis versus that in healthy subjects (5746 vs 82 pg/mL in serum, P < .0001; 2747 vs <218 pg/mL in dermis, P < .001), responsiveness to secukinumab therapy, and synergistic induction by IL-17A and TNF-α in epidermal keratinocytes. In a validation set of sera from 601 patients with autoimmune diseases thought to be IL-17A driven, we found that BD-2 levels are most highly increased in patients with psoriatic skin lesions, and in patients with psoriasis, BD-2 levels correlated well with IL-17A levels (r = 0.70, n = 199, P < .001) and Psoriasis Area and Severity Index scores (r = 0.53, n = 281, P < .001)., Conclusion: IL-17A is a primary driver of skin pathology in patients with psoriasis, and serum BD-2 is an easily measurable biomarker of IL-17A-driven skin pathology., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
8. Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion.
- Author
-
Dragatin C, Polus F, Bodenlenz M, Calonder C, Aigner B, Tiffner KI, Mader JK, Ratzer M, Woessner R, Pieber TR, Cheng Y, Loesche C, Sinner F, and Bruin G
- Subjects
- Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal immunology, Antibodies, Monoclonal, Humanized, Body Weight, Drug Evaluation, Preclinical, Humans, Injections, Subcutaneous, Interleukin-17 immunology, Perfusion, Time Factors, Antibodies, Monoclonal pharmacokinetics, Body Fluids metabolism, Psoriasis metabolism
- Published
- 2016
- Full Text
- View/download PDF
9. Pharmacokinetic and pharmacodynamic interaction of siponimod (BAF312) and propranolol in healthy subjects.
- Author
-
Biswal S, Polus F, Pal P, Veldandi UK, Marbury TC, Perry R, and Legangneux E
- Subjects
- Adult, Azetidines pharmacokinetics, Benzyl Compounds pharmacokinetics, Blood Pressure drug effects, Double-Blind Method, Drug Interactions, Female, Forced Expiratory Volume drug effects, Heart Rate drug effects, Humans, Male, Middle Aged, Propranolol pharmacokinetics, Young Adult, Azetidines pharmacology, Benzyl Compounds pharmacology, Propranolol pharmacology
- Abstract
Objective: To evaluate the cardiac and pulmonary effects of siponimod (BAF312) and propranolol co-administration in healthy subjects., Methods: Healthy subjects (n=76) were randomized in a doubleblind manner to receive propranolol at siponimod steady state (group A), siponimod at propranolol steady state (group B), placebo (group C) and propranolol (group D). Pharmacodynamic evaluations included maximum change from baseline in time-matched hourly average heart rate (Emax HR) and mean arterial blood pressure (Emax MABP) over 24 hours postdose, change from baseline in PR intervals, cardiac rhythm, and forced expiratory volume in 1 second (FEV1). Pharmacokinetic and safety parameters were also assessed., Results: Siponimod and propranolol when administered alone resulted in similar HR decrease at steady state. Compared to propranolol alone, the combination at steady state had an additional 6.21 bpm (95%CI: 2.32, 10.11) decrease of mean EmaxHR, a decrease of 5.04 bpm (0.52, 9.56) for group A and 7.39 bpm (2.87, 11.90) for group B. A minor decrease in MABP and a trend towards PR interval increase were noted with co-administration treatment vs. propranolol alone. There were no episodes of second-degree atrioventricular blocks or sinus pauses>3 seconds. Baseline-corrected FEV1 was reduced by -0.07 L (95% CI: -0.17, 0.03) for group A and -0.05 L (-0.15, 0.05) for group B vs. propranolol alone. There were no cardiovascular adverse events during coadministration treatment., Conclusions: Coadministration of siponimod and propranolol was well tolerated. Bradyarrhythmic effects were less pronounced when propranolol was added to siponimod steady-state therapy compared with siponimod addition to propranolol.
- Published
- 2015
- Full Text
- View/download PDF
10. The Contribution of the Skin Microbiome to Psoriasis Pathogenesis and Its Implications for Therapeutic Strategies.
- Author
-
Radaschin, Diana Sabina, Tatu, Alin, Iancu, Alina Viorica, Beiu, Cristina, and Popa, Liliana Gabriela
- Abstract
Psoriasis is a common chronic inflammatory skin disease, associated with significant morbidity and a considerable negative impact on the patients' quality of life. The complex pathogenesis of psoriasis is still incompletely understood. Genetic predisposition, environmental factors like smoking, alcohol consumption, psychological stress, consumption of certain drugs, and mechanical trauma, as well as specific immune dysfunctions, contribute to the onset of the disease. Mounting evidence indicate that skin dysbiosis plays a significant role in the development and exacerbation of psoriasis through loss of immune tolerance to commensal skin flora, an altered balance between Tregs and effector cells, and an excessive Th1 and Th17 polarization. While the implications of skin dysbiosis in psoriasis pathogenesis are only starting to be revealed, the progress in the characterization of the skin microbiome changes in psoriasis patients has opened a whole new avenue of research focusing on the modulation of the skin microbiome as an adjuvant treatment for psoriasis and as part of a long-term plan to prevent disease flares. The skin microbiome may also represent a valuable predictive marker of treatment response and may aid in the selection of the optimal personalized treatment. We present the current knowledge on the skin microbiome changes in psoriasis and the results of the studies that investigated the efficacy of the different skin microbiome modulation strategies in the management of psoriasis, and discuss the complex interaction between the host and skin commensal flora. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
11. Fast Clinical Response of Bimekizumab in Nail Psoriasis: A Retrospective Multicenter 36-Week Real-Life Study.
- Author
-
Campione, Elena, Artosi, Fabio, Shumak, Ruslana Gaeta, Giunta, Alessandro, Argenziano, Giuseppe, Assorgi, Chiara, Balato, Anna, Bernardini, Nicoletta, Brunasso, Alexandra Maria Giovanna, Burlando, Martina, Caldarola, Giacomo, Campanati, Anna, Carugno, Andrea, Castelli, Franco, Conti, Andrea, Costanzo, Antonio, Cuccia, Aldo, Dapavo, Paolo, Dattola, Annunziata, and De Simone, Clara
- Abstract
(1) Background/Objectives: Nail psoriasis (NP) is a chronic and difficult-to-treat disease, which causes significant social stigma and impairs the patients' quality of life. Moreover, nail psoriasis is a true therapeutic challenge for clinicians. The presence of nail psoriasis can be part of a severe form of psoriasis and can have predictive value for the development of psoriatic arthritis. Our real-world-evidence multicenter study aims to evaluate the efficacy of bimekizumab in nail psoriasis. (2) Methods: A retrospective analysis of a multicenter observational study included 834 patients affected by moderate-to-severe psoriasis, in 33 Dermatologic Units in Italy, treated with bimekizumab from December 2022 to September 2023. Clinimetric assessments were based on Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), and Physician's Global Assessment of Fingernail Psoriasis (PGA-F) for the severity of nail psoriasis at 0, 12, 24, and 36 weeks. (3) Results: Psoriatic nail involvement was present in 27.95% of patients. The percentage of patients who achieved a complete clearance of NP in terms of PGA-F 0 was 31.7%, 57%, and 88.5% at week 4, 16, and 36, respectively. PASI 100 was achieved by 32.03% of patients at week 4, by 61.8% at week 16, and by 78.92% of patients at week 36. The mean baseline PASI was 16.24. The mean DLQI values for the entire group of patients at baseline, at week 4, at week 16, and at week 36 were 14.62, 3.02, 0.83, and 0.5, respectively. (4) Conclusions: Therapies that promote the healing of both the skin and nails in a short time can also ensure a lower risk of subsequently developing arthritis which is disabling over time. Bimekizumab proved to be particularly effective to treat NP, with a fast response in terms of complete clearance, with over 88.5% of patients free from NP after 36 weeks. The findings of our real-world study showed that patients with moderate-to-severe PsO and concomitant NP had significantly faster and more substantial improvements in NP up to 36 weeks with respect to previous research findings. Considering the rapid healing of the nail, the dual inhibition of IL17 A and F might have a great value in re-establishing the dysregulation of keratin 17 at the nail level. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
12. Totally endoscopic coronary artery bypass grafting: experience in 1500 patients.
- Author
-
Claessens, Jade, Packlé, Loren, Oosterbos, Hanne, Smeets, Elke, Geens, Jelena, Gielen, Jens, Van Genechten, Silke, Heuts, Samuel, Maessen, Jos G., and Yilmaz, Alaaddin
- Published
- 2024
- Full Text
- View/download PDF
13. A translocated effector required for Bartonella dissemination from derma to blood safeguards migratory host cells from damage by co-translocated effectors.
- Author
-
Okujava R, Guye P, Lu YY, Mistl C, Polus F, Vayssier-Taussat M, Halin C, Rolink AG, and Dehio C
- Subjects
- Actin Cytoskeleton metabolism, Animals, Bacterial Proteins genetics, Bacterial Proteins metabolism, Bartonella immunology, Bartonella Infections immunology, Bartonella Infections pathology, Bone Marrow Cells cytology, Bone Marrow Cells immunology, Cell Movement, Cells, Cultured, Dendritic Cells cytology, Dendritic Cells immunology, Female, Host-Pathogen Interactions, Human Umbilical Vein Endothelial Cells cytology, Humans, Mice, Mice, Inbred BALB C, Protein Structure, Tertiary, Protein Transport, Rats, Rats, Wistar, Signal Transduction, Virulence Factors genetics, Virulence Factors metabolism, rhoA GTP-Binding Protein metabolism, Bacterial Secretion Systems, Bartonella pathogenicity, Cytoprotection, Dendritic Cells microbiology, Human Umbilical Vein Endothelial Cells microbiology
- Abstract
Numerous bacterial pathogens secrete multiple effectors to modulate host cellular functions. These effectors may interfere with each other to efficiently control the infection process. Bartonellae are Gram-negative, facultative intracellular bacteria using a VirB type IV secretion system to translocate a cocktail of Bartonella effector proteins (Beps) into host cells. Based on in vitro infection models we demonstrate here that BepE protects infected migratory cells from injurious effects triggered by BepC and is required for in vivo dissemination of bacteria from the dermal site of inoculation to blood. Human endothelial cells (HUVECs) infected with a ΔbepE mutant of B. henselae (Bhe) displayed a cell fragmentation phenotype resulting from Bep-dependent disturbance of rear edge detachment during migration. A ΔbepCE mutant did not show cell fragmentation, indicating that BepC is critical for triggering this deleterious phenotype. Complementation of ΔbepE with BepEBhe or its homologues from other Bartonella species abolished cell fragmentation. This cyto-protective activity is confined to the C-terminal Bartonella intracellular delivery (BID) domain of BepEBhe (BID2.EBhe). Ectopic expression of BID2.EBhe impeded the disruption of actin stress fibers by Rho Inhibitor 1, indicating that BepE restores normal cell migration via the RhoA signaling pathway, a major regulator of rear edge retraction. An intradermal (i.d.) model for B. tribocorum (Btr) infection in the rat reservoir host mimicking the natural route of infection by blood sucking arthropods allowed demonstrating a vital role for BepE in bacterial dissemination from derma to blood. While the Btr mutant ΔbepDE was abacteremic following i.d. inoculation, complementation with BepEBtr, BepEBhe or BIDs.EBhe restored bacteremia. Given that we observed a similar protective effect of BepEBhe on infected bone marrow-derived dendritic cells migrating through a monolayer of lymphatic endothelial cells we propose that infected dermal dendritic cells may be involved in disseminating Bartonella towards the blood stream in a BepE-dependent manner.
- Published
- 2014
- Full Text
- View/download PDF
14. Evaluation of Kynu, Defb2, Camp, and Penk Expression Levels as Psoriasis Marker in the Imiquimod‐Induced Psoriasis Model.
- Author
-
Emami, Zahra, Shobeiri, Saeideh Sadat, Khorrami, Razia, Haghnavaz, Navideh, Rezaee, Mohammad Ali, Moghadam, Malihe, Pordel, Safoora, Sankian, Mojtaba, and Zimetti, Francesca
- Subjects
ANTIMICROBIAL peptides ,GENE expression ,SKIN diseases ,LABORATORY mice ,LYMPH nodes - Abstract
Background. Psoriasis is a noncontagious auto‐inflammatory chronic skin disease. So far, some of the inflammatory genes were upregulated in mouse model of psoriasis. This study examined changes in skin mRNA expression of L‐kynureninase (Kynu), cathelicidin antimicrobial peptide (Camp), beta‐defensin 2 (Defb2), and proenkephalin (Penk) in a mouse model of imiquimod‐induced psoriasis. Materials and Methods. Tree groups of C57BL/6 female mice were allocated. The imiquimod (IMQ) cream was administered to the mice dorsal skin of the two groups to induce psoriatic inflammation. In the treatment group, IMQ was administered 10 min after hydrogel‐containing M7 anti‐IL‐17A aptamer treatment. Vaseline (Vas) was administered to the negative control group. The psoriatic skin lesions were evaluated based on the psoriasis area severity index (PASI) score, histopathology, and mRNA expression levels of Kynu, Camp, Defb2, and Penk using real‐time PCR. In order to assess the systemic response, the spleen and lymph node indexes were also evaluated. Results. The PASI and epidermal thickness scores were 6.01 and 1.96, respectively, in the IMQ group, and they significantly decreased after aptamer administration to 1.15 and 0.90, respectively (P < 0.05). Spleen and lymph node indexes showed an increase in the IMQ group, followed by a slight decrease after aptamer treatment (P > 0.05). Additionally, the mRNA expression levels of Kynu, Defb2, Camp, and Penk genes in the IMQ‐treated region showed a significant 2.70, 4.56, 3.29, and 2.61‐fold increase relative to the Vas mice, respectively (P < 0.05). The aptamer‐treated region exhibited a significant decrease in these gene expression levels (P < 0.05). A positive correlation was found between Kynu, Penk, and Camp expression levels and erythema, as well as Camp expression with PASI, scaling, and thickness (P < 0.05). Conclusion. According to our results, it seems that Kynu, Camp, and Penk can be considered appropriate markers for the evaluation of psoriasis in IMQ‐induced psoriasis. Also, the anti‐IL‐17 aptamer downregulated these important genes in this mouse model. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
15. Innovations and Developments in Totally Thoracoscopic Cardiac Procedures.
- Author
-
Qin Jiang, Keli Huang, Dian Zhao, Yi Xiao, Xiaoxiang Ma, and Shengshou Hu
- Published
- 2024
- Full Text
- View/download PDF
16. Proteomics in Psoriasis: Recent Advances.
- Author
-
LEOTSAKOS, GEORGIOS, KATAFIGIOTIS, IOANNIS, LEOTSAKOS, IOANNIS, KOUSTA, FIORI, MOLYMPAKIS, ARISTEIDIS, PERIMENI, AIKATERINI, and KOUTSILIERIS, MICHAEL
- Subjects
PSORIASIS treatment ,PROTEOMICS ,BLOOD plasma ,CYTOKINES ,DATA analysis - Abstract
Psoriasis continues to affect a large percentage of patients worldwide and strongly appears to be a systematic disease. Efforts are being made to understand its etiology, which have led to research extended to genomic analysis with a focus on the role of pro-inflammatory cytokines, which play a major role in the pathogenesis of the disease. Plasma proteomic analysis in various diseases has provided promising results for choosing the right treatment for psoriasis, suggesting that it could play a key role in the prevention, prognosis, and treatment of the disease by individualizing treatment choices based on the proteomic profile of each patient. In this review, we focus on existing data in the bibliography on proteomic analysis in psoriasis and relevant approaches to future targeted therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
17. Multimodality Cardiovascular Imaging for Totally Video-Guided Thorascopic Cardiac Surgery.
- Author
-
Qin Jiang, Keli Huang, Lixue Yin, Bo Zhang, Yiping Wang, and Shengshou Hu
- Abstract
Totally video-guided thorascopic cardiac surgery (TVTCS) represents one of the most minimally invasive access routes to the heart. Its feasibility and safety can be guaranteed by an experienced surgeon with skilled operative techniques under the guidance of a video signal via thoracoscopy and the imaging from transesophageal echocardiography. At present, this surgical approach has been applied for atrioventricular valve disease, atrial septum defects plus and partial anomalous pulmonary venous drainage, cardiac tumors, hypertrophic obstructive cardiomyopathy, aortic valve disease, and atrial fibrillation. Multimodality cardiovascular imaging, including echocardiography, X-ray, computed tomography (CT), magnetic resonance imaging (MRI) and cardiac catheterization, provides morphologic characteristics and function status of the cardiovascular system and a comprehensive view of the target anatomy. In this review, the benefits of multimodality cardiovascular imaging are summarized for the clinical practice of TVTCS, including the preoperative preparation, intraoperative guidance and postoperative supervision. The disease categories are also individually reviewed on the basis of multimodality cardiovascular imaging, to ensure the feasibility and safety for TVTCS. Cardiovascular imaging technologies not only confirm who is a candidate for this surgical technique, but also provide technical support during the procedure and for postop follow to assess the clinical outcomes. Multimodality cardiovascular imaging is instrumental to provide the requirements to solve the problems for conduction of TVTCS; and to provide individualized protocols with high-resolution and real-time dynamic imaging fusion. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
18. Successful Treatment with Bimekizumab of a Psoriatic Patient Undergoing Hemodialysis: A Case Report and Review of the Literature.
- Author
-
Bernardini, Nicoletta, Ambrosio, Luca, Tolino, Ersilia, Proietti, Ilaria, Skroza, Nevena, and Potenza, Concetta
- Subjects
LITERATURE reviews ,TREATMENT effectiveness ,LATENT infection ,CHRONIC kidney failure ,HEMODIALYSIS patients ,PSORIATIC arthritis - Abstract
Background/Objectives: Treating psoriasis patients requires the consideration of potential underlying complications like latent viral infections and chronic kidney disease, which may influence therapy selection. Case presentation: A patient with end-stage kidney disease (ESKD) undergoing hemodialysis (HD) was successfully treated with bimekizumab, an IgG1 humanized monoclonal antibody inhibiting interleukin (IL)-17A and IL-17F. This case appears to be the first documented instance of effective anti-IL-17A/IL-17F antibody treatment in a psoriasis patient undergoing HD, with a sustained positive response for eight months. Discussion: Studies indicate the comparable pharmacokinetics, efficacy, and safety of certain psoriasis drugs in patients with chronic kidney disease (CKD) and those with normal renal function. The positive clinical outcome observed following treatment with bimekizumab aligns with the existing literature on this topic. However, further studies are needed to objectively evaluate the pharmacokinetics, efficacy, and safety of this drug in this specific setting. Conclusions: This documented case represents the first known use of bimekizumab to treat psoriasis in patients undergoing dialysis, suggesting its potential effectiveness and safety in this population. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
19. The oral IRAK4 inhibitors zabedosertib and BAY1830839 suppress local and systemic immune responses in a randomized trial in healthy male volunteers.
- Author
-
Jodl, Stefan J., ten Voorde, Wouter, Klein, Stefan, Wagenfeld, Andrea, Zollmann, Frank S., Feldmüller, Maximilian, Klarenbeek, Naomi B., de Bruin, Digna T., Jansen, Manon A. A., Rissmann, Robert, Rohde, Beate, and Moerland, Matthijs
- Subjects
CALCITONIN ,ACUTE phase proteins ,RANDOMIZED response ,SPECKLE interference ,TOPICAL drug administration ,IMMUNE response ,PERFUSION - Abstract
This study evaluated and characterized the pharmacological activity of the orally administered interleukin‐1 receptor‐associated kinase 4 (IRAK4) inhibitors BAY1834845 (zabedosertib) and BAY1830839 in healthy male volunteers. Participants received one of either IRAK4 inhibitors or a control treatment (prednisolone 20 mg or placebo) twice daily for 7 days. Localized skin inflammation was induced by topical application of imiquimod (IMQ) cream for 3 days, starting at Day 3 of treatment. The inflammatory response was evaluated by laser speckle contrast imaging (skin perfusion) and multispectral imaging (erythema). At Day 7, participants received 1 ng/kg intravenous lipopolysaccharide (LPS). Circulating inflammatory proteins, leukocyte differentiation, acute phase proteins, and clinical parameters were evaluated before and after the systemic LPS challenge. Treatment with BAY1834845 significantly reduced the mean IMQ‐induced skin perfusion response (geometric mean ratio [GMR] vs. placebo: 0.69 for BAY1834845, 0.70 for prednisolone; both p < 0.05). Treatment with BAY1834845 and BAY1830839 significantly reduced IMQ‐induced erythema (GMR vs. placebo: 0.75 and 0.83, respectively, both p < 0.05; 0.86 for prednisolone, not significant). Both IRAK4 inhibitors significantly suppressed the serum TNF‐α and IL‐6 responses (≥80% suppression vs. placebo, p < 0.05) and inhibited C‐reactive protein, procalcitonin, and IL‐8 responses to intravenous LPS. This study demonstrated the pharmacological effectiveness of BAY1834845 and BAY1830839 in suppressing systemically and locally induced inflammatory responses in the same range as prednisolone, underlining the potential value of these IRAK4 inhibitors as future therapies for dermatological or other immune‐mediated inflammatory diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
20. Multi-Omics Approach to Improved Diagnosis and Treatment of Atopic Dermatitis and Psoriasis.
- Author
-
Rusiñol, Lluís and Puig, Lluís
- Subjects
ATOPIC dermatitis ,MULTIOMICS ,PSORIASIS ,MYCOSIS fungoides ,DIAGNOSIS ,PROTEOMICS - Abstract
Psoriasis and atopic dermatitis fall within the category of cutaneous immune-mediated inflammatory diseases (IMIDs). The prevalence of IMIDs is increasing in industrialized societies, influenced by both environmental changes and a genetic predisposition. However, the exact immune factors driving these chronic, progressive diseases are not fully understood. By using multi-omics techniques in cutaneous IMIDs, it is expected to advance the understanding of skin biology, uncover the underlying mechanisms of skin conditions, and potentially devise precise and personalized approaches to diagnosis and treatment. We provide a narrative review of the current knowledge in genomics, epigenomics, and proteomics of atopic dermatitis and psoriasis. A literature search was performed for articles published until 30 November 2023. Although there is still much to uncover, recent evidence has already provided valuable insights, such as proteomic profiles that permit differentiating psoriasis from mycosis fungoides and β-defensin 2 correlation to PASI and its drop due to secukinumab first injection, among others. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
21. Advancements in understanding the molecular and immune mechanisms of Bartonella pathogenicity.
- Author
-
Xiaoxia Jin, Yuze Gou, Yuxian Xin, Jingwei Li, Jingrong Sun, Tingting Li, and Jie Feng
- Subjects
BARTONELLA ,ENDOTHELIAL cells ,ERYTHROCYTES ,IMMUNE response - Abstract
Bartonellae are considered to be emerging opportunistic pathogens. The bacteria are transmitted by blood-sucking arthropods, and their hosts are a wide range of mammals including humans. After a protective barrier breach in mammals, Bartonella colonizes endothelial cells (ECs), enters the bloodstream, and infects erythrocytes. Current research primarily focuses on investigating the interaction between Bartonella and ECs and erythrocytes, with recent attention also paid to immune-related aspects. Various molecules related to Bartonella’s pathogenicity have been identified. The present review aims to provide a comprehensive overview of the newly described molecular and immune responses associated with Bartonella’s pathogenicity. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
22. Minimal-Access Coronary Revascularization: Past, Present, and Future.
- Author
-
Purmessur, Rushmi, Wijesena, Tharushi, and Ali, Jason
- Published
- 2023
- Full Text
- View/download PDF
23. Correlations between antimicrobial peptides and spectrophotometric skin color parameters in patients with basal cell carcinoma.
- Author
-
Fijałkowska, Marta, Koziej, Mateusz, Antoszewski, Bogusław, and Sitek, Aneta
- Subjects
BASAL cell carcinoma ,ANTIMICROBIAL peptides ,HUMAN skin color ,SKIN cancer ,MAST cells ,PEPTIDE antibiotics - Abstract
Background: Antimicrobial peptides (AMPs) are active molecules in the human innate immune system, that participate in host defense and regulate the inflammation process. Previous reports have confirmed that antimicrobial peptides play a critical role in carcinogenesis. Objective: The present study aimed to evaluate the correlations between plasma concentrations of AMPs and spectrophotometric parameters of skin color in patients with basal cell carcinoma and compare the results with those of healthy controls. Methods: The plasma concentrations of cathelicidin and beta-defensin-2 in 100 patients (50 with skin cancer and 50 healthy control subjects) were measured, and skin color parameters were tested using a DermaSpectrophotometer. Results: In patients with basal cell carcinoma, the concentrations of cathelicidin and beta-defensin-2 were significantly higher than those in healthy controls. In healthy control patients, when erythema increases, the levels of cathelicidin and beta-defensin-2 also increase. The direction of the relationship is opposite in people with basal cell carcinoma—the concentration of antimicrobial peptides decreases and the level of erythema increases. Conclusion: A significantly higher level of plasma concentrations of cathelicidin and HBD-2 are correspondent to the presence of basal cell carcinoma. Skin cancer modifies the relationship between intensity of skin erythema and the levels of cathelicidin and HBD-2. This can be related to inadequate immunological response in patients with skin cancers. New direction of research may be pioneered in searching for cytokine or mast cells disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
24. The Emerging Role of Innate Lymphoid Cells (ILCs) and Alarmins in Celiac Disease: An Update on Pathophysiological Insights, Potential Use as Disease Biomarkers, and Therapeutic Implications.
- Author
-
Rizzi, Angela, Di Gioacchino, Mario, Gammeri, Luca, Inchingolo, Riccardo, Chini, Raffaella, Santilli, Francesca, Nucera, Eleonora, and Gangemi, Sebastiano
- Subjects
INNATE lymphoid cells ,CELIAC disease ,IMMUNOGLOBULIN producing cells ,T cells ,INTESTINAL physiology ,B cells - Abstract
Celiac disease (CD) is an intestinal disease that develops in genetically predisposed individuals and is triggered by the ingestion of gluten. CD was considered a Th1-disease. Today, the role of Th17, IL-21, and IL-17A lymphocytes is well known. Inflammation is regulated by the activity of gluten-specific CD4+ T lymphocytes that produce pro-inflammatory cytokines, including IFN-γ, TNF-α, and IL-21, perpetuating the Th1 response. These cytokines determine an inflammatory state of the small intestine, with consequent epithelial infiltration of lymphocytes and an alteration of the architecture of the duodenal mucosa. B cells produce antibodies against tissue transglutaminase and against deamidated gliadin. Although the role of the adaptive immune response is currently known, the evidence about the role of innate immunity cells is still poorly understood. Epithelial damage determines the release of damage-associated molecular patterns (DAMPs), also known as alarmins. Together with the intestinal epithelial cells and the type 1 innate lymphoid cells (ILC1s), alarmins like TSLP, IL-33, and HMGB1 could have a fundamental role in the genesis and maintenance of inflammation. Our study aims to evaluate the evidence in the literature about the role of ILCs and alarmins in celiac disease, evaluating the possible future diagnostic and therapeutic implications. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
25. Patient-Centred Outcomes after Totally Endoscopic Cardiac Surgery: One-Year Follow-Up.
- Author
-
Claessens, Jade, Goris, Pieter, Yilmaz, Alaaddin, Van Genechten, Silke, Claes, Marithé, Packlé, Loren, Pierson, Maud, Vandenbrande, Jeroen, Kaya, Abdullah, and Stessel, Björn
- Subjects
ENDOSCOPIC surgery ,CARDIAC surgery ,QUALITY of life ,VISUAL analog scale - Abstract
Patient-centred outcomes have grown in popularity over recent years in surgical care research. These patient-centred outcomes can be measured through the health-related quality of life (HRQL) without professional interpretations. In May 2022, a study regarding patient-centred outcomes up to 90 days postoperatively was published. Fourteen days after surgery, the HRQL decreased and returned to baseline levels after 30 days. Next, the HRQL significantly improved 90 days postoperatively. However, this study only focuses on a short-term follow-up of the patients. Hence, this follow-up study aims to assess the HRQL one year after totally endoscopic cardiac surgery. At baseline, 14, 30, and 90 days, and one year after surgery, the HRQL was evaluated using a 36-item short form and 5-dimensional European QoL questionnaires (EQ-5D). Using the 36-item short form questionnaire, a physical and mental component score is calculated. Over the period of one year, this physical and mental component score and the EQ-5D index value significantly improve. According to the visual analogue scale of the EQ-5D, patients score their health significantly higher one year postoperatively. In conclusion, after endoscopic cardiac surgery, the HRQL is significantly improved 90 days postoperatively and remains high one year afterward. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
26. Targeted Therapies in Psoriatic Arthritis—An Update.
- Author
-
Sundanum, Sonia, Orr, Carl, and Veale, Douglas
- Subjects
PSORIATIC arthritis ,SYMPTOMS ,RHEUMATOID arthritis ,BIOTHERAPY - Abstract
Psoriatic arthritis (PsA) is a systemic inflammatory condition characterised by multiple clinical manifestations. Over the last decade, significant progress has been made in understanding the pathobiology of the disease. An expanded set of targeted therapies have emerged and have shown efficacy in PsA. Nevertheless, there is still a substantial subset of patients who experience no response or only a partial response to currently licensed therapies. The heterogeneous nature of the disease, together with a varying level of severity at presentation and disease activity during follow-up, brings tremendous challenges to devising management strategies. While there are certain pathophysiological similarities between PsA and rheumatoid arthritis (RA), it has become clear that there are discriminating features between these two conditions at the clinical, cellular, and molecular levels. However, there is a degree of overlap in the clinical approach when treating both PsA and RA, given that many biological and targeted therapies have proven efficacy for both pathologies. With an increasing understanding of the relevance of the IL-23/IL-17 axis in PsA, pharmacological agents blocking this pathway have provided promising possibilities for patients with PsA. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
27. Preoperative SARS-CoV-2 Infection Screening before Thoracic Surgery during COVID-19 Pandemic: A Multicenter Retrospective Study.
- Author
-
Fiorelli, Silvia, Menna, Cecilia, Piccioni, Federico, Zuanetti, Gabriele, Valenza, Franco, Rispoli, Marco, Amore, Dario, Rocco, Monica, Rendina, Erino Angelo, Ibrahim, Mohsen, and Massullo, Domenico
- Abstract
Objectives. During coronavirus disease (COVID-19) pandemic, preoperative screening before thoracic surgery is paramount in order to protect patients and staff from undetected infections. This study aimed to determine which preoperative COVID-19 screening tool was the most effective strategy before thoracic surgery. Methods. This retrospective cohort multicenter study was performed at 3 Italian thoracic surgery centers. All adult patients scheduled for thoracic surgery procedures from 4th March until 24th April, 2020, and submitted to COVID-19 preoperative screenings were included. The primary outcome was the yield of screening of the different strategies. Results. A total of 430 screenings were performed on 275 patients; 275 anamnestic questionnaires were administered. 77 patients were screened by an anamnestic questionnaire and reverse transcriptase polymerase chain reaction (RT-PCR). 78 patients were selected to combine screening with anamnestic questionnaire and chest computed tomography (CT). The positive yield of screening using a combination of anamnestic questionnaire and RT-PCR was 7.8% (95% CI: 2.6–14.3), while using a combination of anamnestic questionnaire and chest CT was 3.8% (95% CI: 0–9). Individual yields were 1.1% (95% CI: 0–2.5) for anamnestic questionnaire, 5.2% (95% CI: 1.3–11.7) for RT-PCR, and 3.8% (95% CI: 0–9). Conclusions. The association of anamnestic questionnaire and RT-PCR is able to detect around 8 positives in 100 asymptomatic patients. This combined strategy could be a valuable preoperative SARS-CoV-2 screening tool before thoracic surgery. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
28. Gelsolin as a Potential Clinical Biomarker in Psoriasis Vulgaris.
- Author
-
Lee, Sul Hee, Park, Young-Lip, and Bae, Youin
- Subjects
GELSOLIN ,LIQUID chromatography-mass spectrometry ,PSORIASIS ,BIOMARKERS - Abstract
Although discovering novel biomarkers for psoriasis is challenging, it may play an essential role in diagnosis, severity assessment, and prediction of treatment outcome and prognosis. The study was aimed to determine potential serum biomarkers of psoriasis via proteomic data analysis and clinical validity assessment. Thirty-one subjects manifested psoriasis and 19 subjects were healthy volunteers who were enrolled in the study. Protein expression was performed via two-dimensional gel electrophoresis (2-DE) using psoriasis patients' sera before and after treatment and sera of patients without psoriasis. Image analysis was then performed. Nano-scale liquid chromatography-tandem mass spectrometry (LC-MS/MS) experiments subsequently identified points showing differential expression in 2-DE image analysis. To measure levels of candidate proteins to validate results obtained from 2-DE, enzyme linked immunosorbent assay (ELISA) was then conducted. Gelsolin was identified as a potential protein through LC-MS/MS analysis and database search. Serum gelsolin levels were lower in the groups of psoriasis patients before treatment than in the control group and the group of psoriasis patients after treatment. Additionally, in subgroup analysis, serum gelsolin level was correlated with various clinical severity scores. In conclusion, low serum gelsolin levels are associated with the severity of psoriasis, proposing the potential role of gelsolin as a biomarker for severity assessment and evaluation of treatment response of psoriasis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
29. An Exploratory Study in Healthy Volunteers to Identify Factors Influencing Bioequivalence Studies on Moderately Lipophilic Drugs Using Dermal Open Flow Microperfusion (dOFM)
- Published
- 2020
30. In vivo monitoring of brain pharmacokinetics and pharmacodynamics with cerebral open flow microperfusion.
- Author
-
Altendorfer‐Kroath, Thomas, Hummer, Joanna, and Birngruber, Thomas
- Subjects
PHARMACODYNAMICS ,PHARMACOKINETICS ,EXTRACELLULAR fluid ,BLOOD-brain barrier ,DRUG development - Abstract
In vivo investigation of brain pharmacokinetics and pharmacodynamics (PK/PD) is an integral part of neurological drug development. However, drugs intended to act in the brain may reach it at very low concentrations due to the protective effect of the blood–brain barrier (BBB). Consequently, very sensitive measurement methods are required to investigate PK/PD of drugs in the brain. Also, these methods must be capable of continuously assessing cerebral drug concentrations with verifiable intact BBB, as disrupted BBB may lead to compound efflux from blood into brain and to biased results. To date, only a few techniques are available that can sensitively measure drug concentrations in the brain over time; one of which is cerebral open flow microperfusion (cOFM). cOFM's key features are that it enables measurement of cerebral compound concentrations with intact BBB, induces only minor tissue reactions, and that no scar formation occurs around the probe. The membrane‐free cOFM probes collect diluted cerebral interstitial fluid (ISF) samples that are containing the whole molecule spectrum of the ISF. Further, combining cOFM with an in vivo calibration protocol (e.g. Zero Flow Rate) enables absolute quantification of compounds in cerebral ISF. In general, three critical aspects have to be considered when measuring cerebral drug concentrations and recording PK/PD profiles with cOFM: (a) the BBB integrity during sampling, (b) the status of the brain tissue next to the cOFM probe during sampling, and (c) the strategy to absolutely quantify drugs in cerebral ISF. This work aims to review recent applications of cOFM for PK/PD assessment with a special focus on these critical aspects. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
31. Izokibep: Preclinical development and first-in-human study of a novel IL-17A neutralizing Affibody molecule in patients with plaque psoriasis.
- Author
-
Klint, Susanne, Feldwisch, Joachim, Gudmundsdotter, Lindvi, Dillner Bergstedt, Karin, Gunneriusson, Elin, Höidén Guthenberg, Ingmarie, Wennborg, Anders, Nyborg, Andrew C., Kamboj, Amol P., Peloso, Paul M., Bejker, David, and Frejd, Fredrik Y.
- Published
- 2023
- Full Text
- View/download PDF
32. The Clinical Significance of Simultaneous IL-17A and IL-17F Blockade in Psoriasis Non-Responding to Anti-IL17A Therapy.
- Author
-
Kokolakis, Georgios and Ghoreschi, Kamran
- Subjects
PSORIASIS ,SPONDYLOARTHROPATHIES ,INTERLEUKIN-17 ,PSORIATIC arthritis - Abstract
The better understanding of the immunopathogenesis of psoriasis has led to the development of highly efficacious targeted therapies with favorable safety profiles. Among them, the class of Interleukin (IL)-17 antibodies are well established for the treatment of psoriasis, psoriatic arthritis and axial spondyloarthritis. Bimekizumab is a new antibody that simultaneously neutralizes IL-17A and IL-17F. We present two patients with psoriasis, who lost response to several biologics, among them IL-17 antagonists such as secukinumab, ixekizumab or brodalumab. Besides plaque-type psoriasis, patients also had psoriasis in hard-to-treat areas such as scalp and groins or psoriatic arthritis. Remarkably, both patients already responded to the therapy with bimekizumab 4 weeks after the first injection and, one year thereafter, both patients sustained PASI100. No side effects were observed. The fast response to bimekizumab emphasizes the crucial role of IL-17F in the pathogenesis of psoriasis. Besides, due to the new mechanism of action, non-responders to other anti-IL-17 therapies could benefit when switched to bimekizumab. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
33. Akkermansia muciniphila and Faecalibacterium prausnitzii in Immune-Related Diseases.
- Author
-
Effendi, Raden Mohamad Rendy Ariezal, Anshory, Muhammad, Kalim, Handono, Dwiyana, Reiva Farah, Suwarsa, Oki, Pardo, Luba M., Nijsten, Tamar E. C., and Thio, Hok Bing
- Subjects
GUT microbiome ,SYSTEMIC lupus erythematosus ,IMMUNOLOGIC diseases ,IMMUNOREGULATION ,ATOPIC dermatitis ,IMMUNE system ,HIV - Abstract
Probiotics and synbiotics are used to treat chronic illnesses due to their roles in immune system modulation and anti-inflammatory response. They have been shown to reduce inflammation in a number of immune-related disorders, including systemic lupus erythematosus (SLE), human immunodeficiency virus (HIV), and chronic inflammatory skin conditions such as psoriasis and atopic dermatitis (AD). Akkermansia muciniphila (A. muciniphila) and Faecalibacterium prausnitzii (F. prausnitzii) are two different types of bacteria that play a significant part in this function. It has been established that Akkermansia and Faecalibacterium are abundant in normal populations and have protective benefits on digestive health while also enhancing the immune system, metabolism, and gut barrier of the host. They have the potential to be a therapeutic target in diseases connected to the microbiota, such as immunological disorders and cancer immunotherapy. There has not been a review of the anti-inflammatory effects of Akkermansia and Faecalibacterium, particularly in immunological diseases. In this review, we highlight the most recent scientific findings regarding A. muciniphila and F. prausnitzii as two significant gut microbiota for microbiome alterations and seek to provide cutting-edge insight in terms of microbiome-targeted therapies as promising preventive and therapeutic tools in immune-related diseases and cancer immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
34. totally endoscopic approach for aortic valve surgery.
- Author
-
Yilmaz, Alaaddin, Genechten, Silke Van, Claessens, Jade, Packlé, Loren, Maessen, Jos, and Kaya, Abdullah
- Subjects
AORTIC valve surgery ,AORTIC valve transplantation ,AORTIC stenosis ,ENDOSCOPIC surgery ,CARDIAC pacemakers - Abstract
Open in new tab Download slide OBJECTIVES Our goal was to describe a new approach for totally endoscopic aortic valve replacement. METHODS From October 2017 through December 2020, a total of 266 consecutive patients underwent totally endoscopic aortic valve replacement. Reoperations and combinations were excluded. RESULTS A total of 266 patients with a median age of 72 (64, 79) years underwent totally endoscopic aortic valve replacement; of these, 250 (93.98%) patients were designated to undergo surgery because of aortic valve stenosis. The median follow-up index was 0.69 (0.30, 0.90). Major adverse cardiac and cerebrovascular events occurred in 4 (1.50%) patients within 30 days. Overall hospital mortality was 1.50%. Twenty additional deaths (7.52%) occurred during the 3-year follow-up period. An early thoracoscopic revision was needed in 7 patients due to signs of bleeding or cardiac tamponade. Fourteen patients required a permanent pacemaker implant. CONCLUSIONS Retrospective analysis of our early experience with totally endoscopic aortic valve replacement in 266 consecutive patients demonstrated satisfactory results, with low mortality and acceptable morbidity rates. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
35. Dermal open flow microperfusion for PK-based clinical bioequivalence studies of topical drug products.
- Author
-
Birngruber, Thomas, Tiffner, Katrin I., Mautner, Selma I., and Sinner, Frank M.
- Subjects
GENERIC drugs ,GENERIC products ,DRUG development ,PRICE increases ,EXTRACELLULAR fluid ,PILOT projects - Abstract
Topically applied drug products have experienced an extraordinary price increase in the United States, mostly due to a lack of generic products. Generic drug development is hindered by high costs and risks associated with clinical endpoint studies required to show bioequivalence (BE) of prospective generic products relative to their reference products. There is a continued need for cost- and time-efficient alternatives to clinical endpoint studies to determine BE of topically applied dermal drug products. Cutaneous PK-based BE studies present such an alternative and dOFM (dermal open flow microperfusion) has already been successfully used in several verifications studies to show an accurate and sensitive assessment of the rate and extent at which drugs become available in the skin. dOFM technology is discussed as well as the dOFM setup of clinical pilot and main studies to achieve BE assessment with a minimum number of participants and an outlook is given on the use of dOFM technology for other drug products. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
36. Transcriptome Meta-Analysis Confirms the Hidradenitis Suppurativa Pathogenic Triad: Upregulated Inflammation, Altered Epithelial Organization, and Dysregulated Metabolic Signaling.
- Author
-
de Oliveira, Ana Sofia Lima Estevao, Bloise, Giovanna, Moltrasio, Chiara, Coelho, Antonio, Agrelli, Almerinda, Moura, Ronald, Tricarico, Paola Maura, Jamain, Stéphane, Marzano, Angelo Valerio, Crovella, Sergio, and Cavalcanti Brandão, Lucas André
- Subjects
HIDRADENITIS suppurativa ,APOCRINE glands ,TRANSCRIPTOMES ,INFLAMMATION ,AXILLA ,HAIR follicles - Abstract
Hidradenitis suppurativa (HS) is an inflammatory skin condition clinically characterized by recurrent painful deep-seated nodules, abscesses, and sinus tracks in areas bearing apocrine glands, such as axillae, breasts, groins, and buttocks. Despite many recent advances, the pathophysiological landscape of HS still demands further clarification. To elucidate HS pathogenesis, we performed a meta-analysis, set analysis, and a variant calling on selected RNA-Sequencing (RNA-Seq) studies on HS skin. Our findings corroborate the HS triad composed of upregulated inflammation, altered epithelial differentiation, and dysregulated metabolism signaling. Upregulation of specific genes, such as KRT6, KRT16, serpin-family genes, and SPRR3 confirms the early involvement of hair follicles and the impairment of barrier function in HS lesioned skin. In addition, our results suggest that adipokines could be regarded as biomarkers of HS and metabolic-related disorders. Finally, the RNA-Seq variant calling identified several mutations in HS patients, suggesting potential new HS-related genes associated with the sporadic form of this disease. Overall, this study provides insights into the molecular pathways involved in HS and identifies potential HS-related biomarkers. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
37. Profiling Serum Cytokines and Anticytokine Antibodies in Psoriasis Patients.
- Author
-
Hong, Dan, Liu, Xiuting, Qiu, Xiaonan, Lu, Siyao, Jiang, Yanyun, Tan, Guozhen, Shi, Zhenrui, and Wang, Liangchun
- Subjects
PSORIASIS ,CYTOKINES ,IMMUNOGLOBULINS ,SKIN diseases ,JOINT diseases ,THERAPEUTIC use of immunoglobulins ,BIOTHERAPY ,THERAPEUTIC use of monoclonal antibodies ,INTERLEUKINS ,AUTOANTIBODIES - Abstract
Cytokines like IL-17A have been consistently found to be elevated in psoriatic lesional skin, and therapeutic antibodies to IL-17 have demonstrated efficacy in treating psoriatic skin and joint disease. However, results about the circulating cytokines in psoriasis patients remained controversial. Anticytokine autoantibodies (ACAAs) were detected in various autoimmune diseases but remained largely unknown in psoriasis. We aimed to investigate the serum levels of cytokines and ACAAs in psoriasis patients. The study included 44 biologics-naive psoriasis patients and 40 healthy controls. Serum cytokines and the corresponding autoantibodies were measured by multiplex bead-based technology. The bioactivity of serum IL-17A was determined by IL-8 production in primary keratinocytes. Herein, we found serum levels of IL-12B (median: 6.16 vs. 9.03, p = 0.0194) and Th17 cytokines (IL-17A: median: 0.32 vs. 1.05, p = 0.0026; IL-22: median: 4.41 vs. 4.41, p = 0.0120) were increased in psoriasis patients. More interestingly, bioactive IL-17A was identified in a proportion of patients and positively correlated with disease severity. A few of cytokines were closely associated with each other and formed into a distinct panel in psoriasis. Of 13 anticytokine antibodies, anti-IL-22 was moderately lower (median: 262.8 vs.190.5, p = 0.0418), and anti-IL-15 was slightly higher (median: 25.5 vs. 30.5, p = 0.0069) in psoriasis than controls. None of ACAAs was related to disease severity. Consequently, the ratios of antibodies to cytokines varied with the pattern of cytokines. In summary, our finding suggested that the levels of circulating bioactive IL-17A were associated with disease activity in psoriasis patients. In contrast, the titers of ACAAs were not significantly altered nor correlated with disease severity. However, the functionality of ACAAs remains to be further demonstrated in vitro in future studies. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
38. Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Moderate-to-Severe Psoriasis.
- Author
-
Greenzaid J and Feldman S
- Subjects
- Humans, Methotrexate therapeutic use, Interleukin-17, Tumor Necrosis Factor-alpha, Cyclosporine, Biological Factors therapeutic use, Cytochrome P-450 Enzyme System, Treatment Outcome, Psoriasis drug therapy, Biological Products pharmacology, Biological Products therapeutic use, Thalidomide analogs & derivatives
- Abstract
Psoriasis is a common inflammatory immune disorder due to chronic activation of the adaptive and innate immune responses. Therapies for psoriasis target reducing inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-17, and interleukin-22. Patients with inflammatory disorders have reduced metabolism by cytochrome P450 enzymes in the liver. The pharmacokinetic and pharmacodynamic changes due to psoriasis also have an impact on reaching therapeutic concentrations of the drug. Pharmacokinetic and pharmacodynamic data help determine the safety and clinical considerations necessary when utilizing drugs for plaque psoriasis. A literature search was performed on PubMed and Ovid MEDLINE for the pharmacokinetic and pharmacodynamic data of oral therapies and biologics utilized for moderate-to-severe plaque psoriasis. The findings from the literature search were organized into two sections: oral therapies and biologics. The pharmacokinetic and pharmacodynamic parameters in healthy patients, patients with psoriasis, and special populations are discussed in each section. The oral therapies described in this review include methotrexate, cyclosporine, apremilast, tofacitinib, and deucravacitinib. Biologics include tumor necrosis factor-alpha inhibitors, interleukin-17 inhibitors, ustekinumab, and interleukin-23 inhibitors. Clinical considerations for these therapies include drug toxicities, dosing frequency, and anti-drug antibodies. Methotrexate and cyclosporine have a risk for hepatoxicity and renal impairment, respectively. Moreover, drugs metabolized via cytochrome P450, including tofacitinib and apremilast have decreased clearance in patients with psoriasis, requiring dose adjustments. Patients treated with therapies such as adalimumab can develop anti-drug antibodies that reduce the long-term efficacy of the drug. Additionally, overweight patients benefit from more frequent dosing to achieve better psoriasis clearance., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
- Published
- 2024
- Full Text
- View/download PDF
39. Comparative Study of Dermal Pharmacokinetics Between Topical Drugs Using Open Flow Microperfusion in a Pig Model.
- Author
-
Bodenlenz M, Yeoh T, Berstein G, Mathew S, Shah J, Banfield C, Hollingshead B, Steyn SJ, Osgood SM, Beaumont K, Kainz S, Holeček C, Trausinger G, Raml R, and Birngruber T
- Subjects
- Swine, Animals, Administration, Cutaneous, Reproducibility of Results, Skin metabolism
- Abstract
Purpose: Accurate methods to determine dermal pharmacokinetics are important to increase the rate of clinical success in topical drug development. We investigated in an in vivo pig model whether the unbound drug concentration in the interstitial fluid as determined by dermal open flow microperfusion (dOFM) is a more reliable measure of dermal exposure compared to dermal biopsies for seven prescription or investigational drugs. In addition, we verified standard dOFM measurement using a recirculation approach and compared dosing frequencies (QD versus BID) and dose strengths (high versus low drug concentrations)., Methods: Domestic pigs were topically administered seven different drugs twice daily in two studies. On day 7, drug exposures in the dermis were assessed in two ways: (1) dOFM provided the total and unbound drug concentrations in dermal interstitial fluid, and (2) clean punch biopsies after heat separation provided the total concentrations in the upper and lower dermis., Results: dOFM showed sufficient intra-study precision to distinguish interstitial fluid concentrations between different drugs, dose frequencies and dose strengths, and had good reproducibility between studies. Biopsy concentrations showed much higher and more variable values. Standard dOFM measurements were consistent with values obtained with the recirculation approach., Conclusions: dOFM pig model is a robust and reproducible method to directly determine topical drug concentration in dermal interstitial fluid. Dermal biopsies were a less reliable measure of dermal exposure due to possible contributions from drug bound to tissue and drug associated with skin appendages., (© 2023. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
40. Advanced Online Monitoring of In Vitro Human 3D Full-Thickness Skin Equivalents.
- Author
-
Schaller-Ammann, Roland, Kreß, Sebastian, Feiel, Jürgen, Schwagerle, Gerd, Priedl, Joachim, Birngruber, Thomas, Kasper, Cornelia, and Egger, Dominik
- Subjects
VIRTUAL culture ,DRUG development ,GLUCOSE ,SKIN permeability ,TEST design ,ACYCLOVIR - Abstract
Skin equivalents and skin explants are widely used for dermal penetration studies in the pharmacological development of drugs. Environmental parameters, such as the incubation and culture conditions affect cellular responses and thus the relevance of the experimental outcome. However, available systems such as the Franz diffusion chamber, only measure in the receiving culture medium, rather than assessing the actual conditions for cells in the tissue. We developed a sampling design that combines open flow microperfusion (OFM) sampling technology for continuous concentration measurements directly in the tissue with microfluidic biosensors for online monitoring of culture parameters. We tested our design with real-time measurements of oxygen, glucose, lactate, and pH in full-thickness skin equivalent and skin explants. Furthermore, we compared dermal penetration for acyclovir, lidocaine, and diclofenac in skin equivalents and skin explants. We observed differences in oxygen, glucose, and drug concentrations in skin equivalents compared to the respective culture medium and to skin explants. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
41. An Exploratory Pilot Study in Healthy Volunteers to Assess the Parameters for the Design of Bioequivalence Studies on Moderately Lipophilic, Moderately to Highly Protein Bound Drugs Using Dermal Open Flow Microperfusion (dOFM)
- Published
- 2018
42. Clinical results after hybrid coronary revascularization with totally endoscopic coronary surgery.
- Author
-
Claessens, Jade, Yilmaz, Alaaddin, Awouters, Camille, Oosterbos, Hanne, Thonnisen, Stef, Benit, Edouard, Kaya, Abdullah, and Bataille, Yoann
- Subjects
CORONARY artery bypass ,ENDOSCOPIC surgery ,PERCUTANEOUS coronary intervention ,PROPENSITY score matching ,LENGTH of stay in hospitals ,CORONARY artery disease ,MEDICAL care ,CARDIOVASCULAR system ,TREATMENT effectiveness ,MYOCARDIAL revascularization - Abstract
Background: The optimal revascularization strategy remains uncertain in multivessel coronary artery disease (MVCAD). The durability of the surgical grafts should be weighed against the decreased invasiveness of percutaneous coronary intervention (PCI). Hybrid coronary revascularization (HCR), a combination of PCI and surgery, could be a feasible alternative. This study aimed to investigate the occurrence of major adverse cardiac and cerebrovascular events (MACCE) and all-cause mortality after both endoscopic coronary artery bypass grafting (Endo-CABG) and the HCR procedure.Methods: In this single-center retrospective observational study, 347 consecutive patients have been subjected to an Endo-CABG procedure, of which 103 underwent HCR between January 2016 and January 2018. A propensity score matching analysis was performed to match 103 Endo-CABG alone patients to the 103 HCR patients. The Endo-CABG procedure was performed through 3 endoscopic ports (5 mm) in the 2nd, 3rd, and 4th intercostal space and a utility port of 3 cm.Results: In both the HCR and matched endo-CABG alone group, the 30-day mortality was acceptable (0% in the HCR group and 1.94% in the matched Endo-CABG alone group, p = 0.155). Additionally, the occurrence of MACCE after a mean follow-up of 1188 ± 538 days was similar in both groups (9.71% and 11.65% for the HCR and matched Endo-CABG alone group, respectively, p = 0.652). Still, the long-term all-cause mortality over this period was significantly higher in the matched Endo-CABG alone group (2.91% after the HCR procedure and 11.65% after matched Endo-CABG alone, p = 0.002).Conclusion: HCR has some advantages over Endo-CABG alone regarding the all-cause mortality, cross-clamping time, intensive care unit, and hospital length of stay. Therefore, HCR may be a suitable alternative therapy for patients with MVCAD. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
43. 90-Day Patient-Centered Outcomes after Totally Endoscopic Cardiac Surgery: A Prospective Cohort Study.
- Author
-
Claessens, Jade, Yilmaz, Alaaddin, Mostien, Toon, Van Genechten, Silke, Claes, Marithé, Packlé, Loren, Pierson, Maud, Vandenbrande, Jeroen, Kaya, Abdullah, and Stessel, Björn
- Subjects
CARDIAC surgery ,HEART valve prosthesis implantation ,MINIMALLY invasive procedures ,ENDOSCOPIC surgery ,LONGITUDINAL method ,COHORT analysis - Abstract
Over the past years, minimally invasive procedures have been developed to reduce surgical trauma after cardiac surgery. The value of patient-centered outcomes, including the quality of recovery after hospital discharge, is increasingly recognized. Identifying meaningful changes in postoperative function that might have a negative impact on patients without noticeable complications can provide a more comprehensive understanding of the impact on the patient's life. In total, 209 patients were included in this trial. Of these, 193 patients underwent totally endoscopic cardiac surgery, 8 underwent cardiac surgery through a sternotomy, and 8 underwent transcatheter aortic valve implantation. Patients who previously underwent cardiac surgery were excluded. Quality of life was determined through the Short Form 36 and European Quality of Life-5 Dimensions questionnaires before the surgery and 14, 30, and 90 days afterward. In patients who underwent totally endoscopic cardiac surgery, the quality of life improved over the three time periods. The different domains of the questionnaire evolved in a positive manner. However, 14 days postoperatively, a decline in quality of life was noted, followed by a return to baseline at 30 days and an increase at 90 days. In conclusion, totally endoscopic cardiac surgery improves the quality of life 90 days after surgery. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
44. Minimal Physiologically-Based Pharmacokinetic (mPBPK) Metamodeling of Target Engagement in Skin Informs Anti-IL17A Drug Development in Psoriasis.
- Author
-
Ayyar, Vivaswath S., Lee, Jong Bong, Wang, Weirong, Pryor, Meghan, Zhuang, Yanli, Wilde, Thomas, and Vermeulen, An
- Subjects
DRUG development ,PHARMACOKINETICS ,PSORIASIS ,SKIN temperature ,CLINICAL trials - Abstract
The pharmacologic effect(s) of biotherapeutics directed against soluble targets are driven by the magnitude and duration of free target suppression at the tissue site(s) of action. Interleukin (IL)-17A is an inflammatory cytokine that plays a key role in the pathogenesis of psoriasis. In this work, clinical trial data from two monoclonal antibodies (mAbs) targeting IL-17A for treatment of psoriasis (secukinumab and ixekizumab) were analyzed simultaneously to quantitatively predict their target engagement (TE) profiles in psoriatic skin. First, a model-based meta-analysis (MBMA) for clinical responses was conducted separately for each drug based on dose. Next, a minimal physiologically-based pharmacokinetic (mPBPK) model was built to assess skin site IL-17A target engagement for ixekizumab and secukinumab simultaneously. The mPBPK model captured the observed drug PK, serum total IL-17A, and skin drug concentration-time profiles reasonably well across the different dosage regimens investigated. The developed mPBPK model was then used to predict the average TE (i.e., free IL-17A suppression) in skin achieved over a 12-weeks treatment period for each drug following their respective regimens and subsequently assess the TE-efficacy response relationship. It was predicted that secukinumab achieved 98.6% average TE in the skin at 300 mg q4w SC while ixekizumab achieved 99.9% average TE under 160 mg (loading) followed by 80 mg q2w SC. While direct quantification of free IL-17A levels at the site of action is technically challenging, integrated mPBPK-MBMA approaches offer quantitative predictions of free IL-17A levels at the site of action to facilitate future drug development via IL-17A suppression in psoriasis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
45. Proteomic Studies of Psoriasis.
- Author
-
Sobolev, Vladimir V., Soboleva, Anna G., Denisova, Elena V., Pechatnikova, Eva A., Dvoryankova, Eugenia, Korsunskaya, Irina M., and Mezentsev, Alexandre
- Subjects
PROTEOMICS ,PSORIASIS ,ETIOLOGY of diseases ,PSORIATIC arthritis ,DRUG efficacy ,CLINICAL medicine - Abstract
In this review paper, we discuss the contribution of proteomic studies to the discovery of disease-specific biomarkers to monitor the disease and evaluate available treatment options for psoriasis. Psoriasis is one of the most prevalent skin disorders driven by a Th17-specific immune response. Although potential patients have a genetic predisposition to psoriasis, the etiology of the disease remains unknown. During the last two decades, proteomics became deeply integrated with psoriatic research. The data obtained in proteomic studies facilitated the discovery of novel mechanisms and the verification of many experimental hypotheses of the disease pathogenesis. The detailed data analysis revealed multiple differentially expressed proteins and significant changes in proteome associated with the disease and drug efficacy. In this respect, there is a need for proteomic studies to characterize the role of the disease-specific biomarkers in the pathogenesis of psoriasis, develop clinical applications to choose the most efficient treatment options and monitor the therapeutic response. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
46. Comparison of monoclonal antibody disposition predictions using different physiologically based pharmacokinetic modelling platforms.
- Author
-
De Sutter PJ, Gasthuys E, and Vermeulen A
- Abstract
Physiologically based pharmacokinetic (PBPK) models can be used to leverage physiological and in vitro data to predict monoclonal antibody (mAb) concentrations in serum and tissues. However, it is currently not known how consistent predictions of mAb disposition are across PBPK modelling platforms. In this work PBPK simulations of IgG, adalimumab and infliximab were compared between three platforms (Simcyp, PK-Sim, and GastroPlus). Accuracy of predicted serum and tissue concentrations was assessed using observed data collected from the literature. Physiological and mAb related input parameters were also compared and sensitivity analyses were carried out to evaluate model behavior when input values were altered. Differences in serum kinetics of IgG between platforms were minimal for a dose of 1 mg/kg, but became more noticeable at higher dosages (> 100 mg/kg) and when reference (healthy) physiological input values were altered. Predicted serum concentrations of both adalimumab and infliximab were comparable across platforms, but were noticeably higher than observed values. Tissue concentrations differed remarkably between the platforms, both for total- and interstitial fluid (ISF) concentrations. The accuracy of total tissue concentrations was within a three-fold of observed values for all tissues, except for brain tissue concentrations, which were overpredicted. Predictions of tissue ISF concentrations were less accurate and were best captured by GastroPlus. Overall, these simulations show that the different PBPK platforms generally predict similar mAb serum concentrations, but variable tissue concentrations. Caution is therefore warranted when PBPK models are used to simulate effect site tissue concentrations of mAbs without data to verify the predictions., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
47. Health- code- based triage versus universal COVID- 19 PCR testing before endoscopy in a low incidence area: a real- world experience.
- Author
-
Zhihui Duan, Dengxiang Liu, Shengyun Zhou, Hui Li, Xiaofang Sun, Chunqian Zhao, Qiong Duan, Liwei Li, Xiaochong Zhang, and Lingxuan Jin
- Subjects
DIAGNOSTIC use of polymerase chain reaction ,CORONAVIRUS diseases ,ENDOSCOPY ,REVERSE transcriptase polymerase chain reaction - Published
- 2023
- Full Text
- View/download PDF
48. Low-Density Granulocytes in Immune-Mediated Inflammatory Diseases.
- Author
-
Ning, Xin, Wang, Wen-Ming, and Jin, Hong-Zhong
- Subjects
MONONUCLEAR leukocytes ,GRANULOCYTES ,DENSITY gradient centrifugation ,CELL populations ,CELL differentiation ,CYTOKINES ,INFLAMMATION ,GENE expression profiling ,IMMUNOLOGIC diseases ,EXTRACELLULAR space ,IMMUNOTHERAPY ,ANIMALS - Abstract
Low-density granulocytes (LDGs), a distinct subset of neutrophils that colocalize with peripheral blood mononuclear cells after density gradient centrifugation, have been observed in many immune-mediated diseases. LDGs are considered highly proinflammatory because of enhanced spontaneous formation of neutrophil extracellular traps, endothelial toxicity, and cytokine production. Concomitantly, increased numbers of LDGs are associated with the severity of many immune-mediated inflammatory diseases. Recent studies, with the help of advanced transcriptomic technologies, demonstrated that LDGs were a mixed cell population composed of immature subset and mature subset, and these two subsets showed different pathogenic features. In this review, we summarize the current knowledge on the composition, origin, and pathogenic properties of LDGs in several immune-mediated inflammatory diseases and discuss potential medical interventions targeting LDGs. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
49. Abuse and dependence potential of sphingosine-1-phosphate (S1P) receptor modulators used in the treatment of multiple sclerosis: a review of literature and public data.
- Author
-
Schoedel, Kerri A., Kolly, Carine, Gardin, Anne, Neelakantham, Srikanth, and Shakeri-Nejad, Kasra
- Subjects
FINGOLIMOD ,SPHINGOSINE-1-phosphate ,MULTIPLE sclerosis ,MEDICATION abuse ,LITERATURE reviews ,DRUG abuse ,NATALIZUMAB ,DRUG addiction ,SUBSTANCE abuse ,ESTROGEN antagonists ,TREATMENT effectiveness ,DRUGS ,PSYCHOPHARMACOLOGY - Abstract
Abuse and misuse of prescription drugs remains an ongoing concern in the USA and worldwide; thus, all centrally active new drugs must be assessed for abuse and dependence potential. Sphingosine-1-phosphate (S1P) receptor modulators are used primarily in the treatment of multiple sclerosis. Among the new S1P receptor modulators, siponimod, ozanimod, and ponesimod have recently been approved in the USA, European Union (EU), and other countries. This review of literature and other public data has been undertaken to assess the potential for abuse of S1P receptor modulators, including ozanimod, siponimod, ponesimod, and fingolimod, as well as several similar compounds in development. The S1P receptor modulators have not shown chemical or pharmacological similarity to known drugs of abuse; have not shown abuse or dependence potential in animal models for subjective effects, reinforcement, or physical dependence; and do not have adverse event profiles demonstrating effects of interest to individuals who abuse drugs (such as sedative, stimulant, mood-elevating, or hallucinogenic effects). In addition, no reports of actual abuse, misuse, or dependence were identified in the scientific literature for fingolimod, which has been on the market since 2010 (USA) and 2011 (EU). Overall, the data suggest that S1P receptor modulators are not associated with significant potential for abuse or dependence, consistent with their unscheduled status in the USA and internationally. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
50. The Impact of Bartonella VirB/VirD4 Type IV Secretion System Effectors on Eukaryotic Host Cells.
- Author
-
Fromm, Katja and Dehio, Christoph
- Subjects
SECRETION ,EUKARYOTIC cells ,BARTONELLA ,POST-translational modification ,IMMUNE response ,INTRACELLULAR pathogens - Abstract
Bartonella spp. are facultative intracellular pathogens that infect a wide range of mammalian hosts including humans. The VirB/VirD4 type IV secretion system (T4SS) is a key virulence factor utilized to translocate Bartonella effector proteins (Beps) into host cells in order to subvert their functions. Crucial for effector translocation is the C-terminal Bep intracellular delivery (BID) domain that together with a positively charged tail sequence forms a bipartite translocation signal. Multiple BID domains also evolved secondary effector functions within host cells. The majority of Beps possess an N-terminal filamentation induced by cAMP (FIC) domain and a central connecting oligonucleotide binding (OB) fold. FIC domains typically mediate AMPylation or related post-translational modifications of target proteins. Some Beps harbor other functional modules, such as tandem-repeated tyrosine-phosphorylation (EPIYA-related) motifs. Within host cells the EPIYA-related motifs are phosphorylated, which facilitates the interaction with host signaling proteins. In this review, we will summarize our current knowledge on the molecular functions of the different domains present in Beps and highlight examples of Bep-dependent host cell modulation. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.