22 results on '"F. Hua"'
Search Results
2. P1048: MYF3001: A RANDOMIZED OPEN LABEL, PHASE 3 STUDY TO EVALUATE IMETELSTAT VERSUS BEST AVAILABLE THERAPY IN PATIENTS WITH INTERMEDIATE-2 OR HIGH-RISK MYELOFIBROSIS REFRACTORY TO JANUS KINASE INHIBITOR
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J. Mascarenhas, C. N. Harrison, J.-J. Kiladjian, R. S. Komrokji, S. Koschmieder, A. M. Vannucchi, T. Berry, D. Redding, L. Sherman, S. Dougherty, L. Peng, L. Sun, F. Huang, Y. Wan, F. M. Feller, A. Rizo, and S. Verstovsek
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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3. PB1971: FREQUENCY AND CHARACTERISTICS OF DEL(6Q) IN PATIENTS WITH MULTIPLE MYELOMA FROM LATIN-AMERICAN COUNTRIES. A REAL-WORLD STUDY
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F. Stella, P. Leone, E. Pedrazzini, C. Galvano, S. Zurita, M. Coccé, M. Gallego, N. Schultz, G. Alfonso, J. Canelos Moreno, A. Noboa, F. Huamán Garaicoa, C. Paz y Miño, M. Ziembar, P. Ochoa, P. Duarte, M. Quatrin, F. Colombi Martínez, D. Fernández, S. Cugliari, F. Uturbey, C. Peña, and I. Slavutsky
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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4. Industry Perspective on First-in-Human and Clinical Pharmacology Strategies to Support Clinical Development of T-Cell Engaging Bispecific Antibodies for Cancer Therapy.
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Nagaraja Shastri P, Shah N, Lechmann M, Mody H, Retter MW, Zhu M, Li T, Wang J, Shaik N, Zheng X, Ovacik M, Hua F, Jawa V, Boetsch C, Cao Y, Burke J, Datta K, Gadkar K, Upreti V, and Betts A
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- Humans, Drug Industry, Drug Development methods, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Agents, Immunological therapeutic use, Antineoplastic Agents, Immunological pharmacology, Antineoplastic Agents, Immunological adverse effects, Maximum Tolerated Dose, Animals, Antibodies, Bispecific pharmacology, Antibodies, Bispecific therapeutic use, Antibodies, Bispecific administration & dosage, T-Lymphocytes immunology, T-Lymphocytes drug effects, Neoplasms drug therapy, Neoplasms immunology
- Abstract
T-cell-engaging bispecific antibodies (TCEs) that target tumor antigens and T cells have shown great promise in treating cancer, particularly in hematological indications. The clinical development of TCEs often involves a lengthy first-in-human (FIH) trial with many dose-escalation cohorts leading up to an early proof of concept (POC), enabling either a no-go decision or dose selection for further clinical development. Multiple factors related to the target, product, disease, and patient population influence the efficacy and safety of TCEs. The intricate mechanism of action limits the translatability of preclinical models to the clinic, thereby posing challenges to streamline clinical development. In addition, unlike traditional chemotherapy, the top dose and recommended phase II doses (RP2Ds) for TCEs in the clinic are often not guided by the maximum tolerated dose (MTD), but rather based on the integrated dose-response assessment of the benefit/risk profile. These uncertainties pose complex challenges for translational and clinical pharmacologists (PK/PD scientists), as well as clinicians, to design an efficient clinical study that guides development. To that end, experts in the field, under the umbrella of the American Association of Pharmaceutical Scientists, have reviewed learnings from published literature and currently marketed products to share perspectives on the FIH and clinical pharmacology strategies to support early clinical development of TCEs., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)
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- 2025
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5. Occlusal interventions for managing temporomandibular disorders.
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Singh BP, Singh N, Jayaraman S, Kirubakaran R, Joseph S, Muthu MS, Jivnani H, and Hua F
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- Humans, Facial Pain therapy, Facial Pain etiology, Randomized Controlled Trials as Topic, Occlusal Adjustment instrumentation, Occlusal Adjustment methods, Occlusal Splints, Temporomandibular Joint Disorders complications, Temporomandibular Joint Disorders therapy
- Abstract
Background: Temporomandibular disorders (TMD) are conditions related to the musculoskeletal structure of the temporomandibular joint, which may lead to muscle or joint pain and other health issues. TMD may present in muscles only (myogenous), joints only (arthrogenous), or both (mixed), and may affect one side or both sides of the face. Myogenous TMD may present with or without limited mouth opening. Arthrogenous TMD may present as disc displacement with or without reduction ('reduction' meaning the articular disc resumes its normal position when the jaw is moving). Occlusal interventions change the occlusal relationship of maxillary and mandibular teeth to improve the alignment of the tooth contact, with the aim of relieving pain, and improving psychosocial functioning and quality of life. Occlusal interventions include splints and adjustments. Occlusal splints are specially designed mouth guards; they are generally classified as stabilisation, reflex or repositioning splints. Occlusal adjustment is the grinding down of teeth to improve occlusion., Objectives: To assess the effects of occlusal interventions in people diagnosed with temporomandibular disorders (TMD), compared to other interventions or no treatment, on joint pain, muscle pain at rest and when chewing, quality of life, discomfort, and recurrence., Search Methods: Cochrane Oral Health's Information Specialist searched following sources up to 9 August 2022: Cochrane Oral Health's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, Embase via Ovid, and two trials registers., Selection Criteria: We included randomised controlled trials (RCTs) of occlusal interventions (splints or adjustment) for managing TMD compared with no treatment, placebo, occlusal splint with a different mechanism of action, or other active treatments., Data Collection and Analysis: We adopted standard Cochrane methods to select studies, extract and analyse data, assess the risk of bias in the studies, and judge the certainty of the evidence. We reported outcomes as short term (three months or less) or long term (more than three months)., Main Results: We included 57 studies (2846 participants) that compared occlusal splints with no treatment, placebo, or another treatment. Most of the studies evaluated full hard stabilisation splint (FHSS) as the occlusal splint. We judged only one study to be at low risk of bias. Our key outcomes of interest were self-reported joint pain when chewing, muscle pain at rest and when chewing, discomfort, severity and frequency of joint noise, and recurrence rate. The duration of the studies ranged from 5 weeks to 84 months. The key results presented below were measured between 4.4 weeks and 4 months. It is important to note that we have very low certainty in the evidence for all comparisons and outcomes assessed. There may be little to no difference in self-reported joint pain when chewing between occlusal splint (FHSS) and placebo (non-occlusal splint) (RR 1.88, 95% CI 0.94 to 3.75; 1 study, 60 participants with mixed TMD), or pharmacological therapy (diclofenac) (RR 2.10, 95% CI 0.83 to 5.30; 1 study, 29 participants with osteoarthritis), but the evidence is very uncertain. Occlusal splint (FHSS) may reduce muscle pain when chewing compared to no treatment (MD -1.97, 95% CI -2.37 to -1.57; 1 study, 84 participants with disc displacement without reduction), but may have little to no effect when compared to physical therapy (low-level laser) (RR 0.17, 95% CI 0.02 to 1.26; 1 study, 40 participants) or acupuncture (with needles) (MD 0.10, 95% CI -0.80 to 1.00, 1 study, 40 participants) in people with myofascial pain TMD, but the evidence is very uncertain. There may be little to no difference in muscle pain at rest when occlusal splint (FHSS) is compared to no treatment (MD -11.63, 95% CI -29.37 to 6.11; 1 study, 37 participants) or physical therapy (physiotherapy) (MD -0.19, 95% CI -1.25 to 0.87; 1 study, 72 participants) in myofascial pain TMD, but the evidence is very uncertain. There may be little to no difference in severity of joint noise when occlusal splint (FHSS) is compared to no treatment, but the evidence is very uncertain (MD -0.58, 95% CI -7.09 to 5.93; 1 study, 20 participants). When FHSS is compared to physical therapy (specifically, orofacial myofunctional therapy), physical therapy may reduce severity of joint noise, but the evidence is very uncertain (MD 5.92, 95% CI 0.18 to 11.66; 1 study, 20 participants with mixed TMD). There may be little to no difference in frequency of joint noise when occlusal splint (FHSS) is compared to placebo (non-occlusal splint) (RR 1.18, 95% CI 0.63 to 2.20; 1 study, 60 myofascial pain TMD participants), occlusal splint with a different mechanism of action (RR 0.80, 95% CI 0.07 to 9.18; 1 study, 9 participants with disc displacement with reduction), or physical therapy (jaw exercise) (RR 1.50, 95% CI 0.32 to 6.94; 1 study, 18 participants with myofascial pain TMD), but the evidence is very uncertain. Discomfort and recurrence rate were not reported in any study. We judged the certainty of the evidence to be very low for all outcomes in all comparisons due to limitations in study design and imprecision., Authors' Conclusions: This review included 57 RCTs with 2846 participants, but the final results are inconclusive, so the research questions remain unanswered. Occlusal splints of the FHSS type may reduce muscle pain when chewing compared to no treatment, but the evidence is very uncertain. Orofacial myofunctional therapy may reduce severity of joint noise compared to occlusal splint (FHSS), but the evidence is very uncertain. For all other comparisons and outcomes, there may be little or no difference between groups, although the evidence is also very uncertain for these findings. Overall, we found insufficient evidence to reach conclusions regarding the effectiveness of occlusal interventions for managing symptoms of TMD, despite the available studies including almost 3000 participants. To make a useful contribution to the debate about the best way to treat TMD, any further research must be well-designed, with enough participants to reach the optimal information size for meaningful results; it requires recruitment from primary care, consensus around key outcomes and measures, and, ideally, long-term follow-up of three to five years, plus inclusion of a cost-effectiveness component., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)
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- 2024
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6. Comparison of dose selection based on target engagement versus inhibition of receptor-ligand interaction for checkpoint inhibitors.
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Head SA, Johnson C, Sarkar S, Matteson A, Marcantonio DH, Hua F, Burke JM, Apgar JF, and Flowers D
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- Humans, Ligands, Dose-Response Relationship, Drug, Models, Theoretical, Immune Checkpoint Inhibitors administration & dosage, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors pharmacokinetics, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized pharmacology
- Abstract
Immune checkpoint inhibitors block the interaction between a receptor on one cell and its ligand on another cell, thus preventing the transduction of an immunosuppressive signal. While inhibition of the receptor-ligand interaction is key to the pharmacological activity of these drugs, it can be technically challenging to measure these intercellular interactions directly. Instead, target engagement (or receptor occupancy) is commonly measured, but may not always be an accurate predictor of receptor-ligand inhibition, and can be misleading when used to inform clinical dose projections for this class of drugs. In this study, a mathematical model explicitly representing the intercellular receptor-ligand interaction is used to compare dose prediction based on target engagement or receptor-ligand inhibition for two checkpoint inhibitors, atezolizumab and magrolimab. For atezolizumab, there is little difference between target engagement and receptor-ligand inhibition, but for magrolimab, the model predicts that receptor-ligand inhibition is significantly less than target engagement. The key variables explaining the difference between these two drugs are the relative concentrations of the target receptors and their ligands. Drug-target affinity and receptor-ligand affinity can also have divergent effects on target engagement and inhibition. These results suggest that it is important to consider ligand-receptor inhibition in addition to target engagement and demonstrate the impact of using modeling for efficacious dose estimation., (© 2024 Applied BioMath. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2024
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7. Low-dose decitabine promotes M2 macrophage polarization in patients with primary immune thrombocytopenia via enhancing KLF4 binding to PPARγ promoter.
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Shao X, Xu P, Ji L, Wu B, Zhan Y, Zhuang X, Ou Y, Hua F, Sun L, Li F, Wang X, Chen H, and Cheng Y
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- Animals, Mice, Decitabine, Interleukin-10, Inflammasomes, Leukocytes, Mononuclear, NLR Family, Pyrin Domain-Containing 3 Protein, Macrophages, PPAR gamma, Purpura, Thrombocytopenic, Idiopathic
- Abstract
Background: The first-line therapy is effective for the treatment of primary immune thrombocytopenia (ITP); however, maintaining the long-term responses remains challenging. Low-dose decitabine (DAC) has been adopted to treat refractory ITP, while its role in macrophage polarization has not been fully understood. We aimed to investigate the mechanistic role of DAC in M2 macrophage polarization and evaluated its therapeutic effect in ITP., Methods: The M2 monocytes were identified by flow cytometry from peripheral blood mononuclear cells in healthy controls (HCs) and ITP patients. The expression of PPARγ, Arg-1, DNMT3b and NLRP3, together with IL-10 plasma levels was measured to examine its function. Bisulfite-sequencing PCR was used to evaluate the methylation status of PPARγ promoter, and the binding affinity of KLF4 was measured by Cut&Tag. A sh-PPARγ THP-1 cell line was created to verify if low-dose DAC-modulated M2 macrophage polarization was PPARγ-dependent. The passive ITP models were used to investigate the therapeutic effects of low-dose DAC and its role in modulating polarization and immunomodulatory function of macrophages. NLRP3 inflammasome and reactive oxygen species were also tested to understand the downstream of PPARγ., Results: The M2 monocytes with impaired immunoregulation were observed in ITP. After high-dose dexamethasone (HD-DXM) treatment, M2 monocytes increased significantly with the elevated expression of PPARγ, Arg-1 and IL-10 in CR patients. Low-dose DAC promoted M2 macrophage polarization in a PPARγ-dependent way via demethylating the promoter of PPARγ, especially the KLF4 binding sites. Low-dose DAC alleviated ITP mice by restoring the M1/M2 balance and fine-tuning immunomodulatory function of macrophages. The downstream of the PPARγ modulation of M2 macrophage polarization might physiologically antagonize NLRP3 inflammasome., Conclusions: Low-dose DAC promoted M2 macrophage polarization due to the demethylation within the promoter of PPARγ, thus enhanced the KLF4 binding affinity in ITP., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
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- 2023
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8. From Cold to Hot: Changing Perceptions and Future Opportunities for Quantitative Systems Pharmacology Modeling in Cancer Immunotherapy.
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Lemaire V, Bassen D, Reed M, Song R, Khalili S, Lien YTK, Huang L, Singh AP, Stamatelos S, Bottino D, and Hua F
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- Humans, Network Pharmacology, Drug Development, Immunotherapy, Medical Oncology, Models, Biological, Tumor Microenvironment, Neoplasms drug therapy, Pharmacology
- Abstract
Immuno-oncology (IO) is a fast-expanding field due to recent success using IO therapies in treating cancer. As IO therapies do not directly kill tumor cells but rather act upon the patients' own immune cells either systemically or in the tumor microenvironment, new and innovative approaches are required to inform IO therapy research and development. Quantitative systems pharmacology (QSP) modeling describes the biological mechanisms of disease and the mode of action of drugs with mathematical equations, which has significant potential to address the big challenges in the IO field, from identifying patient populations that respond to different therapies to guiding the selection, dosing, and scheduling of combination therapy. To assess the perspectives of the community on the impact of QSP modeling in IO drug development and to understand current applications and challenges, the IO QSP working group-under the QSP Special Interest Group (SIG) of the International Society of Pharmacometrics (ISoP)-conducted a survey among QSP modelers, non-QSP modelers, and non-modeling IO program stakeholders. The survey results are presented here with discussions on how to address some of the findings. One of the findings is the differences in perception among these groups. To help bridge this perception gap, we present several case studies demonstrating the impact of QSP modeling in IO and suggest actions that can be taken in the future to increase the real and perceived impact of QSP modeling in IO drug research and development., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2023
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9. Kaempferol-3-O-rutinoside exerts cardioprotective effects through NF-κB/NLRP3/Caspase-1 pathway in ventricular remodeling after acute myocardial infarction.
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Hua F, Li JY, Zhang M, Zhou P, Wang L, Ling TJ, and Bao GH
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- Animals, Anti-Inflammatory Agents, Caspase 1 genetics, Caspase 1 metabolism, Collagen, Glycosides, Inflammasomes, Kaempferols pharmacology, Lipopolysaccharides, Molecular Docking Simulation, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Rats, Tea, Ventricular Remodeling, Myocardial Infarction drug therapy, NF-kappa B genetics, NF-kappa B metabolism
- Abstract
Ventricular remodeling (VR) after acute myocardial infarction (AMI) is the main pathogenesis of chronic heart failure (CHF). Kaempferol-3-O-rutinoside (KR) is the flavonoid glycoside with the highest content in Lu'an GuaPian tea, which has good pharmacological activities. However, the mechanism of KR against VR after AMI remains unclear. Molecular docking was used to predict the targets of KR on the NLRP3/Caspase-1 signaling pathway. Histological changes in the myocardium were visualized using HE staining, Masson staining. Cardiomyocyte apoptosis was detected using TUNEL. Immunohistochemistry was used to examine NLRP3, Caspase-1 p20, and GSDMD. IL-1β level in serum was detected using ELISA. Finally, the expressions of NF-κB p65, NLRP3, ASC, Caspase-1 p20, GSDMD, and IL-1β were measured using RT-PCR and Western blotting. Our results showed that KR had a good binding activity with NLRP3, Caspase-1, and GSDMD, significantly improved cardiac function, alleviated cardiac pathological changes, reduced the excessive deposition of myocardial interstitial collagen, and inhibited cardiomyocyte apoptosis in AMI rats. Furthermore, KR could decrease the IL-1β level and inhibit the expressions of NF-κB p65, NLRP3, ASC, Caspase-1 p20, GSDMD, and IL-1β. Our study suggests that KR can prevent and treat VR after AMI, and the protective effect is related to its regulatory NF-κB/NLRP3/Caspase-1 signaling pathway. PRACTICAL APPLICATIONS: Kaempferol-3-O-rutinoside is present in Carthamus tinctorius L., Nymphaea candida, Afgekia mahidoliae and green tea, which has good pharmacological activities against liver injury, cerebral ischemia/reperfusion injury, dementia, hyperglycemia, and myocardial infarction. Our previous study found that kaempferol-3-O-rutinoside had an obvious anti-inflammatory effect, and could significantly improve the cell survival rate of H9c2 myocardium inflammatory injury induced by LPS. In this study, kaempferol-3-O-rutinoside significantly improved cardiac function, alleviated cardiac pathological changes, reduced the excessive deposition of myocardial interstitial collagen, and inhibited cardiomyocyte apoptosis in AMI rats. Furthermore, kaempferol-3-O-rutinoside could decrease the IL-1β level and inhibit the expressions of NF-κB p65, NLRP3, ASC, Caspase-1, GSDMD and IL-1β, suggesting that kaempferol-3-O-rutinoside could regulate NF-κB/NLRP3/Caspase-1 signaling pathway., (© 2022 Wiley Periodicals LLC.)
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- 2022
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10. Flavonoids in Lu'an GuaPian tea as potential inhibitors of TMA-lyase in acute myocardial infarction.
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Hua F, Zhou P, Bao GH, and Ling TJ
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- Flavonoids, Humans, Kaempferols, Methylamines, Tea, Lyases, Myocardial Infarction drug therapy
- Abstract
Current studies have shown that plasma trimethylamine N-oxide (TMAO) level is closely related to the risk of acute myocardial infarction (AMI), that is, the possibility of AMI occurrence is positively correlated with TMAO level. The production of TMAO is mainly due to the transformation of trimethylamine (TMA) through the hepatic flavin-containing monooxygenase. Hence, inhibition of TMA production is essential. Flavonoids are considered to be mainly responsible for the health-promoting effects, and tea is rich in a variety of flavonoids. However, it is not clear that flavonoids from Lu'an GuaPian tea regulate gut microflora by inhibiting TMA-lyase activity to prevent AMI. Sixteen flavonoids from Lu'an GuaPian tea for the treatment of AMI based on the inhibition of TMA-lyase were summarized and screened. Docking results showed kaempferol 3-O-rutinoside had the highest Vina score, which means that it is the most active and can be used as lead compounds for structural modification. PRACTICAL APPLICATIONS: TMAO can be used as a marker of CHD and thus as a potential research object. Lu'an GuaPian tea is one of the top 10 famous teas in China and has the aroma of chestnuts and orchids. The flavonoids in Lu'an GuaPian tea are mainly composed of flavonoid aglycones and flavonoid glycosides. Since flavonoids have cardiovascular protection and can regulate gut microbiota, and gut microbiota is directly related to TMAO, reduction of TMAO level is to inhibit the transformation from TMA to TMAO. Kaempferol 3-O-rutinoside, quercetin 3-O-rhamnosylgalactoside, kaempferol 3-O-rhamnosylgalactoside, and myricetin 3-O-galactoside in Lu'an GuaPian tea have good binding affinities with TMA-lyase., (© 2022 Wiley Periodicals LLC.)
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- 2022
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11. Quantitative systems pharmacology modeling provides insight into inter-mouse variability of Anti-CTLA4 response.
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Qiao W, Lin L, Young C, Narula J, Hua F, Matteson A, Hooper A, Gruenbaum L, and Betts A
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- Animals, Antibodies, Disease Models, Animal, Immunotherapy methods, Mice, Neoplasms pathology, Network Pharmacology
- Abstract
Clinical responses of immuno-oncology therapies are highly variable among patients. Similar response variability has been observed in syngeneic mouse models. Understanding of the variability in the mouse models may shed light on patient variability. Using a murine anti-CTLA4 antibody as a case study, we developed a quantitative systems pharmacology model to capture the molecular interactions of the antibody and relevant cellular interactions that lead to tumor cell killing. Nonlinear mixed effect modeling was incorporated to capture the inter-animal variability of tumor growth profiles in response to anti-CTLA4 treatment. The results suggested that intratumoral CD8+ T cell kinetics and tumor proliferation rate were the main drivers of the variability. In addition, simulations indicated that nonresponsive mice to anti-CTLA4 treatment could be converted to responders by increasing the number of intratumoral CD8+ T cells. The model provides a mechanistic starting point for translation of CTLA4 inhibitors from syngeneic mice to the clinic., (© 2022 Pfizer Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2022
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12. Quantitative systems pharmacology model for Alzheimer's disease to predict the effect of aducanumab on brain amyloid.
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Lin L, Hua F, Salinas C, Young C, Bussiere T, Apgar JF, Burke JM, Kandadi Muralidharan K, Rajagovindan R, and Nestorov I
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- Amyloid beta-Peptides metabolism, Antibodies, Monoclonal, Humanized, Brain metabolism, Humans, Network Pharmacology, Plaque, Amyloid drug therapy, Plaque, Amyloid metabolism, Alzheimer Disease drug therapy, Alzheimer Disease metabolism
- Abstract
Alzheimer's disease (AD) is an irreversible, progressive brain disorder that impairs memory and cognitive function. Dysregulation of the amyloid-β (Aβ) pathway and amyloid plaque accumulation in the brain are hallmarks of AD. Aducanumab is a human, immunoglobulin gamma 1 monoclonal antibody targeting aggregated forms of Aβ. In phase Ib and phase III studies, aducanumab reduced Aβ plaques in a dose dependent manner, as measured by standard uptake value ratio of amyloid positron emission tomography imaging. The goal of this work was to develop a quantitative systems pharmacology model describing the production, aggregation, clearance, and transport of Aβ as well as the mechanism of action for the drug to understand the relationship between aducanumab dosing regimens and changes of different Aβ species, particularly plaques in the brain. The model was used to better understand the pharmacodynamic effects observed in the clinical trials of aducanumab and assist in the clinical development of future Aβ therapies., (© 2022 Biogen. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2022
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13. Rat plasma protein binding of kaempferol-3-O-rutinoside from Lu'an GuaPian tea and its anti-inflammatory mechanism for cardiovascular protection.
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Hua F, Zhou P, Liu PP, and Bao GH
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- Animals, China, Kaempferols, Molecular Docking Simulation, Protein Binding, Rats, Anti-Inflammatory Agents pharmacology, Tea
- Abstract
Previous study found a high content of kaempferol-3-O-rutinoside (KR) in Lu'an GuaPian tea, however, the rat plasma protein binding and mechanism of KR for cardiovascular protection are unclear. Thus, we studied plasma protein binding using ultrafiltration followed by UPLC, and screened its inhibition against LPS-induced inflammation injury in vitro as well as the underlying mechanism by molecular docking and western blot. KR showed over 74% plasma protein binding ratio. Furthermore, KR may act on the toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). In vitro experiments showed that KR decreases the overexpression of TLR4, MyD88, and nuclear factor-κB (NF-κB), which further validates the molecular docking results, suggesting that KR could block TLR4/MyD88/NF-κB signaling. These results indicate that KR could be a potential active agent in the protection of myocardial injury. PRACTICAL APPLICATIONS: Health benefits of tea are largely dependent on the intake of flavonoids. Flavonoids are a group of compounds beneficial to cardiovascular disease and an important part of "functional foods." Lu'an GuaPian tea is mainly produced in Lu'an City, Anhui Province and is one of the top 10 famous teas in China. Kaempferol-3-O-rutinoside in Lu'an GuaPian has good hypoglycemic effect, mainly manifested in a strong inhibition of α-glucosidase and α-amylase activities. Present study showed that kaempferol-3-O-rutinoside could block TLR4/MyD88/NF-κB signaling, suggesting that it could be a potential active agent in the protection of myocardial injury., (© 2021 Wiley Periodicals LLC.)
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- 2021
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14. A systems pharmacology model for gene therapy in sickle cell disease.
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Zheng B, Wille L, Peppel K, Hagen D, Matteson A, Ahlers J, Schaff J, Hua F, Yuraszeck T, Cobbina E, Apgar JF, Burke JM, Roberts J, and Das R
- Subjects
- Anemia, Sickle Cell genetics, Bone Marrow Cells cytology, Erythrocytes cytology, Hemoglobins metabolism, Humans, Network Pharmacology, Anemia, Sickle Cell therapy, Genetic Therapy methods, Models, Theoretical, Stem Cell Transplantation methods
- Abstract
We developed a mathematical model for autologous stem cell therapy to cure sickle cell disease (SCD). Experimental therapies using this approach seek to engraft stem cells containing a curative gene. These stem cells are expected to produce a lifelong supply of red blood cells (RBCs) containing an anti-sickling hemoglobin. This complex, multistep treatment is expensive, and there is limited patient data available from early clinical trials. Our objective was to quantify the impact of treatment parameters, such as initial stem cell dose, efficiency of lentiviral transduction, and degree of bone marrow preconditioning on engraftment efficiency, peripheral RBC numbers, and anti-sickling hemoglobin levels over time. We used ordinary differential equations to model RBC production from progenitor cells in the bone marrow, and hemoglobin assembly from its constituent globin monomers. The model recapitulates observed RBC and hemoglobin levels in healthy and SCD phenotypes. Treatment simulations predict dynamics of stem cell engraftment and RBC containing the therapeutic gene product. Post-treatment dynamics show an early phase of reconstitution due to short lived stem cells, followed by a sustained RBC production from stable engraftment of long-term stem cells. This biphasic behavior was previously reported in the literature. Sensitivity analysis of the model quantified relationships between treatment parameters and efficacy. The initial dose of transduced stem cells, and the intensity of myeloablative bone marrow preconditioning are predicted to most positively impact long-term outcomes. The quantitative systems pharmacology approach used here demonstrates the value of model-assisted therapeutic design for gene therapies in SCD., (© 2021 CSL Behring. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
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- 2021
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15. Oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia.
- Author
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Zhao T, Wu X, Zhang Q, Li C, Worthington HV, and Hua F
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- Adult, Child, Chlorhexidine therapeutic use, Humans, Incidence, Intensive Care Units statistics & numerical data, Length of Stay, Mouthwashes therapeutic use, Pneumonia, Ventilator-Associated epidemiology, Pneumonia, Ventilator-Associated mortality, Randomized Controlled Trials as Topic, Respiration, Artificial statistics & numerical data, Toothbrushing instrumentation, Toothbrushing methods, Critical Illness, Oral Hygiene methods, Pneumonia, Ventilator-Associated prevention & control, Respiration, Artificial adverse effects
- Abstract
Background: Ventilator-associated pneumonia (VAP) is defined as pneumonia developing in people who have received mechanical ventilation for at least 48 hours. VAP is a potentially serious complication in these patients who are already critically ill. Oral hygiene care (OHC), using either a mouthrinse, gel, swab, toothbrush, or combination, together with suction of secretions, may reduce the risk of VAP in these patients., Objectives: To assess the effects of oral hygiene care (OHC) on incidence of ventilator-associated pneumonia in critically ill patients receiving mechanical ventilation in hospital intensive care units (ICUs)., Search Methods: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 25 February 2020), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2020, Issue 1), MEDLINE Ovid (1946 to 25 February 2020), Embase Ovid (1980 to 25 February 2020), LILACS BIREME Virtual Health Library (1982 to 25 February 2020) and CINAHL EBSCO (1937 to 25 February 2020). We also searched the VIP Database (January 2012 to 8 March 2020). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases., Selection Criteria: We included randomised controlled trials (RCTs) evaluating the effects of OHC (mouthrinse, gel, swab, toothbrush or combination) in critically ill patients receiving mechanical ventilation for at least 48 hours., Data Collection and Analysis: At least two review authors independently assessed search results, extracted data and assessed risk of bias in included studies. We contacted study authors for additional information. We reported risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, using the random-effects model of meta-analysis when data from four or more trials were combined., Main Results: We included 40 RCTs (5675 participants), which were conducted in various countries including China, USA, Brazil and Iran. We categorised these RCTs into five main comparisons: chlorhexidine (CHX) mouthrinse or gel versus placebo/usual care; CHX mouthrinse versus other oral care agents; toothbrushing (± antiseptics) versus no toothbrushing (± antiseptics); powered versus manual toothbrushing; and comparisons of other oral care agents used in OHC (other oral care agents versus placebo/usual care, or head-to-head comparisons between other oral care agents). We assessed the overall risk of bias as high in 31 trials and low in two, with the rest being unclear. Moderate-certainty evidence from 13 RCTs (1206 participants, 92% adults) shows that CHX mouthrinse or gel, as part of OHC, probably reduces the incidence of VAP compared to placebo or usual care from 26% to about 18% (RR 0.67, 95% confidence intervals (CI) 0.47 to 0.97; P = 0.03; I
2 = 66%). This is equivalent to a number needed to treat for an additional beneficial outcome (NNTB) of 12 (95% CI 7 to 128), i.e. providing OHC including CHX for 12 ventilated patients in intensive care would prevent one patient developing VAP. There was no evidence of a difference between interventions for the outcomes of mortality (RR 1.03, 95% CI 0.80 to 1.33; P = 0.86, I2 = 0%; 9 RCTs, 944 participants; moderate-certainty evidence), duration of mechanical ventilation (MD -1.10 days, 95% CI -3.20 to 1.00 days; P = 0.30, I2 = 74%; 4 RCTs, 594 participants; very low-certainty evidence) or duration of intensive care unit (ICU) stay (MD -0.89 days, 95% CI -3.59 to 1.82 days; P = 0.52, I2 = 69%; 5 RCTs, 627 participants; low-certainty evidence). Most studies did not mention adverse effects. One study reported adverse effects, which were mild, with similar frequency in CHX and control groups and one study reported there were no adverse effects. Toothbrushing (± antiseptics) may reduce the incidence of VAP (RR 0.61, 95% CI 0.41 to 0.91; P = 0.01, I2 = 40%; 5 RCTs, 910 participants; low-certainty evidence) compared to OHC without toothbrushing (± antiseptics). There is also some evidence that toothbrushing may reduce the duration of ICU stay (MD -1.89 days, 95% CI -3.52 to -0.27 days; P = 0.02, I2 = 0%; 3 RCTs, 749 participants), but this is very low certainty. Low-certainty evidence did not show a reduction in mortality (RR 0.84, 95% CI 0.67 to 1.05; P = 0.12, I2 = 0%; 5 RCTs, 910 participants) or duration of mechanical ventilation (MD -0.43, 95% CI -1.17 to 0.30; P = 0.25, I2 = 46%; 4 RCTs, 810 participants)., Authors' Conclusions: Chlorhexidine mouthwash or gel, as part of OHC, probably reduces the incidence of developing ventilator-associated pneumonia (VAP) in critically ill patients from 26% to about 18%, when compared to placebo or usual care. We did not find a difference in mortality, duration of mechanical ventilation or duration of stay in the intensive care unit, although the evidence was low certainty. OHC including both antiseptics and toothbrushing may be more effective than OHC with antiseptics alone to reduce the incidence of VAP and the length of ICU stay, but, again, the evidence is low certainty. There is insufficient evidence to determine whether any of the interventions evaluated in the studies are associated with adverse effects., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)- Published
- 2020
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16. Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy.
- Author
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Riley P, Glenny AM, Hua F, and Worthington HV
- Subjects
- Amifostine therapeutic use, Drugs, Chinese Herbal therapeutic use, Female, Fibroblast Growth Factor 7 therapeutic use, Humans, Male, Pilocarpine therapeutic use, Quality of Life, Radiation-Protective Agents adverse effects, Radiation-Protective Agents therapeutic use, Randomized Controlled Trials as Topic, Saliva, Artificial, Salivary Gland Diseases etiology, Salivary Glands radiation effects, Salivation drug effects, Salivation radiation effects, Xerostomia etiology, Radiotherapy adverse effects, Salivary Gland Diseases prevention & control, Xerostomia prevention & control
- Abstract
Background: Salivary gland dysfunction is an 'umbrella' term for the presence of either xerostomia (subjective sensation of dryness), or salivary gland hypofunction (reduction in saliva production). It is a predictable side effect of radiotherapy to the head and neck region, and is associated with a significant impairment of quality of life. A wide range of pharmacological interventions, with varying mechanisms of action, have been used for the prevention of radiation-induced salivary gland dysfunction., Objectives: To assess the effects of pharmacological interventions for the prevention of radiation-induced salivary gland dysfunction., Search Methods: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 14 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 14 September 2016); MEDLINE Ovid (1946 to 14 September 2016); Embase Ovid (1980 to 14 September 2016); CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 14 September 2016); LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 14 September 2016); Zetoc Conference Proceedings (1993 to 14 September 2016); and OpenGrey (1997 to 14 September 2016). We searched the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases., Selection Criteria: We included randomised controlled trials, irrespective of their language of publication or publication status. Trials included participants of all ages, ethnic origin and gender, scheduled to receive radiotherapy on its own or in addition to chemotherapy to the head and neck region. Participants could be outpatients or inpatients. We included trials comparing any pharmacological agent regimen, prescribed prophylactically for salivary gland dysfunction prior to or during radiotherapy, with placebo, no intervention or an alternative pharmacological intervention. Comparisons of radiation techniques were excluded., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane., Main Results: We included 39 studies that randomised 3520 participants; the number of participants analysed varied by outcome and time point. The studies were ordered into 14 separate comparisons with meta-analysis only being possible in three of those.We found low-quality evidence to show that amifostine, when compared to a placebo or no treatment control, might reduce the risk of moderate to severe xerostomia (grade 2 or higher on a 0 to 4 scale) at the end of radiotherapy (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.19 to 0.67; P = 0.001, 3 studies, 119 participants), and up to three months after radiotherapy (RR 0.66, 95% CI 0.48 to 0.92; P = 0.01, 5 studies, 687 participants), but there is insufficient evidence that the effect is sustained up to 12 months after radiotherapy (RR 0.70, 95% CI 0.40 to 1.23; P = 0.21, 7 studies, 682 participants). We found very low-quality evidence that amifostine increased unstimulated salivary flow rate up to 12 months after radiotherapy, both in terms of mg of saliva per 5 minutes (mean difference (MD) 0.32, 95% CI 0.09 to 0.55; P = 0.006, 1 study, 27 participants), and incidence of producing greater than 0.1 g of saliva over 5 minutes (RR 1.45, 95% CI 1.13 to 1.86; P = 0.004, 1 study, 175 participants). However, there was insufficient evidence to show a difference when looking at stimulated salivary flow rates. There was insufficient (very low-quality) evidence to show that amifostine compromised the effects of cancer treatment when looking at survival measures. There was some very low-quality evidence of a small benefit for amifostine in terms of quality of life (10-point scale) at 12 months after radiotherapy (MD 0.70, 95% CI 0.20 to 1.20; P = 0.006, 1 study, 180 participants), but insufficient evidence at the end of and up to three months postradiotherapy. A further study showed no evidence of a difference at 6, 12, 18 and 24 months postradiotherapy. There was low-quality evidence that amifostine is associated with increases in: vomiting (RR 4.90, 95% CI 2.87 to 8.38; P < 0.00001, 5 studies, 601 participants); hypotension (RR 9.20, 95% CI 2.84 to 29.83; P = 0.0002, 3 studies, 376 participants); nausea (RR 2.60, 95% CI 1.81 to 3.74; P < 0.00001, 4 studies, 556 participants); and allergic response (RR 7.51, 95% CI 1.40 to 40.39; P = 0.02, 3 studies, 524 participants).We found insufficient evidence (that was of very low quality) to determine whether or not pilocarpine performed better or worse than a placebo or no treatment control for the outcomes: xerostomia, salivary flow rate, survival, and quality of life. There was some low-quality evidence that pilocarpine was associated with an increase in sweating (RR 2.98, 95% CI 1.43 to 6.22; P = 0.004, 5 studies, 389 participants).We found insufficient evidence to determine whether or not palifermin performed better or worse than placebo for: xerostomia (low quality); survival (moderate quality); and any adverse effects.There was also insufficient evidence to determine the effects of the following interventions: biperiden plus pilocarpine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin)., Authors' Conclusions: There is some low-quality evidence to suggest that amifostine prevents the feeling of dry mouth in people receiving radiotherapy to the head and neck (with or without chemotherapy) in the short- (end of radiotherapy) to medium-term (three months postradiotherapy). However, it is less clear whether or not this effect is sustained to 12 months postradiotherapy. The benefits of amifostine should be weighed against its high cost and side effects. There was insufficient evidence to show that any other intervention is beneficial.
- Published
- 2017
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17. Oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia.
- Author
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Hua F, Xie H, Worthington HV, Furness S, Zhang Q, and Li C
- Subjects
- Adult, Child, Chlorhexidine therapeutic use, Humans, Intensive Care Units, Mouthwashes therapeutic use, Randomized Controlled Trials as Topic, Toothbrushing instrumentation, Toothbrushing methods, Critical Illness, Oral Hygiene methods, Pneumonia, Ventilator-Associated prevention & control, Respiration, Artificial adverse effects
- Abstract
Background: Ventilator-associated pneumonia (VAP) is defined as pneumonia developing in people who have received mechanical ventilation for at least 48 hours. VAP is a potentially serious complication in these patients who are already critically ill. Oral hygiene care (OHC), using either a mouthrinse, gel, toothbrush, or combination, together with aspiration of secretions, may reduce the risk of VAP in these patients., Objectives: To assess the effects of oral hygiene care on incidence of ventilator-associated pneumonia in critically ill patients receiving mechanical ventilation in hospital intensive care units (ICUs)., Search Methods: We searched the following electronic databases: Cochrane Oral Health's Trials Register (to 17 December 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 11), MEDLINE Ovid (1946 to 17 December 2015), Embase Ovid (1980 to 17 December 2015), LILACS BIREME Virtual Health Library (1982 to 17 December 2015), CINAHL EBSCO (1937 to 17 December 2016), Chinese Biomedical Literature Database (1978 to 14 January 2013), China National Knowledge Infrastructure (1994 to 14 January 2013), Wan Fang Database (January 1984 to 14 January 2013) and VIP Database (January 2012 to 4 May 2016). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials to 17 December 2015. We placed no restrictions on the language or date of publication when searching the electronic databases., Selection Criteria: We included randomised controlled trials (RCTs) evaluating the effects of OHC (mouthrinse, swab, toothbrush or combination) in critically ill patients receiving mechanical ventilation for at least 48 hours., Data Collection and Analysis: At least two review authors independently assessed search results, extracted data and assessed risk of bias in included studies. We contacted study authors for additional information. We pooled data from trials with similar interventions and outcomes. We reported risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, using random-effects models unless there were fewer than four studies., Main Results: We included 38 RCTs (6016 participants). There were four main comparisons: chlorhexidine (CHX) mouthrinse or gel versus placebo/usual care; toothbrushing versus no toothbrushing; powered versus manual toothbrushing; and comparisons of oral care solutions. We assessed the overall risk of bias as low in five trials (13%), high in 26 trials (68%), and unclear in seven trials (18%). We did not consider the risk of bias to be serious when assessing the quality of evidence (GRADE) for VAP incidence, but we downgraded other outcomes for risk of bias.High quality evidence from 18 RCTs (2451 participants, 86% adults) shows that CHX mouthrinse or gel, as part of OHC, reduces the risk of VAP compared to placebo or usual care from 25% to about 19% (RR 0.74, 95% confidence intervals (CI) 0.61 to 0.89, P = 0.002, I
2 = 31%). This is equivalent to a number needed to treat for an additional beneficial outcome (NNTB) of 17 (95% CI 10 to 33), which indicates that for every 17 ventilated patients in intensive care receiving OHC including chlorhexidine, one outcome of VAP would be prevented. There is no evidence of a difference between CHX and placebo/usual care for the outcomes of mortality (RR 1.09, 95% CI 0.96 to 1.23, P = 0.18, I2 = 0%, 15 RCTs, 2163 participants, moderate quality evidence), duration of mechanical ventilation (MD -0.09 days, 95% CI -1.73 to 1.55 days, P = 0.91, I2 = 36%, five RCTs, 800 participants, low quality evidence), or duration of intensive care unit (ICU) stay (MD 0.21 days, 95% CI -1.48 to 1.89 days, P = 0.81, I2 = 9%, six RCTs, 833 participants, moderate quality evidence). There is insufficient evidence to determine the effect of CHX on duration of systemic antibiotics, oral health indices, caregivers' preferences or cost. Only two studies reported any adverse effects, and these were mild with similar frequency in CHX and control groups.We are uncertain as to the effects of toothbrushing (± antiseptics) on the outcomes of VAP (RR 0.69, 95% CI 0.44 to 1.09, P = 0.11, I2 = 64%, five RCTs, 889 participants, very low quality evidence) and mortality (RR 0.87, 95% CI 0.70 to 1.09, P = 0.24, I2 = 0%, five RCTs, 889 participants, low quality evidence) compared to OHC without toothbrushing (± antiseptics). There is insufficient evidence to determine whether toothbrushing affects duration of mechanical ventilation, duration of ICU stay, use of systemic antibiotics, oral health indices, adverse effects, caregivers' preferences or cost.Only one trial (78 participants) compared use of a powered toothbrush with a manual toothbrush, providing insufficient evidence to determine the effect on any of the outcomes of this review.Fifteen trials compared various other oral care solutions. There is very weak evidence that povidone iodine mouthrinse is more effective than saline/placebo (RR 0.69, 95% CI 0.50 to 0.95, P = 0.02, I2 = 74%, three studies, 356 participants, high risk of bias), and that saline rinse is more effective than saline swab (RR 0.47, 95% CI 0.37 to 0.62, P < 0.001, I2 = 84%, four studies, 488 participants, high risk of bias) in reducing VAP. Due to variation in comparisons and outcomes among trials, there is insufficient evidence concerning the effects of other oral care solutions., Authors' Conclusions: OHC including chlorhexidine mouthwash or gel reduces the risk of developing ventilator-associated pneumonia in critically ill patients from 25% to about 19%. However, there is no evidence of a difference in the outcomes of mortality, duration of mechanical ventilation or duration of ICU stay. There is no evidence that OHC including both antiseptics and toothbrushing is different from OHC with antiseptics alone, and some weak evidence to suggest that povidone iodine mouthrinse is more effective than saline/placebo, and saline rinse is more effective than saline swab in reducing VAP. There is insufficient evidence to determine whether powered toothbrushing or other oral care solutions are effective in reducing VAP. There is also insufficient evidence to determine whether any of the interventions evaluated in the studies are associated with adverse effects.- Published
- 2016
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18. Using a Systems Pharmacology Model of the Blood Coagulation Network to Predict the Effects of Various Therapies on Biomarkers.
- Author
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Nayak S, Lee D, Patel-Hett S, Pittman DD, Martin SW, Heatherington AC, Vicini P, and Hua F
- Abstract
A number of therapeutics have been developed or are under development aiming to modulate the coagulation network to treat various diseases. We used a systems model to better understand the effect of modulating various components on blood coagulation. A computational model of the coagulation network was built to match in-house in vitro thrombin generation and activated Partial Thromboplastin Time (aPTT) data with various concentrations of recombinant factor VIIa (FVIIa) or factor Xa added to normal human plasma or factor VIII-deficient plasma. Sensitivity analysis applied to the model revealed that lag time, peak thrombin concentration, area under the curve (AUC) of the thrombin generation profile, and aPTT show different sensitivity to changes in coagulation factors' concentrations and type of plasma used (normal or factor VIII-deficient). We also used the model to explore how variability in concentrations of the proteins in coagulation network can impact the response to FVIIa treatment.
- Published
- 2015
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19. Anti-IL21 receptor monoclonal antibody (ATR-107): Safety, pharmacokinetics, and pharmacodynamic evaluation in healthy volunteers: a phase I, first-in-human study.
- Author
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Hua F, Comer GM, Stockert L, Jin B, Nowak J, Pleasic-Williams S, Wunderlich D, Cheng J, and Beebe JS
- Subjects
- Adolescent, Adult, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal, Humanized, Biological Availability, Cohort Studies, Dose-Response Relationship, Drug, Double-Blind Method, Electrocardiography drug effects, Female, Half-Life, Humans, Injections, Intravenous, Injections, Subcutaneous, Male, Middle Aged, Young Adult, Antibodies, Monoclonal pharmacology, Receptors, Interleukin-21 antagonists & inhibitors
- Abstract
Safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ATR-107, a fully human monoclonal anti-IL-21 receptor (IL-21R) antibody, administered as ascending single doses, subcutaneously or intravenously, was evaluated in a placebo-controlled, double-blind trial in healthy subjects. The dose levels were 3-300 mg by SC and 30-120 mg by IV. The most important adverse events were hypersensitivity reactions occurring in three out of six subjects in 300 mg SC cohort and considered as dose limiting toxicity. More than 75% of the subjects who received ATR-107 developed anti-drug antibodies (ADAs), which had no discernible impact on PK or safety. The PK of ATR-107 appeared to be dose -proportional. T1/2 was shorter than typical therapeutic antibodies. Bioavailability of ATR-107 was about 30%. IL-21R occupancy was measured in circulating B cells in the 60 and 120 mg IV cohort. The data indicated that single dose of ATR-107 was able to maximally occupy IL-21Rs through at least Day 42. Further escalation in the FIH study was halted partially due to the high rates of ADA formation. In conclusion, ATR-107 had a prolonged PD effect measured by IL-21R occupancy; was highly immunogenic after single dose administration and had PK properties with rapid clearance and low bioavailability., (© 2013, The American College of Clinical Pharmacology.)
- Published
- 2014
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20. Aberrant frequency of IL-10-producing B cells and its association with Treg/Th17 in adult primary immune thrombocytopenia patients.
- Author
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Hua F, Ji L, Zhan Y, Li F, Zou S, Chen L, Gao S, Li Y, Chen H, and Cheng Y
- Subjects
- Adult, Aged, Antigens, CD19 metabolism, B-Lymphocytes metabolism, Brefeldin A chemistry, CD3 Complex metabolism, CD4-Positive T-Lymphocytes cytology, Female, Flow Cytometry, Humans, Interleukin-17 metabolism, Interleukin-2 Receptor alpha Subunit metabolism, Ionomycin chemistry, Leukocytes, Mononuclear cytology, Male, Middle Aged, Phorbol Esters chemistry, Polymerase Chain Reaction, Treatment Outcome, Young Adult, B-Lymphocytes cytology, Interleukin-10 metabolism, Purpura, Thrombocytopenic, Idiopathic blood, Th17 Cells cytology
- Abstract
Background: Regulatory B cells (Breg) are a distinct B cell subset with immunoregulatory properties. Pivotal to Breg function is interleukin-10. This study was to investigate the role of IL-10-producing B cell (B10) and its association with Treg and Th17 subsets in immune thrombocytopenia (ITP) patients., Methods: Peripheral blood mononuclear cells from ITP patients and controls were stimulated with PMA, ionomycin, and Brefeldin A. The frequencies of CD19(+)IL-10(+) B cells, CD3(+)CD4(+)IL-17(+) Th17 cells, and CD4(+)CD25(hi)Foxp3(+) Treg cells were analyzed by flow cytometry. The mRNA expression of Foxp3 and RORγt was detected by real-time quantitative PCR., Results: The number of B10 cells was elevated in ITP patients. After first-line therapies, it remained at high level in patients who achieved complete or partial response but decreased in those who acquired no response. There was a positive correlation between B10 cells and Tregs in ITP both before and after therapies. The ratio of Treg/Th17 decreased in ITP, and it strongly correlated with B10 cells., Conclusions: The frequency of B10 cells is elevated in ITP and it correlates with both the Tregs counts and the Treg/Th17 ratio. B10 cells to regulate functional T cell subsets might be impaired in patients with ITP.
- Published
- 2014
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21. The absence of the calcium-buffering protein calbindin is associated with faster age-related decline in hippocampal metabolism.
- Author
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Moreno H, Burghardt NS, Vela-Duarte D, Masciotti J, Hua F, Fenton AA, Schwaller B, and Small SA
- Subjects
- Analysis of Variance, Animals, Avoidance Learning physiology, Calbindins, Cerebrovascular Circulation physiology, Dentate Gyrus physiopathology, Hippocampus physiopathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Parvalbumins genetics, Parvalbumins metabolism, S100 Calcium Binding Protein G genetics, Aging metabolism, Dentate Gyrus metabolism, Hippocampus metabolism, Magnetic Resonance Imaging, S100 Calcium Binding Protein G metabolism
- Abstract
Although reductions in the expression of the calcium-buffering proteins calbindin D-28K (CB) and parvalbumin (PV) have been observed in the aging brain, it is unknown whether these changes contribute to age-related hippocampal dysfunction. To address this issue, we measured basal hippocampal metabolism and hippocampal structure across the lifespan of C57BL/6J, calbindin D-28k knockout (CBKO) and parvalbumin knockout (PVKO) mice. Basal metabolism was estimated using steady state relative cerebral blood volume (rCBV), which is a variant of fMRI that provides the highest spatial resolution, optimal for the analysis of individual subregions of the hippocampal formation. We found that like primates, normal aging in C57BL/6J mice is characterized by an age-dependent decline in rCBV-estimated dentate gyrus (DG) metabolism. Although abnormal hippocampal fMRI signals were observed in CBKO and PVKO mice, only CBKO mice showed accelerated age-dependent decline of rCBV-estimated metabolism in the DG. We also found age-independent structural changes in CBKO mice, which included an enlarged hippocampus and neocortex as well as global brain hypertrophy. These metabolic and structural changes in CBKO mice correlated with a deficit in hippocampus-dependent learning in the active place avoidance task. Our results suggest that the decrease in CB that occurs during normal aging is involved in age-related hippocampal metabolic decline. Our findings also illustrate the value of using multiple MRI techniques in transgenic mice to investigate mechanisms involved in the functional and structural changes that occur during aging., (Copyright © 2011 Wiley Periodicals, Inc.)
- Published
- 2012
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22. Longitudinal mapping of mouse cerebral blood volume with MRI.
- Author
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Moreno H, Hua F, Brown T, and Small S
- Subjects
- Animals, Contrast Media administration & dosage, Contrast Media metabolism, Disease Models, Animal, Gadolinium DTPA administration & dosage, Gadolinium DTPA metabolism, Injections, Intraperitoneal, Injections, Intravenous, Mice, Mice, Inbred C57BL, Mice, Transgenic, Time Factors, Blood Volume Determination, Cerebrovascular Circulation, Magnetic Resonance Imaging methods
- Abstract
MRI estimations of cerebral blood volume (CBV), useful in mapping brain dysfunction, typically require intravenous (IV) injections of contrast agents. Transgenically engineered mice have emerged as the dominant animal model with which to investigate disorders of the brain and novel therapeutic agents. The difficulty in gaining IV access in mice prohibits repeated administration of contrast in the same animal, limiting the ability to map CBV changes over time. Here we address this limitation by first optimizing an approach for estimating CBV that relies on intraperitoneal (IP) rather than IV injections of the contrast agent gadodiamide. Next, we show that CBV maps generated with IP or IV injections are quantitatively comparable. Finally, we show that CBV maps generated with IP gadodiamide can be acquired repeatedly, reliably and safely over time. Although this approach has certain limitations, estimating CBV with IP injections is well-suited for mapping the spatiotemporal pattern of brain dysfunction in mice models of disease, and for testing pharmacological agents.
- Published
- 2006
- Full Text
- View/download PDF
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