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Vedolizumab serum trough concentrations with and without thiopurines in ulcerative colitis: The prospective VIEWS pharmacokinetics study

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World Journal of Gastroenterology 2025年第2期31卷 102-112页

作者： Thanaboon Chaemsupaphan Aviv Pudipeddi Hui-Yu Lin Sudarshan Paramsothy Viraj C Kariyawasam Melissa Kermeen Rupert W Leong Department of Gastroenterology and Liver Services Concord Repatriation General HospitalSydney 2139New South WalesAustralia Faculty of Medicine Siriraj HospitalMahidol UniversityBangkok 10700Thailand Faculty of Medicine and Health University of SydneySydney 2139New South WalesAustralia Department of Gastroenterology Tan Tock Seng HospitalSingapore 308433Singapore Faculty of Medicine and Health Sciences Macquarie UniversitySydney 2139New South WalesAustralia Department of Gastroenterology and Hepatology Blacktown HospitalSydney 2148New South WalesAustralia Blacktown clinical school Western Sydney UniversitySydney 2148New South WalesAustralia

BACKGROUND Ulcerative colitis(UC)is a chronic inflammatory condition requiring continuous treatment and *** is limited pharmacokinetic data on vedolizumab during maintenance therapy and the effect of thiopurines on vedolizumab trough concentrations is *** To investigate the exposure-response relationship of vedolizumab and the impact of thiopurine withdrawal in UC patients who have achieved sustained clinical and endoscopic remission during maintenance *** This is a post-hoc analysis of prospective randomized clinical trial(VIEWS)involving UC patients across 8 centers in Australia from 2018 to *** in clinical and endoscopic remission were randomized to continue or withdraw thiopurine while receiving *** evaluated vedolizumab serum trough concentrations,presence of anti-vedolizumab antibodies,and clinical outcomes over 48 weeks to assess exposure-response asso-ciation and impact of thiopurine *** There were 62 UC participants with mean age of 43.4 years and 42%were *** participants received vedolizumab as maintenance therapy with 67.7%withdrew *** serum trough concentrations remained stable over 48 weeks regardless of thiopurine use,with no anti-vedolizumab antibodies ***-tients with clinical remission had higher trough concentrations at week *** quartile analysis,a threshold of>11.3μg/mL was associated with sustained clinical remission,showing a sensitivity of 82.4%,specificity of 60.0%,and an area of receiver operating characteristic of 0.71(95%CI:0.49-0.93).Patients discontinuing thiopurine required higher vedolizumab concentrations for achieving *** A positive exposure-response relationship between vedolizumab trough concentrations and UC outcomes suggests that monitoring drug levels may be *** thiopurine did not influence vedolizumab levels,its with-drawal may necessitate higher vedolizumab trough concentrations to maintain remi

关键词： Pharmacokinetic Vedolizumab Thiopurine Ulcerative colitis Trough concentration Antibody Inflammatory bowel diseases

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Endogenous Glucocorticoids and Bone

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Bone Research 2013年第2期1卷 107-119页

作者： Hong Zhou Mark S. Cooper Markus J. Seibel Bone Research Program ANZAC Research Institute concord clinical school The University of Sydney Department of Endocrinology & Metabolism Concord Hospital

While the adverse effects of glucocorticoids on bone are well described, positive effects of glucocorticoids on the differentiation of osteoblasts are also observed. These paradoxical effects of glucocorticoids are dose dependent. At both physiologicaland supraphysiological levels of glucocorticoids, osteoblasts and osteocytes are the major glucocorticoid target cells. However, the response of the osteoblasts to each of these is quite distinct. At physiology levels, glucocorticoids direct mesenchymal progenitor cells to differentiate towards osteoblasts and thus increase bone formation in a positive way. In contrast with ageing, the excess production of glucocorticoids, at both systemic and intracellular levels, appear to impact on osteoblast and osteocytes in a negative way in a similar fashion to that seen with therapeutic glucocorticoids. This review will focus on therole of glucocorticoids in normal bone physiology, with particular emphasis on the mechanism by which endogenous glucocorticoids impact on bone and its constituent cells.

关键词： glucocorticoids mechanisms of action bone osteoblasts skeletal development Wnt signaling

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Faecal microbiota transplantation as an elixir of youth

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Hepatobiliary Surgery and Nutrition 2020年第4期9卷 488-489页

作者： Craig Haifer Sudarshan Paramsothy Rupert W.Leong concord clinical school The University of SydneySydneyAustralia Gastroenterology and Liver Services Concord Repatriation General HospitalSydneyAustralia South Western clinical school UNSWSydneyAustralia

The intestinal microbiota has been increasingly seen to be responsible for various gastrointestinal disorders such as inflammatory bowel diseases(1).However,their effects on systemic physiological processes unrelated ... 详细信息

关键词： diseases gastrointestinal unrelated

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Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/β-catenin signaling

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Bone Research 2017年第3期5卷 195-206页

作者： Yu Zheng Trupti Trivedi Ruby CY Lin Colette Fong-Yee Rick Nolte Jeline Manibo Yunzhao Chen Musharraf Hossain Konstantin Horas Colin Dunstan Hong Zhou Markus J Seibel Bone Research Program ANZAC Research Institute Asbestos Diseases Research Institute Cardiothoracic Genomics school of Medical Sciences University of New South Wales Department of Pathology Shihezi University School of Medicine Biomedical Engineering AMME University of Sydney concord clinical school The University of Sydney

Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihydroxy-vitamin D [1,25（OH）2D] are mediated through binding to the vitamin D receptor （VDR）. Here, we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad （MDA-MB-231）, subcutaneously （PC3） or intra-tibially （both cell lines） in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls. These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/0-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1, interleukin-6 （IL-6）, and IL-8. Stabilization of 0-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.

关键词： MDA Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt catenin signaling VDR Wnt

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Indications and surgical options for small bowel, large bowel and perianal Crohn's disease

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World Journal of Gastroenterology 2016年第40期22卷 8892-8904页

作者： James WT Toh Peter Stewart Matthew JFX Rickard Rupert Leong Nelson Wang Christopher J Young Department of Colorectal Surgery Concord Repatriation General Hospital South Western Sydney clinical school University of New South Wales Liverpool Hospital school of Medicine Western Sydney University Liverpool Hospital Ingham Institute of Applied Research Liverpool Hospital Discipline of Surgery Sydney Medical School the University of Sydney Department of Gastroenterology Concord Repatriation General Hospital Department of Colorectal Surgery Royal Prince Alfred Hospital

Despite advancements in medical therapy of Crohn's disease(CD), majority of patients with CD will eventually require surgical intervention, with at least a third of patients requiring multiple surgeries. It is important to understand the role and timing of surgery, with the goals of therapy to reduce the need for surgery without increasing the odds of emergency surgery and its associated morbidity, as well as to limit surgical recurrence and avoid intestinal failure. The profile of CD patients requiring surgical intervention has changed over the decades with improvements in medical therapy with immunomodulators and biological agents. The most common indication for surgery is obstruction from stricturing disease, followed by abscesses and fistulae. The risk of gastrointestinal bleeding in CD is high but the likelihood of needing surgery for bleeding is low. Most major gastrointestinal bleeding episodes resolve spontaneously, albeit the risk of re-bleeding is high. The risk of colorectal cancer associated with CD is low. While current surgical guidelines recommend a total proctocolectomy for colorectal cancer associated with CD, subtotal colectomy or segmental colectomy with endoscopic surveillance may be a reasonable option. Approximately 20%-40% of CD patients will need perianal surgery during their lifetime. This review assesses the practice parameters and guidelines in the surgical management of CD, with a focus on the indications for surgery in CD(and when not to operate), and a critical evaluation of the timing and surgical options available to improve outcomes and reduce recurrence rates.

关键词： Surgery Crohn’s disease Major abdominal surgery Perianal Inflammatory bowel disease Colon cancer

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Cell therapy for severe burn wound healing

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Burns & Trauma 2018年第2期6卷 72-81页

作者： Zhe Li Peter Maitz Burns Unit Concord HospitalConcordNew South Wales 2139Australia Skin Laboratory NSW Statewide Burns ServiceConcordNew South WalesAustralia Discipline of Surgery University of Sydney Medical SchoolCamperdownNew South WalesAustralia

Cell therapy has emerged as an important component of life-saving procedures in treating burns. Over past decades, advances in stem cells and regenerative medicine have offered exciting opportunities of developing cell-based alternatives and demonstrated the potential and feasibility of various stem cells for burn wound healing. However, there are still scientific and technical issues that should be resolved to facilitate the full potential of the cellular devices. More evidence from large, randomly controlled trials is also needed to understand the clinical impact of cell therapy in burns. This article aims to provide an up-to-date review of the research development and clinical applications of cell therapies in burn wound healing and skin regeneration.

关键词： Skin Burn injuries Stem cells Cell therapy Wound healing Skin regeneration

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Distinct Cytoskeletal Injuries Induced by As,Cd,Co,Cr,and Ni Compounds

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Biomedical and Environmental Sciences 1989年第4期2卷 358-365页

作者： IIH-NAN CHOU Departments of Microbiology and Pathology Boston University School of Medicine80 East Concord StreetBostonMassachusetts 02118

The risks of metal compounds to human health are highlighted by the ubiquity of exposure and their persistence in the *** compounds of As,Cd,Co,Cr,and Ni are known or“reasonably anticipated”to be carcinogenic to humans and/or experimental animals, the cellular targets of these health hazards and the underlying mechanisms of their carcinogenic- ity are still *** show in this report that dramatic,time-and dose-dependent cytoskeletal perturbations,especially in the distribution and organization patterns of microtubules and mi- crofilaments,two of the principal components of the cytoskeleton,occurred in 3T3 cells upon exposure to these metal *** metal salt appeared to induce a different,typical pattern of cytoskeletal injury,probably reflecting the specificity of action of each metal *** results suggest that the cytoskeleton can indeed act as a target for injury by epigenetic carcinogenic metal compounds in the *** findings should help our efforts to understand the mechanisms of action of metal compounds at the subcellular and molecular levels.1989 Academic Press,Inc.

关键词： MT Distinct Cytoskeletal Injuries Induced by As,Cd,Co,Cr,and Ni Compounds MF NISO As Cr Ni

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Thermal transport properties of defective graphene:A molecular dynamics investigation

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Chinese Physics B 2014年第10期23卷 405-410页

作者：杨宇霖卢宇 school of Opto-electronic and Communication Engineering Xiamen University of Technology College of Physics and Energy Fujian Normal University Department of Information Technology Concord University CollegeFuzhou

In this work the thermal transport properties of graphene nanoribbons with randomly distributed vacancy defects are investigated by the reverse non-equilibrium molecular dynamics method. We find that the thermal conductivity of the graphene nanoribbons decreases as the defect coverage increases and is saturated in a high defect ratio range. Further analysis reveals a strong mismatch in the phonon spectrum between the unsaturated carbon atoms in 2-fold coordination around the defects and the saturated carbon atoms in 3-fold coordination, which induces high interfacial thermal resistance in defective graphene and suppresses the thermal conductivity. The defects induce a complicated bonding transform from sp2 to hybrid sp--sp2 network and trigger vibration mode density redistribution, by which the phonon spectrum conversion and strong phonon scattering at defect sites are explained. These results shed new light on the understanding of the thermal transport behavior of graphene-based nanomaterials with new structural configurations and pave the way for future designs of thermal management phononic devices.

关键词： thermal conductivity vacancy defect graphene molecular dynamics simulation

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Low-protein diet accelerates wound healing in mice post-acute injury

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Burns & Trauma 2021年第1期9卷 339-350页

作者： Jonathan J.Hew Roxanne J.Parungao Craig P.Mooney Julian K.Smyth Sarah Kim Kevin H.-Y.Tsai Huaikai Shi Cassandra Chong Renee C.F.Chan Beba Attia Caroline Nicholls Zhe Li Samantha M.Solon-Biet David G.Le Couteur Stephen J.Simpson Marc G.Jeschke Peter K.Maitz Yiwei Wang Burns Research and Reconstructive Surgery ANZAC Research InstituteConcord HospitalUniversity of SydneySydneyAustralia 2139 Bone Biology Group ANZAC Research InstituteConcord HospitalUniversity of SydneySydneyAustralia 2139 Adrenal Steroids Laboratory ANZAC Research InstituteConcord HospitalUniversity of SydneySydneyAustralia 2139 Electron Microscopy Unit Anatomical PathologyConcord HospitalSydneyAustralia 2139 Burns Unit Concord Repatriation General HospitalConcordAustralia 2139 Ageing and Alzheimer Institute and ANZAC Research Institute Concord HospitalUniversity of SydneySydneyAustralia 2139 Charles Perkins Centre and school of Life and Environmental Sciences University of SydneyAustralia 2006 Sunnybrook Research Institute TorontoOntarioCanadaM4N 3M5 school of Pharmacy Nanjing University of Chinese MedicineNanjingPR China 210023

Background:Wound healing processes are influenced by macronutrient intake(protein,carbohydrate and fat).The most favourable diet for cutaneous wound healing is not known,although highprotein diets are currently favoured *** experimental study investigates the optimal macronutrient balance for cutaneous wound healing using a mouse model and the Geometric Framework,a nutrient modelling method,capable of analyzing the individual and interactive effects of a wide spectrum of macronutrient ***:Two adjacent and identical full-thickness skin excisions(1 cm^(2))were surgically created on the dorsal area of male C57BL/6 *** were then allocated to one of 12 high-energy diets that varied in protein,carbohydrate and fat *** select diets,wound healing processes,cytokine expression,energy expenditure,body composition,muscle and fat reserves were ***:Using the Geometric Framework,we show that a low-protein intake,coupled with a balanced intake of carbohydrate and fat is optimal for wound *** fed a low-protein diet progressed quickly through wound healing stages with favourable wound inflammatory cytokine expression and significantly accelerated collagen *** local processes were associated with an increased early systemic inflammatory response and a higher overall energy expenditure,related to metabolic changes occurring in key macronutrient reserves in lean body mass and fat ***:The results suggest that a low-protein diet may have a greater potential to accelerate wound healing than the current clinically used high-protein diets.

关键词： Wound healing Macronutrients Cutaneous Geometric Framework Mouse model Low-protein diet Nutrition

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Osteoblastic glucocorticoid signaling exacerbates high-fat-diet-induced bone loss and obesity

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Bone Research 2021年第4期9卷 537-548页

作者： Sarah Kim Holger Henneicke Lauryn L.Cavanagh Eugenie Macfarlane Lee Joanne Thai Daphne Foong Sylvia J.Gasparini Colette Fong-Yee Michael M.Swarbrick Markus J.Seibel Hong Zhou Bone Research Program ANZAC Research InstituteThe University of SydneySydneyNSWAustralia concord clinical school The University of SydneySydneyNSWAustralia Department of MedicineⅢ Technische University Dresden Medical CenterDresdenGermany Center for Healthy Aging Technische Universitat Dresden Medical CenterDresdenGermany Center for Regenerative Therapies Dresden Technische University DresdenDresdenGermany Department of Endocrinology and Metabolism Concord Repatriation General HospitalThe University of SydneySydneyNSWAustralia

Chronic high-fat diet(HFD)consumption not only promotes obesity and insulin resistance,but also causes bone loss through mechanisms that are not well ***,we fed wild-type CD-1 mice either chow or a HFD(43%of energy from fat)for 18 weeks;HFD-fed mice exhibited decreased trabecular volume(-28%)and cortical thickness(-14%)compared to chow-fed *** HFD-fed mice,bone loss was due to reduced bone formation and mineral apposition,without obvious effects on bone *** feeding also increased skeletal expression of sclerostin and caused deterioration of the osteocyte lacunocanalicular network(LCN).In mice fed HFD,skeletal glucocorticoid signaling was activated relative to chow-fed mice,independent of serum corticosterone *** therefore examined whether skeletal glucocorticoid signaling was necessary for HFD-induced bone loss,using transgenic mice lacking glucocorticoid signaling in osteoblasts and osteocytes(HSD2^(OB/OCY)-tg mice).In HSD2^(OB/OCY)-tg mice,bone formation and mineral apposition rates were not suppressed by HFD,and bone loss was significantly ***,in HSD2^(OB/OCY)-tg mice fed HFD,both Wnt signaling(less sclerostin induction,increased P

关键词： glucocorticoid obesity matched

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