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Chauhan K, Tyagi M. Update on non-infectious uveitis treatment: anti-TNF-alpha and beyond. FRONTIERS IN OPHTHALMOLOGY 2024; 4:1412930. [PMID: 39157460 PMCID: PMC11327136 DOI: 10.3389/fopht.2024.1412930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 07/16/2024] [Indexed: 08/20/2024]
Abstract
Non-infectious uveitis (NIU) encompasses a range of conditions marked by inflammation within various layers of the eye. NIU is a significant contributor to irreversible vision loss among the working-age population in developed countries. The aim of treating uveitis is to manage inflammation, prevent its recurrences and to restore or salvage vision. Presently, the standard treatment protocol for NIU involves initiating corticosteroids as the primary therapeutic agents, although more aggressive approaches and steroid sparing agent may be necessary in certain cases. These advanced treatments option include synthetic immunosuppressants like antimetabolites, calcineurin inhibitors and alkylating agents. For patients who exhibit an intolerance or resistance to corticosteroids and conventional immunosuppressive therapies, biologic agents have emerged as a promising alternative. Notably, among the biologic treatments evaluated, TNF-α inhibitors, anti-CD20 therapy and alkylating agents have shown considerable efficacy. In this review, we delve into the latest evidence surrounding the effectiveness of biologic therapy and introduce novel therapeutic strategies targeting immune components as potential avenues for advancing treatment of NIU.
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Affiliation(s)
- Khushboo Chauhan
- Saroja A Rao Centre for Uveitis, L V Prasad Eye Institute, Hyderabad, India
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India
| | - Mudit Tyagi
- Saroja A Rao Centre for Uveitis, L V Prasad Eye Institute, Hyderabad, India
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India
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2
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Gao M, Liu W, Li T, Song Z, Wang X, Zhang X. Identifying Genetic Signatures Associated with Oncogene-Induced Replication Stress in Osteosarcoma and Screening for Potential Targeted Drugs. Biochem Genet 2024; 62:1690-1715. [PMID: 37672187 DOI: 10.1007/s10528-023-10497-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 08/07/2023] [Indexed: 09/07/2023]
Abstract
Osteosarcoma is the most common type of primary malignant bone tumor. Due to the lack of selectivity and sensitivity of chemotherapy drugs to tumor cells, coupled with the use of large doses, chemotherapy drugs often have systemic toxicity. The use of modern sequencing technology to screen tumor markers in a large number of tumor samples is a common method for screening highly specific and selective anti-tumor drugs. This study aims to identify potential biomarkers using the latest reported gene expression signatures of oncogene-induced replication stress (ORS) in aggressive cancers, and potential anti-osteosarcoma drugs were screened in different drug databases. In this study, we obtained 89 osteosarcoma-related samples in the TARGET database, all of which included survival information. According to the median expression of each of six reported ORS gene markers (NAT10/DDX27/ZNF48/C8ORF33/MOCS3/MPP6), we divided 89 osteosarcoma gene expression datasets into a high expression group and a low expression group and then performed a differentially expressed gene (DEG) analysis. The coexisting genes of 6 groups of DEGs were used as replication stress-related genes (RSGs) of osteosarcoma. Then, key RSGs were screened using LASSO regression, a Cox risk proportional regression prognostic model and a tenfold cross-validation test. GSE21257 datasets collected from the Gene Expression Omnibus (GEO) database were used to verify the prognostic model. The final key RSGs selected were used in the L1000PWD and DGIdb databases to mine potential drugs. After further validation by the prognostic model, we identified seven genes associated with ORS in osteosarcoma as key RSGs, including transcription factor 7 like 2 (TCF7L2), solute carrier family 27 member 4 (SLC27A4), proprotein convertase subtilisin/kexin type 5 (PCSK5), nucleolar protein 6 (NOL6), coiled-coil-coil-coil-coil-helix domain containing 4 (CHCHD4), eukaryotic translation initiation factor 3 subunit B (EIF3B), and synthesis of cytochrome C oxidase 1 (SCO1). Then, we screened the seven key RSGs in two drug databases and found six potential anti-osteosarcoma drugs (D GIdb database: repaglinide, tacrolimus, sirolimus, cyclosporine, and hydrochlorothiazide; L1000PWD database: the small molecule VU-0365117-1). Seven RSGs (TCF7L2, SLC27A4, PCSK5, NOL6, CHCHD4, EIF3B, and SCO1) may be associated with the ORS gene signatures in osteosarcoma. Repaglinide, tacrolimus, sirolimus, cyclosporine, hydrochlorothiazide and the small molecule VU-0365117-1 are potential therapeutic drugs for osteosarcoma.
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Affiliation(s)
- Meng Gao
- School of Medicine, Nankai University, Tianjin, China
- Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General Hospital, Haidian District, 51 Fucheng Road, Beijing, 100048, China
| | - Weibo Liu
- Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General Hospital, Haidian District, 51 Fucheng Road, Beijing, 100048, China
| | - Teng Li
- Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General Hospital, Haidian District, 51 Fucheng Road, Beijing, 100048, China
| | - ZeLong Song
- School of Medicine, Nankai University, Tianjin, China
- Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General Hospital, Haidian District, 51 Fucheng Road, Beijing, 100048, China
| | - XiangYu Wang
- Department of Pain Medicine, First Medical Center, PLA General Hospital, Beijing, 100000, China.
| | - XueSong Zhang
- School of Medicine, Nankai University, Tianjin, China.
- Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General Hospital, Haidian District, 51 Fucheng Road, Beijing, 100048, China.
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Kabore MD, McElrath CC, Ali MAE, Almengo K, Gangaplara A, Fisher C, Barreto MA, Shaikh A, Olkhanud PB, Xu X, Gaskin D, Lopez-Ocasio M, Saxena A, McCoy JP, Fitzhugh CD. Low dose post-transplant cyclophosphamide and sirolimus induce mixed chimerism with CTLA4-Ig or lymphocyte depletion in an MHC-mismatched murine allotransplantation model. Bone Marrow Transplant 2024; 59:615-624. [PMID: 38347187 PMCID: PMC11073977 DOI: 10.1038/s41409-024-02237-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 01/26/2024] [Accepted: 01/31/2024] [Indexed: 02/18/2024]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) offers a curative option for patients with certain non-malignant hematological diseases. High-dose post-transplant cyclophosphamide (PT-Cy) (200 mg/kg) and sirolimus (3 mg/kg), (HiC) synergistically induce stable mixed chimerism. Further, sirolimus and cytotoxic T lymphocyte-associated antigen-4 immunoglobulin (CTLA4-Ig), also known as Abatacept (Aba), promote immune tolerance and allograft survival. Here, in a major histocompatibility complex (MHC)-mismatched allo-HCT murine model, we combined Aba and/or T-cell depleting anti-Thy1.2 (Thy) with a lower dose of PT-Cy (50 mg/kg) and Sirolimus (3 mg/kg), (LoC). While mice in the LoC group showed graft rejection, the addition of Thy to LoC induced similar donor chimerism levels when compared to the HiC group. However, the addition of Aba to LoC led to graft acceptance only in younger mice. When Thy was added to the LoC+Aba setting, graft acceptance was restored in both age groups. Engrafted groups displayed significantly reduced frequencies of recipient-specific interferon-γ-producing T cells as well as an increased frequency in regulatory T cells (Tregs) except in the LoC+Aba group. Splenocytes from engrafted mice showed no proliferation upon restimulation with Balb/c stimulators. Collectively, in combination with Aba or Thy, LoC may be considered to reduce graft rejection in patients who undergo allo-HCT.
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Affiliation(s)
- Mariama D Kabore
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Corbin C McElrath
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Mohamed A E Ali
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Katherine Almengo
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Arunakumar Gangaplara
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
- Miltenyi Biotec, Gaithersburg, MD, 20878, USA
| | - Cameron Fisher
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Mauricio A Barreto
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ahmad Shaikh
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Purevdorj B Olkhanud
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Xin Xu
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Deanna Gaskin
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Maria Lopez-Ocasio
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ankit Saxena
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - J Philip McCoy
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Courtney D Fitzhugh
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
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Moldvai D, Sztankovics D, Dankó T, Vetlényi E, Petővári G, Márk Á, Patonai A, Végső G, Piros L, Hosszú Á, Pápay J, Krencz I, Sebestyén A. Tumorigenic role of tacrolimus through mTORC1/C2 activation in post-transplant renal cell carcinomas. Br J Cancer 2024; 130:1119-1130. [PMID: 38341510 PMCID: PMC10991560 DOI: 10.1038/s41416-024-02597-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 01/19/2024] [Accepted: 01/22/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND Kidney transplant recipients (KTRs) face an increased risk of renal cell carcinoma (RCC), in which the immunosuppressive regimen plays an important role. This study aimed to identify intracellular signalling alterations associated with post-transplant (post-tx) tumour formation. METHODS Expression of mTOR-related proteins were analysed in kidneys obtained from end-stage renal disease (ESRD) patients and RCCs developed in KTRs or non-transplant patients. The effects of tacrolimus (TAC) and rapamycin (RAPA) on mTOR activity, proliferation, and tumour growth were investigated through different in vitro and in vivo experiments. RESULTS Elevated mTORC1/C2 activity was observed in post-tx RCCs and in kidneys of TAC-treated ESRD patients. In vitro experiments demonstrated that TAC increases mTOR activity in a normal tubular epithelial cell line and in the investigated RCC cell lines, moreover, promotes the proliferation of some RCC cell line. In vivo, TAC elevated mTORC1/C2 activity in ischaemic kidneys of mice and enhanced tumour growth in xenograft model. CONCLUSIONS We observed significantly increased mTOR activity in ischaemic kidneys and post-tx RCCs, which highlights involvement of mTOR pathway both in the healing or fibrotic processes of kidney and in tumorigenesis. TAC-treatment further augmented the already elevated mTOR activity of injured kidney, potentially contributing to tumorigenesis during immunosuppression.
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Affiliation(s)
- Dorottya Moldvai
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26., H-1085, Budapest, Hungary
| | - Dániel Sztankovics
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26., H-1085, Budapest, Hungary
| | - Titanilla Dankó
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26., H-1085, Budapest, Hungary
| | - Enikő Vetlényi
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26., H-1085, Budapest, Hungary
| | - Gábor Petővári
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26., H-1085, Budapest, Hungary
| | - Ágnes Márk
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26., H-1085, Budapest, Hungary
| | - Attila Patonai
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Üllői út 78., H-1082, Budapest, Hungary
| | - Gyula Végső
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Üllői út 78., H-1082, Budapest, Hungary
| | - László Piros
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Üllői út 78., H-1082, Budapest, Hungary
| | - Ádám Hosszú
- Department of Paediatrics (Bókay street Unit), Semmelweis University, Üllői út. 26, H-1085, Budapest, Hungary
- MTA-SE Lendulet Diabetes Research Group, Bókay János utca 53-54., H-1083, Budapest, Hungary
| | - Judit Pápay
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26., H-1085, Budapest, Hungary
| | - Ildikó Krencz
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26., H-1085, Budapest, Hungary
| | - Anna Sebestyén
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26., H-1085, Budapest, Hungary.
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5
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Schrezenmeier E, Dörner T, Halleck F, Budde K. Cellular Immunobiology and Molecular Mechanisms in Alloimmunity-Pathways of Immunosuppression. Transplantation 2024; 108:148-160. [PMID: 37309030 DOI: 10.1097/tp.0000000000004646] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Current maintenance immunosuppression commonly comprises a synergistic combination of tacrolimus as calcineurin inhibitor (CNI), mycophenolic acid, and glucocorticoids. Therapy is often individualized by steroid withdrawal or addition of belatacept or inhibitors of the mechanistic target of rapamycin. This review provides a comprehensive overview of their mode of action, focusing on the cellular immune system. The main pharmacological action of CNIs is suppression of the interleukin-2 pathway that leads to inhibition of T cell activation. Mycophenolic acid inhibits the purine pathway and subsequently diminishes T and B cell proliferation but also exerts a variety of effects on almost all immune cells, including inhibition of plasma cell activity. Glucocorticoids exert complex regulation via genomic and nongenomic mechanisms, acting mainly by downregulating proinflammatory cytokine signatures and cell signaling. Belatacept is potent in inhibiting B/T cell interaction, preventing formation of antibodies; however, it lacks the potency of CNIs in preventing T cell-mediated rejections. Mechanistic target of rapamycin inhibitors have strong antiproliferative activity on all cell types interfering with multiple metabolic pathways, partly explaining poor tolerability, whereas their superior effector T cell function might explain their benefits in the case of viral infections. Over the past decades, clinical and experimental studies provided a good overview on the underlying mechanisms of immunosuppressants. However, more data are needed to delineate the interaction between innate and adaptive immunity to better achieve tolerance and control of rejection. A better and more comprehensive understanding of the mechanistic reasons for failure of immunosuppressants, including individual risk/benefit assessments, may permit improved patient stratification.
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Affiliation(s)
- Eva Schrezenmeier
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Academy, Clinician Scientist Program Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Dörner
- Department of Rheumatology and Clinical Immunology - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Deutsches Rheumaforschungszentrum (DRFZ), Berlin, Germany
| | - Fabian Halleck
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Amanam I, Otoukesh S, Al Malki MM, Salhotra A. Chronic GVHD: review advances in prevention, novel endpoints, and targeted strategies. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2023; 2023:164-170. [PMID: 38066845 PMCID: PMC10727045 DOI: 10.1182/hematology.2023000427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for many malignant and non-malignant hematologic disorders. Chronic graft-versus-host (cGVHD) disease remains a significant hurdle for long-term survival in patients post allo-HCT, and it remains the leading cause of late non-relapse mortality. The risk factors for development of cGVHD include degree of human leukocyte antigen (HLA) disparity, increasing recipient age, use of peripheral blood stem cells as a source, myeloablative conditioning regimens, prior acute GVHD (aGVHD), and female donor to male recipient. Our biological understanding of cGVHD is mostly derived from transplantation mouse models and patient data. There are three distinct phases in the development of cGVHD. Approaches to prevent GVHD include pharmacologic strategies such as calcineurin inhibitors (cyclosporine, tacrolimus) combined with methotrexate or mTOR inhibitors (sirolimus), and IMP dehydrogenase inhibitors (mycophenolate mofetil). Increasingly, posttransplant cyclophosphamide is emerging as a promising strategy for GVCHD prevention especially in a setting of reduced intensity conditioning. Other approaches include serotherapy (ATG, Campath) and graft manipulation strategies. A significant obstacle to evaluating the response of novel GVHD-directed therapies has been standardized response assessments. This has functioned as a barrier to designing and interpreting clinical trials that are structured around the treatment of cGVHD. Novel endpoints including failure-free survival, Graft-versus-host disease-free, relapse-free survival (GRFS), and current GVHD-free, relapse-free survival (CGRFS) may create a clearer picture for post-HCT outcomes. Targeted therapies including Bruton's tyrosine kinase inhibition, JAK1/2 inhibition, and ROCK2 inhibitors have improved cGVHD therapy, especially in the steroid refractory setting. Continued improvement in prophylactic strategies for cGVHD, identification of accurate cGVHD treatment endpoints, and access to novel therapeutic agents are expected to improve cGVHD outcomes.
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Wagle Shukla A, Lunny C, Mahboob O, Khalid U, Joyce M, Jha N, Nagaraja N, Shukla AM. Tremor Induced by Cyclosporine, Tacrolimus, Sirolimus, or Everolimus: A Review of the Literature. Drugs R D 2023; 23:301-329. [PMID: 37606750 PMCID: PMC10676343 DOI: 10.1007/s40268-023-00428-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2023] [Indexed: 08/23/2023] Open
Abstract
Calcineurin inhibitors such as cyclosporine and tacrolimus are immunosuppressant drugs that are known to induce tremors. Non-calcineurin inhibitors such as sirolimus and everolimus have also reportedly been accompanied by tremors, albeit less likely. However, the prevalence rates reported in the literature are notably wide, and the risk profiles for these drug-induced tremors are less understood. We searched PubMed to extract data on the risk of tremors with these drugs when prescribed for various transplant and non-transplant indications. We ascertained whether the risk of drug-induced tremor is influenced by the underlying diagnosis, dosing formulations, drug concentrations, and blood monitoring. We extracted data on treatment strategies and outcomes for tremors. Articles were primarily screened based on English language publications, abstracts, and studies with n ≥ 5, which included case series, retrospective studies, case-controlled studies, and prospective studies. We found 81 eligible studies comprising 33 cyclosporine, 43 tacrolimus, 6 sirolimus, and 1 everolimus that discussed tremor as an adverse event. In the pooled analysis of studies with n > 100, the incidence of tremor was 17% with cyclosporine, 21.5% with tacrolimus, and 7.8% with sirolimus and everolimus together. Regarding the underlying diagnosis, tremor was more frequently reported in kidney transplant (cyclosporine 28%, tacrolimus 30.1%) and bone marrow transplant (cyclosporine 40%, tacrolimus 41.9%) patients compared with liver transplant (cyclosporine 9%, tacrolimus 11.5%) and nontransplant indications (cyclosporine 21.5%, tacrolimus 11.3%). Most studies did not report whether the risk of tremors correlated with drug concentrations in the blood. The prevalence of tremors when using the twice-daily formulation of tacrolimus was nearly the same as the once-daily formulation (17% vs 18%). Data on individual-level risk factors for tremors were lacking. Except for three studies that found some benefit to maintaining magnesium levels, there were minimal data on treatments and outcomes. A large body of data supports a substantive and wide prevalence of tremor resulting from tacrolimus use followed by cyclosporine, especially in patients receiving a kidney transplant. However, there is little reporting on the patient-related risk factors for tremor, risk relationship with drug concentrations, treatment strategies, and outcomes.
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Affiliation(s)
- Aparna Wagle Shukla
- Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Fixel Institute for Neurological Disorders, 3009 Williston Road, Gainesville, FL, 32608, USA.
| | - Caroline Lunny
- Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Fixel Institute for Neurological Disorders, 3009 Williston Road, Gainesville, FL, 32608, USA
| | - Omar Mahboob
- Florida State University Medical School, Tallahassee, FL, USA
| | - Uzair Khalid
- University of Toronto Medical School, Toronto, ON, Canada
| | - Malea Joyce
- North Florida South Georgia Veteran Healthcare System, Gainesville, FL, USA
| | - Nivedita Jha
- Department of Neurology, Tower Health, Reading Hospital, Reading, PA, USA
| | - Nandakumar Nagaraja
- Department of Neurology, Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Ashutosh M Shukla
- North Florida South Georgia Veteran Healthcare System, Gainesville, FL, USA
- Division of Nephrology, Department of Medicine, University of Florida, Gainesville, FL, USA
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Marrone G, Leone MS, Biolato M, Liguori A, Bianco G, Spoletini G, Gasbarrini A, Miele L, Pompili M. Therapeutic Approach to Post-Transplant Recurrence of Hepatocellular Carcinoma: Certainties and Open Issues. Cancers (Basel) 2023; 15:5593. [PMID: 38067299 PMCID: PMC10705300 DOI: 10.3390/cancers15235593] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/03/2023] [Accepted: 11/18/2023] [Indexed: 01/12/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a growing indication for liver transplantation (LT). Careful candidate selection is a prerequisite to keep post-LT recurrence rates within acceptable percentages. In the pre-LT period, various types of locoregional treatments and/or systemic therapies can be used for bridging or downstaging purposes. In this context, one of the factors limiting the possibility of treatment is the degree of functional liver impairment. In the LT subject, no widely accepted indications are available to guide treatment of disease recurrence and heterogeneity exists between transplant centers. Improved liver function post LT makes multiple therapeutic strategies theoretically feasible, but patient management is complicated by the need to adjust immunosuppressive therapy and to assess potential toxicities and drug-drug interactions. Finally, there is controversy and uncertainty about the use of recently introduced immunotherapeutic drugs, mainly due to the risk of organ rejection. In this paper, we will review the most recent available literature on the management of post-transplant HCC recurrence, discussing evidence and controversies.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Maurizio Pompili
- Medical and Surgical Sciences Department, Policlinico Universitario A. Gemelli-IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Turolo S, Edefonti A, Syren ML, Montini G. Pharmacogenomics of Old and New Immunosuppressive Drugs for Precision Medicine in Kidney Transplantation. J Clin Med 2023; 12:4454. [PMID: 37445489 DOI: 10.3390/jcm12134454] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/16/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Kidney transplantation is the preferred therapeutic option for end-stage kidney disease, but, despite major therapeutic advancements, allograft rejection continues to endanger graft survival. Every patient is unique due to his or her clinical history, drug metabolism, genetic background, and epigenetics. For this reason, examples of "personalized medicine" and "precision medicine" have steadily increased in recent decades. The final target of precision medicine is to maximize drug efficacy and minimize toxicity for each individual patient. Immunosuppressive drugs, in the setting of kidney transplantation, require a precise dosage to avoid either adverse events (overdosage) or a lack of efficacy (underdosage). In this review, we will explore the knowledge regarding the pharmacogenomics of the main immunosuppressive medications currently utilized in kidney transplantation. We will focus on clinically relevant pharmacogenomic data, that is, the polymorphisms of the genes that metabolize immunosuppressive drugs.
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Affiliation(s)
- Stefano Turolo
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplant Unit, 20122 Milan, Italy
| | - Alberto Edefonti
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplant Unit, 20122 Milan, Italy
| | - Marie Luise Syren
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Giovanni Montini
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplant Unit, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
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10
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Zhang J, Wang X, Wang R, Chen G, Wang J, Feng J, Li Y, Yu Z, Xiao H. Rapamycin Treatment Alleviates Chronic GVHD-Induced Lupus Nephritis in Mice by Recovering IL-2 Production and Regulatory T Cells While Inhibiting Effector T Cells Activation. Biomedicines 2023; 11:biomedicines11030949. [PMID: 36979928 PMCID: PMC10045991 DOI: 10.3390/biomedicines11030949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/07/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
In this study, we test the therapeutic effects of rapamycin in a murine model of SLE-like experimental lupus nephritis induced by chronic graft-versus-host disease (cGVHD). Our results suggest that rapamycin treatment reduced autoantibody production, inhibited T lymphocyte and subsequent B cell activation, and reduced inflammatory cytokine and chemokine production, thereby protecting renal function and alleviating histological lupus nephritis by reducing the occurrence of albuminuria. To explore the potential mechanism of rapamycin's reduction of kidney damage in mice with lupus nephritis, a series of functional assays were conducted. As expected, rapamycin remarkably inhibited the lymphocytes' proliferation within the morbid mice. Interestingly, significantly increased proportions of peripheral CD4+FOXP3+ and CD4+CD25high T cells were observed in rapamycin-treated group animals, suggesting an up-regulation of regulatory T cells (Tregs) in the periphery by rapamycin treatment. Furthermore, consistent with the results regarding changes in mRNA abundance in kidney by real-time PCR analysis, intracellular cytokine staining demonstrated that rapamycin treatment remarkably diminished the secretion of Th1 and Th2 cytokines, including IFN-γ, IL-4 and IL-10, in splenocytes of the morbid mice. However, the production of IL-2 from splenocytes in rapamycin-treated mice was significantly higher than in the cells from control group animals. These findings suggest that rapamycin treatment might alleviate systemic lupus erythematosus (SLE)-like experimental lupus nephritis through the recovery of IL-2 production, which promotes the expansion of regulatory T cells while inhibiting effector T cell activation. Our studies demonstrated that, unlike other commonly used immunosuppressants, rapamycin does not appear to interfere with tolerance induction but permits the expansion and suppressive function of Tregs in vivo.
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Affiliation(s)
- Jilu Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
- Department of Biomedicine, Institute of Frontier Medical Sciences, Jilin University, Changchun 130021, China
| | - Xun Wang
- Department of Experimental Hematology and Biochemistry, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Renxi Wang
- Laboratory of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Beijing Institute of Brain Disorders, Capital Medical University, Ministry of Science and Technology, Beijing 100054, China
| | - Guojiang Chen
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Jing Wang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Jiannan Feng
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Yan Li
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Zuyin Yu
- Department of Experimental Hematology and Biochemistry, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - He Xiao
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
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11
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Patterson CM, Jolly EC, Burrows F, Ronan NJ, Lyster H. Conventional and Novel Approaches to Immunosuppression in Lung Transplantation. Clin Chest Med 2023; 44:121-136. [PMID: 36774159 DOI: 10.1016/j.ccm.2022.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Most therapeutic advances in immunosuppression have occurred over the past few decades. Although modern strategies have been effective in reducing acute cellular rejection, excess immunosuppression comes at the price of toxicity, opportunistic infection, and malignancy. As our understanding of the immune system and allograft rejection becomes more nuanced, there is an opportunity to evolve immunosuppression protocols to optimize longer term outcomes while mitigating the deleterious effects of traditional protocols.
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Affiliation(s)
- Caroline M Patterson
- Transplant Continuing Care Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Elaine C Jolly
- Division of Renal Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Fay Burrows
- Department of Pharmacy, St Vincent's Hospital, Sydney, New South Wales, Australia
| | - Nicola J Ronan
- Transplant Continuing Care Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Haifa Lyster
- Cardiothoracic Transplant Unit, Royal Brompton and Harefield Hospitals, Part of Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom; Kings College, London, United Kingdom; Pharmacy Department, Royal Brompton and Harefield Hospitals, Part of Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom.
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12
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Evaluation of pH-Sensitive Polymeric Micelles Using Citraconic Amide Bonds for the Co-Delivery of Paclitaxel, Etoposide, and Rapamycin. Pharmaceutics 2023; 15:pharmaceutics15010154. [PMID: 36678783 PMCID: PMC9866473 DOI: 10.3390/pharmaceutics15010154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/13/2022] [Accepted: 12/14/2022] [Indexed: 01/03/2023] Open
Abstract
Paclitaxel (PTX), etoposide (ETP), and rapamycin (RAPA) have different mechanisms, allowing multiple pathways to be targeted simultaneously, effectively treating various cancers. However, these drugs have a low hydrosolubility, limiting clinical applications. Therefore, we used pH-sensitive polymeric micelles to effectively control the drug release in cancer cells and to improve the water solubility of PTX, ETP, and RAPA. The synergistic effect of PTX, ETP, and RAPA was evaluated in gastric cancer, and the combination index values were evaluated. Thin-film hydration was used to prepare PTX/ETP/RAPA-loaded mPEG-pH-PCL micelles, and various physicochemical properties of these micelles were evaluated. In vitro cytotoxicity, pH-sensitivity, drug release profiles, in vivo pharmacokinetics, and biodistribution studies of PTX/ETP/RAPA-loaded mPEG-pH-PCL micelles were evaluated. In the pH-sensitivity evaluation, the size of the micelles increased more rapidly at a pH of 5.5 than at a pH of 7.4. The release rate of each drug increased with decreasing pH values in PTX/ETP/RAPA-loaded mPEG-pH-PCL micelles. In vitro and in vivo studies demonstrated that PTX/ETP/RAPA-loaded mPEG-pH-PCL micelles exhibit different drug release behaviors depending on the pH of the tumor and normal tissues and increased bioavailability and circulation time in the blood than solutions. Therefore, we propose that PTX/ETP/RAPA- loaded mPEG-pH-PCL micelles are advantageous for gastric cancer treatment in drug delivery systems.
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13
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The Role of Nrf2 in Pulmonary Fibrosis: Molecular Mechanisms and Treatment Approaches. Antioxidants (Basel) 2022; 11:antiox11091685. [PMID: 36139759 PMCID: PMC9495339 DOI: 10.3390/antiox11091685] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/21/2022] [Accepted: 08/26/2022] [Indexed: 11/21/2022] Open
Abstract
Pulmonary fibrosis is a chronic, progressive, incurable interstitial lung disease with high mortality after diagnosis and remains a global public health problem. Despite advances and breakthroughs in understanding the pathogenesis of pulmonary fibrosis, there are still no effective methods for the prevention and treatment of pulmonary fibrosis. The existing treatment options are imperfect, expensive, and have considerable limitations in effectiveness and safety. Hence, there is an urgent need to find novel therapeutic targets. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular antioxidative responses, inflammation, and restoration of redox balance. Accumulating reports reveal that Nrf2 activators exhibit potent antifibrosis effects and significantly attenuate pulmonary fibrosis in vivo and in vitro. This review summarizes the current Nrf2-related knowledge about the regulatory mechanism and potential therapies in the process of pulmonary fibrosis. Nrf2 orchestrates the activation of multiple protective genes that target inflammation, oxidative stress, fibroblast–myofibroblast differentiation (FMD), and epithelial–mesenchymal transition (EMT), and the mechanisms involve Nrf2 and its downstream antioxidant, Nrf2/HO−1/NQO1, Nrf2/NOX4, and Nrf2/GSH signaling pathway. We hope to indicate potential for Nrf2 system as a therapeutic target for pulmonary fibrosis.
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14
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Zhang Z, Li Y, Zhang G, Yang K, Qiu T, Zhou J, Gong X, Ji Y. Safety Evaluation of Oral Sirolimus in the Treatment of Childhood Diseases: A Systematic Review. CHILDREN (BASEL, SWITZERLAND) 2022; 9:1295. [PMID: 36138604 PMCID: PMC9497617 DOI: 10.3390/children9091295] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/18/2022] [Accepted: 08/24/2022] [Indexed: 11/17/2022]
Abstract
Background: Sirolimus, a mammalian target of rapamycin inhibitor, has been widely used in pediatric patients, but the safety of sirolimus in pediatric patients has not been well determined. Objective: The objective of this study was to systematically evaluate prospective studies reporting the safety of sirolimus in the treatment of childhood diseases. Methods: The following data were extracted in a standardized manner: study design, demographic characteristics, intervention, and safety outcomes. Results: In total, 9 studies were included, encompassing 575 patients who received oral sirolimus for at least 6 months. Various adverse events occurred. The most common adverse event was oral mucositis (8.2%, 95% CI: 0.054 to 0.110). Through comparative analysis of the subgroups based on the targeted concentration range, we discovered that many adverse events were significantly higher in the high concentration group (≥10 ng/mL) than in the low concentration group (<10 ng/mL) (p < 0.01). More interestingly, we found that oral mucositis was more frequently reported in children with vascular anomalies than tuberous sclerosis complex. Conclusions: This study shows that oral sirolimus in the treatment of childhood diseases is safe and reliable. However, sirolimus treatment in the pediatric population should be strictly monitored to reduce the occurrence of serious or fatal adverse events.
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Affiliation(s)
- Zixin Zhang
- Division of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
- Med-X Center for Informatics, Sichuan University, Chengdu 610041, China
| | - Yanan Li
- Division of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Guangyue Zhang
- Division of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Kaiying Yang
- Division of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Tong Qiu
- Division of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jiangyuan Zhou
- Division of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Xue Gong
- Division of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yi Ji
- Division of Oncology, Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
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15
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Zhao L, Hu X, Xiao F, Zhang X, Zhao L, Wang M. Mitochondrial impairment and repair in the pathogenesis of systemic lupus erythematosus. Front Immunol 2022; 13:929520. [PMID: 35958572 PMCID: PMC9358979 DOI: 10.3389/fimmu.2022.929520] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/28/2022] [Indexed: 12/12/2022] Open
Abstract
Nucleic acid autoantibodies, increase type I interferon (IFN-α) levels, and immune cell hyperactivation are hallmarks of systemic lupus erythematosus (SLE). Notably, immune cell activation requires high level of cellular energy that is predominately generated by the mitochondria. Mitochondrial reactive oxygen species (mROS), the byproduct of mitochondrial energy generation, serves as an essential mediator to control the activation and differentiation of cells and regulate the antigenicity of oxidized nucleoids within the mitochondria. Recently, clinical trials on normalization of mitochondrial redox imbalance by mROS scavengers and those investigating the recovery of defective mitophagy have provided novel insights into SLE prophylaxis and therapy. However, the precise mechanism underlying the role of oxidative stress-related mitochondrial molecules in skewing the cell fate at the molecular level remains unclear. This review outlines distinctive mitochondrial functions and pathways that are involved in immune responses and systematically delineates how mitochondrial dysfunction contributes to SLE pathogenesis. In addition, we provide a comprehensive overview of damaged mitochondrial function and impaired metabolic pathways in adaptive and innate immune cells and lupus-induced organ tissues. Furthermore, we summarize the potential of current mitochondria-targeting drugs for SLE treatment. Developing novel therapeutic approaches to regulate mitochondrial oxidative stress is a promising endeavor in the search for effective treatments for systemic autoimmune diseases, particularly SLE.
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Affiliation(s)
- Like Zhao
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianda Hu
- Beijing Tibetan Hospital, China Tibetology Research Center, Beijing, China
| | - Fei Xiao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Xuan Zhang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lidan Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science and Technology, Beijing, China
- *Correspondence: Min Wang, ; Lidan Zhao,
| | - Min Wang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Min Wang, ; Lidan Zhao,
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16
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Zorzetti N, Lauro A, Khouzam S, Marino IR. Immunosuppression, Compliance, and Tolerance After Orthotopic Liver Transplantation: State of the Art. EXP CLIN TRANSPLANT 2022; 20:3-9. [PMID: 35384800 DOI: 10.6002/ect.mesot2021.l13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Orthotopic liver transplantation is the treatment of choice for several otherwise irreversible forms of acute and chronic liver diseases. Early implemented immunosuppressant regimens have had disappointing results with high rejection rates. However, new drugs have reduced the daily immunosuppression requirements, thereby improving graft and patient survival as well as kidney function. Liver rejection is a T-cell-driven immune response and is the active target of immunosuppressive agents. Immunosuppressants can be divided into pharmacological or biological drugs: the gold standard is the calcineurin inhibitors, steroids, mycophenolate mofetil, and mechanistic target of rapamycin inhibitors. Compliance with these agents is essential, although they can increase the risk of infections and neoplastic diseases. In some patients, graft tolerance can be achieved. Graft tolerance is defined as the absence of acute and chronic rejection in a graft, with normal function and histology in an immunosuppression-free, fully immunocompetent host, usually as the final result of a successful attempt at immunosuppression withdrawal. The occurrence of immunosuppressive-related complications has led to new protocols aimed at protecting renal function and preventing de novo cancer and dysmetabolic syndrome. The backbone of immunosuppression remains calcineurin inhibitors in association with other drugs, mainly over the short-term period. To avoid rejection and the side effects on renal dysfunction, de novo cancer, and cardiovascular syndrome, optimal long-term immunosuppressive therapy should be tailored in liver transplant recipients.
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Affiliation(s)
- Noemi Zorzetti
- From the Department of General Surgery, Ospedale A. Costa, Porretta Terme-Bologna, Italy
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17
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Clare J, Ganly J, Bursill CA, Sumer H, Kingshott P, de Haan JB. The Mechanisms of Restenosis and Relevance to Next Generation Stent Design. Biomolecules 2022; 12:biom12030430. [PMID: 35327622 PMCID: PMC8945897 DOI: 10.3390/biom12030430] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/07/2022] [Accepted: 03/08/2022] [Indexed: 02/04/2023] Open
Abstract
Stents are lifesaving mechanical devices that re-establish essential blood flow to the coronary circulation after significant vessel occlusion due to coronary vessel disease or thrombolytic blockade. Improvements in stent surface engineering over the last 20 years have seen significant reductions in complications arising due to restenosis and thrombosis. However, under certain conditions such as diabetes mellitus (DM), the incidence of stent-mediated complications remains 2–4-fold higher than seen in non-diabetic patients. The stents with the largest market share are designed to target the mechanisms behind neointimal hyperplasia (NIH) through anti-proliferative drugs that prevent the formation of a neointima by halting the cell cycle of vascular smooth muscle cells (VSMCs). Thrombosis is treated through dual anti-platelet therapy (DAPT), which is the continual use of aspirin and a P2Y12 inhibitor for 6–12 months. While the most common stents currently in use are reasonably effective at treating these complications, there is still significant room for improvement. Recently, inflammation and redox stress have been identified as major contributing factors that increase the risk of stent-related complications following percutaneous coronary intervention (PCI). The aim of this review is to examine the mechanisms behind inflammation and redox stress through the lens of PCI and its complications and to establish whether tailored targeting of these key mechanistic pathways offers improved outcomes for patients, particularly those where stent placement remains vulnerable to complications. In summary, our review highlights the most recent and promising research being undertaken in understanding the mechanisms of redox biology and inflammation in the context of stent design. We emphasize the benefits of a targeted mechanistic approach to decrease all-cause mortality, even in patients with diabetes.
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Affiliation(s)
- Jessie Clare
- Department of Chemistry and Biotechnology, Swinburne University of Technology, Melbourne, VIC 3122, Australia; (J.C.); (J.G.); (P.K.)
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Justin Ganly
- Department of Chemistry and Biotechnology, Swinburne University of Technology, Melbourne, VIC 3122, Australia; (J.C.); (J.G.); (P.K.)
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Christina A. Bursill
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5000, Australia;
- Vascular Research Centre, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
- ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5000, Australia
| | - Huseyin Sumer
- Department of Chemistry and Biotechnology, Swinburne University of Technology, Melbourne, VIC 3122, Australia; (J.C.); (J.G.); (P.K.)
- Correspondence: (H.S.); (J.B.d.H.)
| | - Peter Kingshott
- Department of Chemistry and Biotechnology, Swinburne University of Technology, Melbourne, VIC 3122, Australia; (J.C.); (J.G.); (P.K.)
- ARC Training Centre in Surface Engineering for Advanced Materials (SEAM), Swinburne University of Technology, Melbourne, VIC 3122, Australia
| | - Judy B. de Haan
- Department of Chemistry and Biotechnology, Swinburne University of Technology, Melbourne, VIC 3122, Australia; (J.C.); (J.G.); (P.K.)
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Department Cardiometabolic Health, University of Melbourne, Melbourne, VIC 3010, Australia
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
- Correspondence: (H.S.); (J.B.d.H.)
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18
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Asleh R, Vucicevic D, Petterson TM, Kremers WK, Pereira NL, Daly RC, Edwards BS, Steidley DE, Scott RL, Kushwaha SS. Sirolimus-Based Immunosuppression Is Associated with Decreased Incidence of Post-Transplant Lymphoproliferative Disorder after Heart Transplantation: A Double-Center Study. J Clin Med 2022; 11:jcm11020322. [PMID: 35054016 PMCID: PMC8779206 DOI: 10.3390/jcm11020322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/03/2022] [Accepted: 01/07/2022] [Indexed: 02/01/2023] Open
Abstract
Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein-Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8-26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04-0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03-0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.
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Affiliation(s)
- Rabea Asleh
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
- Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel
- Correspondence: or
| | - Darko Vucicevic
- Department of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
| | - Tanya M. Petterson
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA;
| | - Walter K. Kremers
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA;
| | - Naveen L. Pereira
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
| | - Richard C. Daly
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
| | - Brooks S. Edwards
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
| | - D. Eric Steidley
- Department of Cardiovascular Diseases, Mayo Clinic Arizona, Phoenix, AZ 85054, USA; (D.E.S.); (R.L.S.)
| | - Robert L. Scott
- Department of Cardiovascular Diseases, Mayo Clinic Arizona, Phoenix, AZ 85054, USA; (D.E.S.); (R.L.S.)
| | - Sudhir S. Kushwaha
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
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19
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Shinde A, Panchal K, Katke S, Paliwal R, Chaurasiya A. Tyrosine kinase inhibitors as next generation oncological therapeutics: Current strategies, limitations and future perspectives. Therapie 2021; 77:425-443. [PMID: 34823895 DOI: 10.1016/j.therap.2021.10.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 10/04/2021] [Accepted: 10/19/2021] [Indexed: 02/09/2023]
Abstract
Protein kinases, a class of enzymes that govern various biological phenomena at a cellular level, are responsible for signal transduction in cells that regulate cellular proliferation, differentiation, and growth. Protein kinase enzyme mutation results in abnormal cell division leading to a pathological condition like cancer. Tyrosine kinase (TK) inhibitors, which helps as a potential drug candidate for the treatment of cancer, are continuously being developed. Majority of these drug candidates are being administered as conventional oral dosage form, which provides limited safety and efficacy due to non-specific delivery and uncontrolled biodistribution resulting into the adverse effects. A controlled drug delivery approach for the delivery of TK inhibitors may be a potential strategy with significant safety and efficacy profile. Novel drug delivery strategies provide target-specific drug delivery, improved pharmacokinetic behaviour, and sustained release leading to lower doses and dosing frequency with significantly reduced side effects. Along with basic aspects of tyrosine kinase, this review discusses various aspects related to the application of tyrosine kinase inhibitors in clinical oncological setting. Furthermore, the limitations/challenges and formulation advancements related to this class of candidates particularly for cancer management have been reviewed. It is expected that innovations in drug delivery approaches for TK inhibitors using novel techniques will surely provide a new insights for improved cancer treatment and patients' life quality.
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Affiliation(s)
- Aishwarya Shinde
- Translational Pharmaceutics Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, Telangana 500078, India
| | - Kanan Panchal
- Translational Pharmaceutics Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, Telangana 500078, India
| | - Sumeet Katke
- Translational Pharmaceutics Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, Telangana 500078, India
| | - Rishi Paliwal
- Nanomedicine and Bioengineering Research Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak 484886, India
| | - Akash Chaurasiya
- Translational Pharmaceutics Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, Telangana 500078, India.
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20
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L R, T I, Mpaw C, H M, G S. THE MANAGEMENT OF POST-TRANSPLANTATION RECURRENCE OF HEPATOCELLULAR CARCINOMA. Clin Mol Hepatol 2021; 28:1-16. [PMID: 34610652 PMCID: PMC8755475 DOI: 10.3350/cmh.2021.0217] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/03/2021] [Indexed: 11/15/2022] Open
Abstract
The annual incidence of hepatocellular carcinoma (HCC) continues to rise. Over the last two decades, liver transplantation (LT) has become the preferable treatment of HCC, when feasible and strict selection criteria are met. With the rise in HCC-related LT, compounded by downstaging techniques and expansion of transplant selection criteria, a parallel increase in number of post-transplantation HCC recurrence is expected. Additionally, in the context of an immunosuppressed transplant host, recurrences may behave aggressively and more challenging to manage, resulting in poor prognosis. Despite this, no consensus or best practice guidelines for post-transplantation cancer surveillance and recurrence management for HCC currently exist. Studies with adequate population sizes and high-level evidence are lacking, and the role of systemic and locoregional therapies for graft and extrahepatic recurrences remains under debate. This review seeks to summarize the existing literature on post-transplant HCC surveillance and recurrence management. It highlights the value of early tumour detection, re-evaluating the immunosuppression regimen, and staging to differentiate disseminated recurrence from intrahepatic or extrahepatic oligo-recurrence. This ultimately guides decision-making and maximizes treatment effect. Treatment recommendations specific to recurrence type are provided based on currently available locoregional and systemic therapies.
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Affiliation(s)
- Rajendran L
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Ivanics T
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Department of Surgery, Henry Ford Hospital, Detroit, MI, USA.,Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden
| | - Claasen Mpaw
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Department of Surgery, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - Muaddi H
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Sapisochin G
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada.,Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
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21
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Zhang X, Liu D, He M, Lin M, Tu C, Zhang B. Polymeric nanoparticles containing rapamycin and autoantigen induce antigen-specific immunological tolerance for preventing vitiligo in mice. Hum Vaccin Immunother 2021; 17:1923-1929. [PMID: 33616474 DOI: 10.1080/21645515.2021.1872342] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Vitiligo is an autoimmune disease in which pigment is lost in patches of the skin. CD4+ T cells are implicated in vitiligo while regulatory T cells (Tregs) could ameliorate vitiligo. Rapamycin together with autoantigen have been shown to induce immunological tolerance and promote Tregs in multiple autoimmune diseases. In the current study, we synthesized nanoparticles containing rapamycin and autoantigen HEL46-61 (NPHEL46-61/Rapa) and investigated their effects on vitiligo. We treated bone marrow-derived dendritic cells (BMDCs) from TrpHEL mice with NPHEL46-61/Rapa and monitored the phenotype of BMDCs. We investigated the effects of NPHEL46-61/Rapa-treated BMDCs on CD4+ T cell proliferation and differentiation. We administrated NPHEL46-61/Rapa to TCR-TrpHEL mice and investigated the effects on vitiligo. We found that BMDCs can uptake the NPHEL46-61/Rapa, which resulted in decreased expression of costimulation molecules CD80 and CD86 in BMDCs. BMDCs treated with NPHEL46-61/Rapa suppressed antigen-specific CD4+ T cell proliferation while promoted the differentiation of these CD4+ T cell to Tregs in vitro. Administration of NPHEL46-61/Rapa to TCR-TrpHEL mice ameliorated vitiligo, promoted Treg production, and suppressed IFN-γ and IL-6 production, while induced IL-10 production. Therefore, our study provides experimental evidence that nanoparticles containing rapamycin and autoantigen could induce antigen-specific immunological tolerance and prevent vitiligo.
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Affiliation(s)
- Xia Zhang
- Department of Dermatology, Weifang Yidu Central Hospital, Qingzhou, Shandong, China
| | - Daji Liu
- Department of Rheumatology, Weifang Yidu Central Hospital, Qingzhou, Shandong, China
| | - Minghong He
- Department of Respiratory Medicine, Weifang Yidu Central Hospital, Qingzhou, Shandong, China
| | - Mao Lin
- Department of Dermatology, Chongqing Chinese Medicine Hospital, Chongqing, China
| | - Caixia Tu
- Department of Dermatology, The 2nd Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Baoxiang Zhang
- Department of Dermatology, Weifang Yidu Central Hospital, Qingzhou, Shandong, China
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22
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Stevens JR, Zamani A, Osborne JIA, Zamani R, Akrami M. Critical evaluation of stents in coronary angioplasty: a systematic review. Biomed Eng Online 2021; 20:46. [PMID: 33964954 PMCID: PMC8105986 DOI: 10.1186/s12938-021-00883-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 04/26/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Coronary stents are routinely placed in the treatment and prophylaxis of coronary artery disease (CAD). Current coronary stent designs are prone to developing blockages: in-stent thrombosis (IST) and in-stent re-stenosis (ISR). This is a systematic review of the design of current coronary stent models, their structural properties and their modes of application, with a focus on their associated risks of IST and ISR. The primary aim of this review is to identify the best stent design features for reducing the risk of IST and ISR. To review the three major types of stents used in clinical settings today, determining best and relevant clinical practice by exploring which types and features of offer improved patient outcomes regarding coronary angioplasty. This information can potentially be used to increase the success rate of coronary angioplasty and stent technology in the future taking into account costs and benefits. METHODS Scientific databases were searched to find studies concerning stents. After the exclusion criteria were applied, 19 of the 3192 searched literature were included in this review. Studies investigating three major types of stent design were found: bare-metal stents (BMS), drug-eluting stents (DES) and bioresorbable stents (BRS). The number of participants varied between 14 and 1264. On average 77.4% were male, with a mean age of 64 years. RESULTS From the findings of these studies, it is clear that DES are superior in reducing the risk of ISR when compared to BMS. Conflicting results do not clarify whether BRS are superior to DES at reducing IST occurrence, although studies into newer BRS technologies show reducing events of IST to 0, creating a promising future for BRS showing them to be non-inferior. Thinner stents were shown to reduce IST rates, due to better re-endothelialisation. Scaffold material has also been shown to play a role with cobalt alloy stents reducing the risk of IST. This study found that thinner stents that release drugs were better at preventing re-blockages. Some dissolvable stents might be better at stopping blood clots blocking the arteries when compared to metal stents. The method and procedure of implanting the stent during coronary angioplasty influences success rate of these stents, meaning stent design is not the only significant factor to consider. CONCLUSIONS Positive developments in coronary angioplasty could be made by designing new stents that encompass all the most desirable properties of existing stent technology. Further work is needed to investigate the benefits of BRS in reducing the risk of IST compared to DES, as well as to investigate the effects of different scaffold materials on IST and ISR outcomes.
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Affiliation(s)
| | - Ava Zamani
- Medical School, University College London (UCL), London, UK
| | | | - Reza Zamani
- Medical School, College of Medicine and Health, Exeter, UK
| | - Mohammad Akrami
- Department of Mechanical Engineering, College of Engineering, Mathematics, and Physical Sciences, University of Exeter, Exeter, UK.
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23
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Yang M, Xu Z, Yan H, Tsai HI, Su D, Yan F, Lu Q, Feng J, Zeng W, Xi L, Zha H, Ling Y, He C, Wu Y, Xu X, Zheng G, Liu G, Chen H, Cheng F. PD-L1 cellular nanovesicles carrying rapamycin inhibit alloimmune responses in transplantation. Biomater Sci 2021; 9:1246-1255. [PMID: 33367372 DOI: 10.1039/d0bm01798a] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Organ transplantation has been employed upon serious injuries, but a T-cell-mediated potent inflammatory immune response often leads to graft rejection. Immunosuppressive drugs such as rapamycin (RAPA) have to be taken after organ transplantation, but long-term use of these drugs causes severe adverse effects. Immune checkpoint pathways such as the programmed death-receptor 1/programmed death-ligand 1 (PD-1/PD-L1) provides an immunosuppressive environment, preventing excessive tissue destruction due to inflammatory immune responses. In this study, we bioengineered cell membrane-derived PD-L1 nanovesicles (PD-L1 NVs) to carry low doses of RAPA. These NVs inhibited T-cell activation and proliferation in vitro, by enhancing the PD-1/PD-L1 immune co-inhibitory signaling axis and inhibiting the mTOR pathway. Importantly, PD-L1 NVs encapsulated with rapamycin exerted stronger effects on inhibiting T-cell proliferation than PD-L1 NVs or rapamycin alone. This can be recapitulated in a mouse skin transplantation model, leading to the weakened alloimmune response and allograft tolerance. We also found that PD-L1/rapamycin vesicles have additional function to induce regulatory T cells in the recipient spleens. Our study highlighted the power of combining low-dose rapamycin and PD-L1 in the nanovesicles as immunosuppressants to promote allograft acceptance.
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Affiliation(s)
- Min Yang
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Zhanxue Xu
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Hailan Yan
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Hsiang-I Tsai
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Dandan Su
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Fuxia Yan
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Qiumei Lu
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Jianhua Feng
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Weiwei Zeng
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Lifang Xi
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Hualian Zha
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Yunzhi Ling
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Chao He
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Yingyi Wu
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Xiaowei Xu
- Clinical Neuroscience Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China
| | - Gang Zheng
- XuZhou Central Hospital Affiliated to Medical School of Southeast University, XuZhou, 221000, China
| | - Gan Liu
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Hongbo Chen
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
| | - Fang Cheng
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
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24
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Mengus C, Ozkurt S, Oztas E, Yasar Bilge NS, Isiksoy S, Yalcin AU. De novo isolated gastrointestinal tract vasculitis without associated systemic disease in renal transplant recipients successfully treated with rituximab. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION 2021; 31:281-284. [PMID: 32129226 DOI: 10.4103/1319-2442.279954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Systemic vasculitic diseases can show recurrence after kidney transplantation, but de novo systemic vasculitis is rarely seen after kidney transplantation, and in literature, there are only a few cases. In general population, the incidence of isolated organ vasculitis is unknown, and according to the best of our knowledge, there is no information about de novo isolated organ vasculitis after renal transplantation. We report, most probably, the first case of a 40-year-old woman who was restarted on dialysis treatment after renal transplantation and developed isolated gastrointestinal vasculitis and intestinal hemorrhage under immunosuppressive treatment. She was treated successfully with rituximab.
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Affiliation(s)
- Cigdem Mengus
- Department of Nephrology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Sultan Ozkurt
- Department of Nephrology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Erkin Oztas
- Department of Gastroenterology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Nazife Sule Yasar Bilge
- Department of Rheumatology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Serap Isiksoy
- Department of Pathology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Ahmet Ugur Yalcin
- Department of Nephrology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
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25
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Li YH, Hsu SL, Sheu SJ. A Review of Local Therapy for the Management of Cystoid Macular Edema in Uveitis. Asia Pac J Ophthalmol (Phila) 2021; 10:87-92. [PMID: 33512830 DOI: 10.1097/apo.0000000000000352] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
ABSTRACT Uveitic macular edema is a significant cause of visual impairment in most uveitis types. Treatment options of uveitis have advanced remarkably in recent years. Up to now, corticosteroids remain the mainstay of treatment. Nonsteroidal immunomodulators, and recently the biologic agents, which can reinforce efficacy and enable discontinuation or reduction of steroids to maintenance doses, are becoming increasingly popular in the management of uveitic macular edema. Several medications can be used in intraocular delivery and more and more sustained releasing implants are being developed. This review will briefly focus on the review of local therapy for the management of cystoid macular edema in uveitis, as many of these novel approaches are currently being evaluated in clinical trials.
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Affiliation(s)
- Yi Hsuan Li
- Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shiuh-Liang Hsu
- Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shwu-Jiuan Sheu
- Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Kaohsiung Medical University, Kaohsiung, Taiwan
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26
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Alnsasra H, Asleh R, Oh JK, Maleszewski JJ, Lerman A, Toya T, Chandrasekaran K, Bois MC, Kushwaha SS. Impact of Sirolimus as a Primary Immunosuppressant on Myocardial Fibrosis and Diastolic Function Following Heart Transplantation. J Am Heart Assoc 2020; 10:e018186. [PMID: 33325244 PMCID: PMC7955460 DOI: 10.1161/jaha.120.018186] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Myocardial fibrosis is an important contributor for development of diastolic dysfunction. We investigated the impact of sirolimus as primary immunosuppression on diastolic dysfunction and fibrosis progression among heart transplantation recipients. Methods and Results In 100 heart transplantation recipients who were either treated with a calcineurin inhibitor (CNI) (n=51) or converted from CNI to sirolimus (n=49), diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations. Myocardial fibrosis was quantified on serial myocardial biopsies. After 3 years, lateral e′ increased within the sirolimus group but decreased in the CNI group (0.02±0.04 versus −0.02±0.04 m/s delta change; P=0.003, respectively). Both pulmonary capillary wedge pressure and diastolic pulmonary artery pressure significantly decreased in the sirolimus group but remained unchanged in the CNI group (−1.50±2.59 versus 0.20±2.20 mm Hg/year; P=0.02; and −1.72±3.39 versus 0.82±2.59 mm Hg/year; P=0.005, respectively). A trend for increased percentage of fibrosis was seen in the sirolimus group (8.48±3.17 to 10.10±3.0%; P=0.07) as compared with marginally significant progression in the CNI group (8.76±3.87 to 10.56±4.34%; P=0.04). The percent change in fibrosis did not differ significantly between the groups (1.62±4.67 versus 1.80±5.31%, respectively; P=0.88). Conclusions Early conversion to sirolimus is associated with improvement in diastolic dysfunction and filling pressures as compared with CNI therapy. Whether this could be attributed to attenuation of myocardial fibrosis progression with sirolimus treatment warrants further investigation.
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Affiliation(s)
- Hilmi Alnsasra
- Department of Cardiovascular Diseases Mayo Clinic Rochester MN
| | - Rabea Asleh
- Department of Cardiovascular Diseases Mayo Clinic Rochester MN.,Department of Cardiology Hadassah University Medical Center Jerusalem Israel
| | - Jae K Oh
- Department of Cardiovascular Diseases Mayo Clinic Rochester MN
| | | | - Amir Lerman
- Department of Cardiovascular Diseases Mayo Clinic Rochester MN
| | - Takumi Toya
- Department of Cardiovascular Diseases Mayo Clinic Rochester MN
| | | | - Melanie C Bois
- Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN
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27
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The Immune System and Pathogenesis of Melanoma and Non-melanoma Skin Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1268:211-226. [DOI: 10.1007/978-3-030-46227-7_11] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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28
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Ji L, Xie W, Zhang Z. Efficacy and safety of sirolimus in patients with systemic lupus erythematosus: A systematic review and meta-analysis. Semin Arthritis Rheum 2020; 50:1073-1080. [PMID: 32911286 DOI: 10.1016/j.semarthrit.2020.07.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/04/2020] [Accepted: 07/08/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Emerging evidence suggested a potential therapeutic role of targeting mTOR in the treatment of SLE. But most studies were observational studies with limited sample size or case reports. OBJECTIVE To evaluate the efficacy and safety of sirolimus in treatment of SLE by systematic review and meta-analysis. METHODS Systematic searches of Medline/PubMed, EMBASE, the Cochrane library and Scopus were performed. Original case reports, case series, observational studies and clinical trials reporting the efficacy or safety data on SLE patients treated with sirolimus were included. A random-effects meta-analysis was performed to calculate the pooled efficacy, when possible. RESULTS A total of 9 studies comprising 145 patients were identified. The exposure of sirolimus was 245.8 patient-years, with 1-3 mg/day adopted in majority studies. In 111 clinical active patients, the pooled decrease of SLEDAI, BILAG and prednisone dosage was 4.85 (95% CI 3.44-6.25), 1.98 (95% CI 0.23-3.74) and 13.17 mg/day (95% CI 0.71-25.63) respectively. 23 patients initiating sirolimus for active SLE yielded remission in 17 (73.9%) patients. In 22 quiescent lupus nephritis patients, 21 (95.5%) patients sustained remission. Hematological, mucocutaneous abnormalities and dyslipidemia were the most common adverse events. Early cessation due to side effects was reported in 9.28% (13/140) patients, most of the side effects were mild and recovered quickly after cessation. CONCLUSIONS Summary of the available datasets indicated sirolimus was promising and well-tolerated in the treatment of SLE. Further randomized controlled trials evaluating the potential benefits and risk of sirolimus in SLE are warranted.
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Affiliation(s)
- Lanlan Ji
- Department of Rheumatology and Clinical Immunology, Peking University First Hospital, Beijing 100034, China.
| | - Wenhui Xie
- Department of Rheumatology and Clinical Immunology, Peking University First Hospital, Beijing 100034, China.
| | - Zhuoli Zhang
- Department of Rheumatology and Clinical Immunology, Peking University First Hospital, Beijing 100034, China.
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29
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Ekpanyapong S, Philips N, Loza BL, Abt P, Furth EE, Tondon R, Khungar V, Olthoff K, Shaked A, Hoteit MA, Reddy KR. Predictors, Presentation, and Treatment Outcomes of Recurrent Hepatocellular Carcinoma After Liver Transplantation: A Large Single Center Experience. J Clin Exp Hepatol 2020; 10:304-315. [PMID: 32655233 PMCID: PMC7335705 DOI: 10.1016/j.jceh.2019.11.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 11/14/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Liver transplantation (LT) is an accepted therapeutic option for hepatocellular carcinoma (HCC) in patients with cirrhosis. Despite careful candidate selection, HCC recurrence occurs. We aimed to describe the predictors of recurrence, clinical presentation, and predictors of survival after HCC recurrence post-LT. METHODS Patients with recurrent HCC after LT between January 1996 and December 2017 were retrospectively reviewed. RESULTS Of 711 patients, 96 (13.5%) patients had post-LT HCC recurrence. The median time to recurrence was 17.1 months, and the median survival was 10.1 months. Initial recurrence was more often in the graft (34.4%), and most (60.4%) had multiple recurrent lesions, and 26% were in multiple sites. In multivariate analysis, factors associated with shorter survival were poorly differentiated histology in explant (Hazard ratio [HR] = 1.96; p = 0.027), bilirubin ≥1.2 mg/dL (HR = 2.47; p = 0.025), and albumin <3.5 mg/dL (HR = 2.13; p = 0.014) at recurrence, alpha-fetoprotein at recurrence ≥ 1000 ng/mL (HR = 2.96; p = 0.005), and peritoneal disease (HR = 3.20; p = 0.022). There was an increased survival in patients exposed to sirolimus (HR = 0.32; p < 0.0001). CONCLUSIONS Recurrent HCC after LT is often in extrahepatic sites with a decreased survival in those with poorly differentiated explant pathology, high bilirubin, low albumin, marked elevation of alpha-fetoprotein at recurrence, and peritoneal recurrence. Sirolimus-based immunosuppression may provide benefit.
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Key Words
- AFP, alpha-fetoprotein
- ALP, alkaline phosphatase
- ALT, alanine transaminase
- CNI, calcineurin inhibitor
- CT, computed tomography
- HBV, hepatitis B virus
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- INR, international normalized ratio
- LT, Liver transplantation
- MRI, magnetic resonance imaging
- NASH, nonalcoholic steatohepatitis
- RETREAT, Risk Estimation of Tumor Recurrence After Transplant
- RFA, radiofrequency ablation
- TACE, transarterial chemoembolization
- UCSF, University of California San Francisco
- UNOS, United Network for Organ Sharing
- hepatocellular carcinoma
- immunosuppression
- liver transplantation
- mTOR, mammalian target of rapamycin
- recurrence
- survival
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Affiliation(s)
- Sirina Ekpanyapong
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA
| | - Neil Philips
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA
| | - Bao-Li Loza
- Department of Surgery, Penn Transplant Institute, University of Pennsylvania, Philadelphia, PA, USA
| | - Peter Abt
- Department of Surgery, Penn Transplant Institute, University of Pennsylvania, Philadelphia, PA, USA
| | - Emma E. Furth
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Rashmi Tondon
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Vandana Khungar
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA
| | - Kim Olthoff
- Department of Surgery, Penn Transplant Institute, University of Pennsylvania, Philadelphia, PA, USA
| | - Abraham Shaked
- Department of Surgery, Penn Transplant Institute, University of Pennsylvania, Philadelphia, PA, USA
| | - Maarouf A. Hoteit
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA
| | - K. Rajender Reddy
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA
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30
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Saegusa C, Hosoya M, Nishiyama T, Saeki T, Fujimoto C, Okano H, Fujioka M, Ogawa K. Low-dose rapamycin-induced autophagy in cochlear outer sulcus cells. Laryngoscope Investig Otolaryngol 2020; 5:520-528. [PMID: 32596496 PMCID: PMC7314457 DOI: 10.1002/lio2.392] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 04/02/2020] [Accepted: 04/26/2020] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVES Autophagy is an intracellular housekeeping process that degrades cytoplasmic organelles, damaged molecules, and abnormal proteins or pathogens and is essential for normal hearing. Recent studies revealed the essential roles of autophagy in hearing and balance. The aim of this study was to evaluate the activation state of rapamycin-induced autophagy in cochlear outer sulcus cells (OSCs). METHODS We used autophagy reporter transgenic mice expressing the green fluorescent protein-microtubule-associated protein light chain 3 (GFP-LC3) fusion protein and counted GFP-LC3 puncta in cochlear OSCs to evaluate the activation state of autophagy after oral administration of rapamycin. RESULTS We observed basal level GFP-LC3 expression and an increase in the number of GFP-LC3 puncta in cochlear OSCs by oral administration of rapamycin. This increase was detected when the daily rapamycin intake was as low as 0.025 mg/kg, and it was dose dependent. The increased number of puncta was more at the basal turn than the apical turn. CONCLUSION Oral intake of low-dose rapamycin activates autophagy in cochlear OSCs. LEVEL OF EVIDENCE NA.
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Affiliation(s)
- Chika Saegusa
- Department of Otorhinolaryngology, Head and Neck SurgeryKeio University School of MedicineTokyoJapan
| | - Makoto Hosoya
- Department of Otorhinolaryngology, Head and Neck SurgeryKeio University School of MedicineTokyoJapan
| | - Takanori Nishiyama
- Department of Otorhinolaryngology, Head and Neck SurgeryKeio University School of MedicineTokyoJapan
| | - Tsubasa Saeki
- Department of PhysiologyKeio University School of MedicineTokyoJapan
| | - Chisato Fujimoto
- Department of Otolaryngology and Head and Neck SurgeryGraduate School of Medicine, University of TokyoTokyoJapan
| | - Hideyuki Okano
- Department of PhysiologyKeio University School of MedicineTokyoJapan
| | - Masato Fujioka
- Department of Otorhinolaryngology, Head and Neck SurgeryKeio University School of MedicineTokyoJapan
| | - Kaoru Ogawa
- Department of Otorhinolaryngology, Head and Neck SurgeryKeio University School of MedicineTokyoJapan
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Au KP, Chok KSH. Mammalian target of rapamycin inhibitors after post-transplant hepatocellular carcinoma recurrence: Is it too late? World J Gastrointest Surg 2020; 12:149-158. [PMID: 32426094 PMCID: PMC7215969 DOI: 10.4240/wjgs.v12.i4.149] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/21/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce the risk of tumour recurrence after liver transplantation for hepatocellular carcinoma (HCC). However, their role in established post-transplant HCC recurrence is uncertain.
AIM To investigate whether mTOR inhibitor offers a survival benefit in post-transplant HCC recurrence.
METHODS A retrospective study of 143 patients who developed HCC recurrence after liver transplantation was performed. They were divided into 2 groups based on whether they had received mTOR inhibitor-based immunosuppression. The primary endpoint was post-recurrence survival.
RESULTS Seventy-nine (55%) patients received an mTOR inhibitor-based immunosuppressive regime, while 64 (45%) patients did not. The mTOR inhibitor group had a lower number of recurrent tumours (2 vs 5, P = 0.02) and received more active treatments including radiotherapy (39 vs 22%, P = 0.03) and targeted therapy (59 vs 23%, P < 0.001). The median post-recurrence survival was 21.0 ± 4.1 mo in the mTOR inhibitor group and 11.2 ± 2.5 mo in the control group. Multivariate Cox regression analysis confirmed that mTOR inhibitor therapy was independently associated with improved post-recurrence survival (P = 0.04, OR = 0.482, 95%CI: 0.241-0.966). The number of recurrent tumours and use of other treatment modalities did not affect survival. No survival difference was observed between mTOR inhibitor monotherapy and combination therapy with calcineurin inhibitor.
CONCLUSION mTOR inhibitors prolonged survival after post-transplant HCC recurrence.
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Affiliation(s)
- Kin Pan Au
- Department of Surgery, Queen Mary Hospital, Hong Kong 999077, China
| | - Kenneth Siu Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong 999077, China
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Ogata T, Makino H, Ishizuka N, Iwamoto E, Masaki T, Kizaki K, Kim YH, Sato S. Long-term high-grain diet alters ruminal pH, fermentation, and epithelial transcriptomes, leading to restored mitochondrial oxidative phosphorylation in Japanese Black cattle. Sci Rep 2020; 10:6381. [PMID: 32286493 PMCID: PMC7156705 DOI: 10.1038/s41598-020-63471-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 03/22/2020] [Indexed: 01/16/2023] Open
Abstract
To increase intramuscular fat accumulation, Japanese Black beef cattle are commonly fed a high-grain diet from 10 to 30 months of age. Castrated and fistulated cattle (n = 9) were fed a high-concentrate diets during the early, middle, and late stages consecutively (10-14, 15-22, 23-30 months of age, respectively). Ruminal pH was measured continuously, and rumen epithelium and fluid samples were collected on each stage. The 24-h mean ruminal pH during the late stage was significantly lower than that during the early stage. Total volatile fatty acid (VFA) and lactic acid levels during the late stage were significantly lower and higher, respectively, than those during the early and middle stages. In silico analysis of differentially expressed genes showed that "Oxidative Phosphorylation" was the pathway inhibited most between the middle and early stages in tandem with an inhibited upstream regulator (PPARGC1A, also called PGC-1α) but the most activated pathway between the late and middle stages. These results suggest that mitochondrial dysfunction and thereby impaired cell viability due to acidic irritation under the higher VFA concentration restored stable mitochondrial oxidative phosphorylation and cell viability by higher lactic acid levels used as cellular oxidative fuel under a different underlying mechanism in subacute ruminal acidosis.
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Affiliation(s)
- Toru Ogata
- United Graduate School of Veterinary Sciences, Gifu University, Gifu, 501-1193, Japan
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, Morioka, Iwate, 020-8550, Japan
| | - Hiroki Makino
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, Morioka, Iwate, 020-8550, Japan
| | - Naoki Ishizuka
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, Morioka, Iwate, 020-8550, Japan
| | - Eiji Iwamoto
- Hyogo Prefectural Technology Center of Agriculture, Forestry and Fisheries, Hyogo, 679-0198, Japan
| | - Tatsunori Masaki
- Hyogo Prefectural Technology Center of Agriculture, Forestry and Fisheries, Hyogo, 679-0198, Japan
| | - Keiichiro Kizaki
- United Graduate School of Veterinary Sciences, Gifu University, Gifu, 501-1193, Japan
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, Morioka, Iwate, 020-8550, Japan
| | - Yo-Han Kim
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, Morioka, Iwate, 020-8550, Japan.
| | - Shigeru Sato
- United Graduate School of Veterinary Sciences, Gifu University, Gifu, 501-1193, Japan.
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, Morioka, Iwate, 020-8550, Japan.
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Passerini L, Barzaghi F, Curto R, Sartirana C, Barera G, Tucci F, Albarello L, Mariani A, Testoni PA, Bazzigaluppi E, Bosi E, Lampasona V, Neth O, Zama D, Hoenig M, Schulz A, Seidel MG, Rabbone I, Olek S, Roncarolo MG, Cicalese MP, Aiuti A, Bacchetta R. Treatment with rapamycin can restore regulatory T-cell function in IPEX patients. J Allergy Clin Immunol 2020; 145:1262-1271.e13. [PMID: 31874182 DOI: 10.1016/j.jaci.2019.11.043] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/08/2019] [Accepted: 11/15/2019] [Indexed: 12/23/2022]
Abstract
BACKGROUND Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear. OBJECTIVE We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations. METHODS Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR. RESULTS Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor-related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor-related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells. CONCLUSIONS Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.
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Affiliation(s)
- Laura Passerini
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Federica Barzaghi
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Paediatric Immunohematology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rosalia Curto
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Claudia Sartirana
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Graziano Barera
- Department of Paediatrics, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesca Tucci
- Department of Paediatric Immunohematology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luca Albarello
- Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alberto Mariani
- Gastroenterology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Elena Bazzigaluppi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Emanuele Bosi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita Salute San Raffaele University, Milan, Italy
| | - Vito Lampasona
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Olaf Neth
- Department of Paediatric Infectious Diseases, Rheumatology and Immunodeficiency, Instituto de Biomedicina de Sevilla/Consejo Superior de Investigaciones Científicas/Universidad de Sevilla, Seville, Spain
| | - Daniele Zama
- Department of Pediatrics, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Manfred Hoenig
- Clinic of Pediatrics and Adolescent Medicine, Ulm University, Ulm, Germany
| | - Ansgar Schulz
- Clinic of Pediatrics and Adolescent Medicine, Ulm University, Ulm, Germany
| | - Markus G Seidel
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria
| | - Ivana Rabbone
- Department of Pediatrics, University of Turin, Turin, Italy
| | | | - Maria G Roncarolo
- Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif
| | - Maria P Cicalese
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Paediatric Immunohematology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessandro Aiuti
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Paediatric Immunohematology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita Salute San Raffaele University, Milan, Italy
| | - Rosa Bacchetta
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif.
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Wang H, Sobral MC, Snyder T, Brudno Y, Gorantla VS, Mooney DJ. Clickable, acid labile immunosuppressive prodrugs forin vivotargeting. Biomater Sci 2020; 8:266-277. [DOI: 10.1039/c9bm01487j] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Clickable immunosuppressive prodrugs enablein vivoreplenishment of drugs in biomaterial depots to maintain long-term immunosuppression in tissue/organ transplantation.
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Affiliation(s)
- Hua Wang
- Harvard John A. Paulson School of Engineering and Applied Sciences
- Harvard University
- Cambridge
- Massachusetts 02138
- USA
| | - Miguel C. Sobral
- Harvard John A. Paulson School of Engineering and Applied Sciences
- Harvard University
- Cambridge
- Massachusetts 02138
- USA
| | - Tracy Snyder
- Wyss Institute for Biologically Inspired Engineering
- Cambridge
- USA
| | - Yevgeny Brudno
- Harvard John A. Paulson School of Engineering and Applied Sciences
- Harvard University
- Cambridge
- Massachusetts 02138
- USA
| | - Vijay S. Gorantla
- Surgery
- Ophthalmology and Bioengineering
- Wake Forest School of Medicine
- Winston-Salem
- USA
| | - David J. Mooney
- Harvard John A. Paulson School of Engineering and Applied Sciences
- Harvard University
- Cambridge
- Massachusetts 02138
- USA
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Nagy A, Robbins NL. The hurdles of nanotoxicity in transplant nanomedicine. Nanomedicine (Lond) 2019; 14:2749-2762. [DOI: 10.2217/nnm-2019-0192] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Nanomedicine has matured significantly in the past 20 years and a number of nanoformulated therapies are cleared by regulatory agencies for use across the globe. Transplant medicine is one area that has significantly benefited from the advancement of nanomedicine in recent times. However, while nanoparticle-based therapies have improved toxicological profiles of some drugs, there are still a number of aspects regarding the biocompatibility and toxicity of nanotherapies that require further research. The goal of this article is to review toxicological profiles of immunosuppressant therapies and their conversion into nanomedicine formulations as well as introduce future challenges associated with current in vitro and in vivo toxicological models.
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Affiliation(s)
- Amber Nagy
- 59th Medical Wing, Office of Science & Technology, Joint Base San Antonio-Lackland, TX 78236, USA
| | - Nicholas L Robbins
- 59th Medical Wing, Office of Science & Technology, Joint Base San Antonio-Lackland, TX 78236, USA
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Abud MB, Louzada RN, Isaac DLC, Souza LG, Dos Reis RG, Lima EM, de Ávila MP. In vivo and in vitro toxicity evaluation of liposome-encapsulated sirolimus. Int J Retina Vitreous 2019; 5:35. [PMID: 31572617 PMCID: PMC6757363 DOI: 10.1186/s40942-019-0186-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 08/12/2019] [Indexed: 12/22/2022] Open
Abstract
Background To evaluate the in vivo and in vitro toxicity of a new formulation of liposome-encapsulated sirolimus (LES). Methods In vitro experiments were done using ARPE-19 and HRP cells. An MTT assay was used to determine cell metabolic activity and a TUNEL assay for detecting DNA fragmentation. In vivo experiments were conducted on New Zealand albino rabbits that received intravitreal injections of empty liposomes (EL) or different concentrations of LES. Histopathological and immunohistochemical analyses were performed on the rabbit’s eyes following injection. Results Eighteen eyes of nine rabbits were used. MTT assay cell viability was 95.04% in group 1 (12.5 µL/mL LES). 92.95% in group 2 (25 µL/mL LES), 91.59% in group 3 (50 µL/mL LES), 98.09% in group 4 (12.5 µL/mL EL), 95.20% on group 5 (50 µL/mL EL), 98.53% in group 6 (50 µL/mL EL), and 2.84% on group 8 (50 µL/mL DMSO). There was no statistically significant difference among groups 1 to 7 in cell viability (p = 1.0), but the comparison of all groups with group 8 was significant (p < 0.0001). The TUNEL assay comparing two groups was not statistically significant from groups 1 to 7 (p = 1.0). The difference between groups 1 to 7 and group 8 (p < 0.0001) was significant. Histopathological changes were not found in any group. No activation of Müller cells was detected. Conclusion A novel formulation of LES delivered intravitreally did not cause in vitro toxicity, as evaluated by MTT and TUNEL assays, nor in vivo toxicity as evaluated by histopathology and immunohistochemistry in rabbit eyes.
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Affiliation(s)
| | - Ricardo Noguera Louzada
- 1Federal University of Goias, Goiania, GO Brazil.,Present Address: Instituto de Olhos São Sebastião, Largo do Machado 54, 1208, Rio de Janeiro, RJ 22221-020 Brazil
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Asleh R, Briasoulis A, Kremers WK, Adigun R, Boilson BA, Pereira NL, Edwards BS, Clavell AL, Schirger JA, Rodeheffer RJ, Frantz RP, Joyce LD, Maltais S, Stulak JM, Daly RC, Tilford J, Choi WG, Lerman A, Kushwaha SS. Long-Term Sirolimus for Primary Immunosuppression in Heart Transplant Recipients. J Am Coll Cardiol 2019; 71:636-650. [PMID: 29420960 DOI: 10.1016/j.jacc.2017.12.005] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 12/04/2017] [Accepted: 12/05/2017] [Indexed: 01/09/2023]
Abstract
BACKGROUND Small studies have reported superiority of sirolimus (SRL) over calcineurin inhibitor (CNI) in mitigating cardiac allograft vasculopathy (CAV) after heart transplantation (HT). However, data on the long-term effect on CAV progression and clinical outcomes are lacking. OBJECTIVES The aim of this study was to test the long-term safety and efficacy of conversion from CNI to SRL as maintenance therapy on CAV progression and outcomes after HT. METHODS A cohort of 402 patients who underwent HT and were either treated with CNI alone (n = 134) or converted from CNI to SRL (n = 268) as primary immunosuppression was analyzed. CAV progression was assessed using serial coronary intravascular ultrasound during treatment with CNI (n = 99) and after conversion to SRL (n = 235) in patients who underwent at least 2 intravascular ultrasound studies. RESULTS The progression in plaque volume (2.8 ± 2.3 mm3/mm vs. 0.46 ± 1.8 mm3/mm; p < 0.0001) and plaque index (plaque volume-to-vessel volume ratio) (12.2 ± 9.6% vs. 1.1 ± 7.9%; p < 0.0001) were significantly attenuated when treated with SRL compared with CNI. Over a mean follow-up period of 8.9 years from time of HT, all-cause mortality occurred in 25.6% of the patients and was lower during treatment with SRL compared with CNI (adjusted hazard ratio: 0.47; 95% confidence interval: 0.31 to 0.70; p = 0.0002), and CAV-related events were also less frequent during treatment with SRL (adjusted hazard ratio: 0.35; 95% confidence interval: 0.21 to 0.59; p < 0.0001). Further analyses suggested more attenuation of CAV and more favorable clinical outcomes with earlier conversion to SRL (≤2 years) compared with late conversion (>2 years) after HT. CONCLUSIONS Early conversion to SRL is associated with attenuated CAV progression and with lower long-term mortality and fewer CAV-related events compared with continued CNI use.
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Affiliation(s)
- Rabea Asleh
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Alexandros Briasoulis
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Walter K Kremers
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Rosalyn Adigun
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Barry A Boilson
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Naveen L Pereira
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Brooks S Edwards
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Alfredo L Clavell
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - John A Schirger
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Richard J Rodeheffer
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Robert P Frantz
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Lyle D Joyce
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Simon Maltais
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - John M Stulak
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Richard C Daly
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Jonella Tilford
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Woong-Gil Choi
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Amir Lerman
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota
| | - Sudhir S Kushwaha
- Department of Cardiovascular Diseases and Health Sciences Research and the William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.
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Different Secondary Metabolite Profiles of Phylogenetically almost Identical Streptomyces griseus Strains Originating from Geographically Remote Locations. Microorganisms 2019; 7:microorganisms7060166. [PMID: 31174336 PMCID: PMC6616549 DOI: 10.3390/microorganisms7060166] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/04/2019] [Accepted: 06/04/2019] [Indexed: 12/14/2022] Open
Abstract
As Streptomyces have shown an outstanding capacity for drug production, different campaigns in geographically distant locations currently aim to isolate new antibiotic producers. However, many of these newly isolated Streptomyces strains are classified as identical to already described species. Nevertheless, as discrepancies in terms of secondary metabolites and morphology are possible, we compared two Streptomyces strains with identical 16S rRNA gene sequences but geographically distant origins. Chosen were an Easter Island Streptomyces isolate (Streptomyces sp. SN25_8.1) and the next related type strain, which is Streptomyces griseus subsp. griseus DSM 40236T isolated from Russian garden soil. Compared traits included phylogenetic relatedness based on 16S rRNA gene sequences, macro and microscopic morphology, antibiotic activity and secondary metabolite profiles. Both Streptomyces strains shared several common features, such as morphology and core secondary metabolite production. They revealed differences in pigmentation and in the production of accessory secondary metabolites which appear to be strain-specific. In conclusion, despite identical 16S rRNA classification Streptomyces strains can present different secondary metabolite profiles and may well be valuable for consideration in processes for drug discovery.
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Kanaujia P, Poovizhi P, Ng WK, Tan RBH. Preparation, Characterization and Prevention of Auto-oxidation of Amorphous Sirolimus by Encapsulation in Polymeric Films Using Hot Melt Extrusion. Curr Drug Deliv 2019; 16:663-671. [PMID: 31038065 DOI: 10.2174/1567201816666190416123939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 02/11/2019] [Accepted: 02/22/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Sirolimus (SIR) is a macrocyclic lactone antibiotic and used therapeutically as a potent immunosuppressant for prophylaxis of kidney transplant rejection. The development of an oral dosage form is challenging because of very poor aqueous solubility (2.6µg/ml). The oral bioavailability of SIR is only 15-20 % and is affected by food and other drugs. The main reasons for low bioavailability are intestinal degradation by enzymes especially by cytochrome P4503A4, efflux by P-glycoprotein and hepatic first-pass metabolism. OBJECTIVE The main objective was to prepare a mouth dissolving film dosage form of amorphous SIR to improve dissolution. METHODS Crystalline SIR was transformed to its form amorphous by milling for 2 h at room temperature. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and powder x-ray diffraction (PXRD) were used for characterisation. The stability of amorphous SIR was studied at 4°C and 40°C/75% RH. Amorphous SIR was formulated as oral films by melt extrusion with polyvinylpyrrolidone- vinyl acetate (PVP-VA), Soluplus® and hydroxypropyl cellulose (HPC) as carriers. The films were characterized for drug content, physical state, dissolution profile and stability at 4°C and 40°C/75% RH. RESULTS The PRXD and DSC confirmed the conversion of crystalline SIR to amorphous form by milling. The solubility of amorphous SIR was several folds higher than its crystalline form, but amorphous SIR was highly unstable at all tested temperatures (4° and 40°C). The extruded films exhibited higher dissolution and stability compared to milled SIR powder alone, but the process of extrusion had some detrimental effect on the chemical stability of amorphous SIR. CONCLUSION The film formulations showed a significant improvement in the storage stability of the amorphous form of SIR and the solubility advantage of the amorphous form was evident in the dissolution testing. The oral films can potentially improve the bioavailability of SIR by absorption through the buccal mucosa.
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Affiliation(s)
- Parijat Kanaujia
- Institute of Chemical and Engineering Sciences, 1, Pesek Road Jurong Island, Singapore-627833, Singapore
| | - Ponnammal Poovizhi
- Institute of Chemical and Engineering Sciences, 1, Pesek Road Jurong Island, Singapore-627833, Singapore.,Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, Singapore
| | - Wai Kiong Ng
- Institute of Chemical and Engineering Sciences, 1, Pesek Road Jurong Island, Singapore-627833, Singapore.,Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Reginald B H Tan
- Institute of Chemical and Engineering Sciences, 1, Pesek Road Jurong Island, Singapore-627833, Singapore.,Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, Singapore
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Zhu C, Yang H, Shen L, Zheng Z, Zhao S, Li Q, Yu F, Cen L. Microfluidic preparation of PLGA microspheres as cell carriers with sustainable Rapa release. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2019; 30:737-755. [DOI: 10.1080/09205063.2019.1602930] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Chengcheng Zhu
- Shanghai Key Laboratory of Multiphase Materials Chemical Engineering, State Key Laboratory of Chemical Engineering, Department of Product Engineering, School of Chemical Engineering, East China University of Science and Technology, Shanghai, China
| | - Haibo Yang
- Shanghai Key Laboratory of Multiphase Materials Chemical Engineering, State Key Laboratory of Chemical Engineering, Department of Product Engineering, School of Chemical Engineering, East China University of Science and Technology, Shanghai, China
| | - Liang Shen
- Shanghai Key Laboratory of Multiphase Materials Chemical Engineering, State Key Laboratory of Chemical Engineering, Department of Product Engineering, School of Chemical Engineering, East China University of Science and Technology, Shanghai, China
| | - Zhuoyuan Zheng
- Shanghai Key Laboratory of Multiphase Materials Chemical Engineering, State Key Laboratory of Chemical Engineering, Department of Product Engineering, School of Chemical Engineering, East China University of Science and Technology, Shanghai, China
| | - Shicheng Zhao
- Shanghai Key Laboratory of Multiphase Materials Chemical Engineering, State Key Laboratory of Chemical Engineering, Department of Product Engineering, School of Chemical Engineering, East China University of Science and Technology, Shanghai, China
| | - Qingguo Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengbin Yu
- Department of Orthopaedic Surgery, No. 98 Hospital of PLA, Huzhou, China
| | - Lian Cen
- Shanghai Key Laboratory of Multiphase Materials Chemical Engineering, State Key Laboratory of Chemical Engineering, Department of Product Engineering, School of Chemical Engineering, East China University of Science and Technology, Shanghai, China
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Cabahug VLO, Uy HS, Yu-Keh E, Sapno KJD. Outcomes of treatment with sirolimus for non-infectious uveitis: a meta-analysis and systematic review. Clin Ophthalmol 2019; 13:649-669. [PMID: 31114144 PMCID: PMC6478489 DOI: 10.2147/opth.s198401] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Uveitis is a group of intraocular inflammatory diseases whose primary treatment involves immunosuppression. Although corticosteroids (CSs) remain the mainstay therapy, sirolimus is among the recently studied immunomodulatory drugs for treating noninfectious uveitis (NIU). Objective The aim of this review was to assess and summarize the updated evidence on the outcomes of treatment with sirolimus for NIU. Materials and methods Two reviewers conducted a systematic search on November 5, 2018, of electronic databases (EMBASE, MEDLINE, and The Cochrane Library) and clinical trial registers having no restrictions on language or publication date. The primary outcome was uveitis activity as measured by vitreous haze (VH), while the secondary outcomes included central macular thickness (CMT), best-corrected visual acuity (BCVA), CS-sparing effect, IOP elevation, and other adverse events. A meta-analysis was conducted on selected studies with appropriate clinical and methodological homogeneity. Results Seven studies were included and reviewed. Four randomized clinical trials were eligible for meta-analysis: SAVE 2013, One-year outcomes of the SAVE study, SAVE 2 2016, SAKURA 2016. The pooled proportions of inflammation control (VH improvement) were 38% (95% CI 16.19%-62.66%) during a 6-month follow-up and 49.97% (95% CI 16.19%-83.03%) during a 6- to 12-month follow-up with the latter showing a significantly higher response rate (p=0.0472). BCVA improvement was 62.2% (95% CI 33.17%-87.11%) during a 6-month follow-up and 56.86% (95% CI 20.91%-89.05%) during a 6- to 12-month follow-up with no significant difference between the two (p=0.3705). Increased IOP remained at 7.11% (95% CI 3.46%-12.68%) for both a 6-month follow-up and up to a 12-month follow-up duration. The CS-sparing effect of sirolimus was also well demonstrated. A reduction in CMT was observed, and only minor drug-related adverse events were reported in all the studies reviewed. Conclusion This review provided evidence that sirolimus is a promising treatment option for controlling inflammatory activity, improving visual acuity, and sparing CS use with minor adverse events for NIU.
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Affiliation(s)
| | - Harvey S Uy
- St Luke's Medical Center, Quezon City, Philippines, .,University of the Philippines, Manila, Philippines
| | - Ellen Yu-Keh
- St Luke's Medical Center, Quezon City, Philippines,
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The Effect of Tanreqing Injection on the Pharmacokinetics of Sirolimus in Rats. BIOMED RESEARCH INTERNATIONAL 2019; 2019:1854323. [PMID: 30956975 PMCID: PMC6431440 DOI: 10.1155/2019/1854323] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 12/18/2018] [Accepted: 12/20/2018] [Indexed: 12/30/2022]
Abstract
To evaluate the effect of Tanreqing injection on the pharmacokinetics of sirolimus in rats, a high performance liquid chromatography tandem mass spectrometry method was developed for sirolimus assay in whole blood. Calibration curve of sirolimus was acquired over a concentration ranging from 2.5 to 100 ng/mL with r2= 0.9955. The matrix effects and extraction recoveries of sirolimus ranged from 144% to 152% and from 80% to 96%, respectively. The inter- and intraday relative standard deviations were both <10%. The stability investigation showed that the blood samples were stable for 30-day-storage at −20°C, for 8 h storage at room temperature, for 24 h storage in the auto-sampler at 4°C, and for three freeze-thaw cycle process. The pharmacokinetic results demonstrated that the Cmax, AUC, and AUMC of sirolimus in rats (7.5 mg/kg, i.g.) were increased after beincoadministration with Tanreqing Injection at 2.5, 5.0, and 7.5 mL/kg (i.v.), respectively, or at 5 min, 2 h, and 4 h (5.0 mL/kg, i.v.) after SRL dosing, respectively. For the first time, the results proved the herb-drug interaction between Tanreqing Injection and sirolimus and accordingly suggested avoiding concurrent reception of those two drugs for patients.
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Antitumor Anthraquinones from an Easter Island Sea Anemone: Animal or Bacterial Origin? Mar Drugs 2019; 17:md17030154. [PMID: 30841562 PMCID: PMC6471592 DOI: 10.3390/md17030154] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/26/2019] [Accepted: 02/26/2019] [Indexed: 11/17/2022] Open
Abstract
The presence of two known anthraquinones, Lupinacidin A and Galvaquinone B, which have antitumor activity, has been identified in the sea anemone (Gyractis sesere) from Easter Island. So far, these anthraquinones have been characterized from terrestrial and marine Actinobacteria only. In order to identify the anthraquinones producer, we isolated Actinobacteria associated with the sea anemone and obtained representatives of seven actinobacterial genera. Studies of cultures of these bacteria by HPLC, NMR, and HRLCMS analyses showed that the producer of Lupinacidin A and Galvaquinone B indeed was one of the isolated Actinobacteria. The producer strain, SN26_14.1, was identified as a representative of the genus Verrucosispora. Genome analysis supported the biosynthetic potential to the production of these compounds by this strain. This study adds Verrucosispora as a new genus to the anthraquinone producers, in addition to well-known species of Streptomyces and Micromonospora. By a cultivation-based approach, the responsibility of symbionts of a marine invertebrate for the production of complex natural products found within the animal’s extracts could be demonstrated. This finding re-opens the debate about the producers of secondary metabolites in sea animals. Finally, it provides valuable information about the chemistry of bacteria harbored in the geographically-isolated and almost unstudied, Easter Island.
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High diversity and novelty of Actinobacteria isolated from the coastal zone of the geographically remote young volcanic Easter Island, Chile. Int Microbiol 2019; 22:377-390. [PMID: 30811004 DOI: 10.1007/s10123-019-00061-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 01/08/2019] [Accepted: 01/24/2019] [Indexed: 10/27/2022]
Abstract
Easter Island is an isolated volcanic island in the Pacific Ocean. Despite the extended knowledge about its origin, flora, and fauna, little is known about the bacterial diversity inhabiting this territory. Due to its isolation, Easter Island can be considered as a suitable place to evaluate microbial diversity in a geographically isolated context, what could shed light on actinobacterial occurrence, distribution, and potential novelty. In the present study, we performed a comprehensive analysis of marine Actinobacteria diversity of Easter Island by studying a large number of coastal sampling sites, which were inoculated into a broad spectrum of different culture media, where most important variations in composition included carbon and nitrogen substrates, in addition to salinity. The isolates were characterized on the basis of 16S ribosomal RNA gene sequencing and phylogenetic analysis. High actinobacterial diversity was recovered with a total of 163 pure cultures of Actinobacteria representing 72 phylotypes and 20 genera, which were unevenly distributed in different locations of the island and sample sources. The phylogenetic evaluation indicated a high degree of novelty showing that 45% of the isolates might represent new taxa. The most abundant genera in the different samples were Micromonospora, Streptomyces, Salinispora, and Dietzia. Two aspects appear of primary importance in regard to the high degree of novelty and diversity of Actinobacteria found. First, the application of various culture media significantly increased the number of species and genera obtained. Second, the geographical isolation is considered to be of importance regarding the actinobacterial novelty found.
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Colomb F, Giron LB, Premeaux TA, Mitchell BI, Niki T, Papasavvas E, Montaner LJ, Ndhlovu LC, Abdel-Mohsen M. Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling. Front Immunol 2019; 10:267. [PMID: 30842775 PMCID: PMC6391929 DOI: 10.3389/fimmu.2019.00267] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 01/31/2019] [Indexed: 12/18/2022] Open
Abstract
Endogenous plasma levels of the immunomodulatory carbohydrate-binding protein galectin-9 (Gal-9) are elevated during HIV infection and remain elevated after antiretroviral therapy (ART) suppression. We recently reported that Gal-9 regulates HIV transcription and potently reactivates latent HIV. However, the signaling mechanisms underlying Gal-9-mediated viral transcription remain unclear. Given that galectins are known to modulate T cell receptor (TCR)-signaling, we hypothesized that Gal-9 modulates HIV transcriptional activity, at least in part, through inducing TCR signaling pathways. Gal-9 induced T cell receptor ζ chain (CD3ζ) phosphorylation (11.2 to 32.1%; P = 0.008) in the J-Lat HIV latency model. Lck inhibition reduced Gal-9-mediated viral reactivation in the J-Lat HIV latency model (16.8-0.9%; P < 0.0001) and reduced both Gal-9-mediated CD4+ T cell activation (10.3 to 1.65% CD69 and CD25 co-expression; P = 0.0006), and IL-2/TNFα secretion (P < 0.004) in primary CD4+ T cells from HIV-infected individuals on suppressive ART. Using phospho-kinase antibody arrays, we found that Gal-9 increased the phosphorylation of the TCR-downstream signaling molecules ERK1/2 (26.7-fold) and CREB (6.6-fold). ERK and CREB inhibitors significantly reduced Gal-9-mediated viral reactivation (16.8 to 2.6 or 12.6%, respectively; P < 0.0007). Given that the immunosuppressive rapamycin uncouples HIV latency reversal from cytokine-associated toxicity, we also investigated whether rapamycin could uncouple Gal-9-mediated latency reactivation from its concurrent pro-inflammatory cytokine production. Rapamycin reduced Gal-9-mediated secretion of IL-2 (4.4-fold, P = 0.001) and TNF (4-fold, P = 0.02) without impacting viral reactivation (16.8% compared to 16.1%; P = 0.2). In conclusion, Gal-9 modulates HIV transcription by activating the TCR-downstream ERK and CREB signaling pathways in an Lck-dependent manner. Our findings could have implications for understanding the role of endogenous galectin interactions in modulating TCR signaling and maintaining chronic immune activation during ART-suppressed HIV infection. In addition, uncoupling Gal-9-mediated viral reactivation from undesirable pro-inflammatory effects, using rapamycin, may increase the potential utility of recombinant Gal-9 within the reversal of HIV latency eradication framework.
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Affiliation(s)
- Florent Colomb
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United States
| | - Leila B. Giron
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United States
| | - Thomas A. Premeaux
- Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
| | - Brooks I. Mitchell
- Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
| | - Toshiro Niki
- GalPharma Co. Ltd., Takamatsu-shi, Takamatsu, Japan
- Department of Immunology and Immunopathology, Kagawa University, Takamatsu, Japan
| | - Emmanouil Papasavvas
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United States
| | - Luis J. Montaner
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United States
| | - Lishomwa C. Ndhlovu
- Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
| | - Mohamed Abdel-Mohsen
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United States
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Farjadian F, Ghasemi A, Gohari O, Roointan A, Karimi M, Hamblin MR. Nanopharmaceuticals and nanomedicines currently on the market: challenges and opportunities. Nanomedicine (Lond) 2019; 14:93-126. [PMID: 30451076 PMCID: PMC6391637 DOI: 10.2217/nnm-2018-0120] [Citation(s) in RCA: 324] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 10/15/2018] [Indexed: 12/23/2022] Open
Abstract
There has been a revolution in nanotechnology and nanomedicine. Since 1980, there has been a remarkable increase in approved nano-based pharmaceutical products. These novel nano-based systems can either be therapeutic agents themselves, or else act as vehicles to carry different active pharmaceutical agents into specific parts of the body. Currently marketed nanostructures include nanocrystals, liposomes and lipid nanoparticles, PEGylated polymeric nanodrugs, other polymers, protein-based nanoparticles and metal-based nanoparticles. A range of issues must be addressed in the development of these nanostructures. Ethics, market size, possibility of market failure, costs and commercial development, are some topics which are on the table to be discussed. After passing all the ethical and biological assessments, and satisfying the investors as to future profitability, only a handful of these nanoformulations, successfully obtained marketing approval. We survey the range of nanomedicines that have received regulatory approval and are marketed. We discuss ethics, costs, commercial development and possible market failure. We estimate the global nanomedicine market size and future growth. Our goal is to summarize the different approved nanoformulations on the market, and briefly cover the challenges and future outlook.
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Affiliation(s)
- Fatemeh Farjadian
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz 71468-64685, Iran
| | - Amir Ghasemi
- Department of Materials Science & Engineering, Sharif University of Technology, Tehran 11365-9466, Iran
- Advances Nanobiotechnology & Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran 14496-4535, Iran
| | - Omid Gohari
- Department of Materials Science & Engineering, Sharif University of Technology, Tehran 11365-9466, Iran
| | - Amir Roointan
- Department of Medical Biotechnology, School of Advanced Medical Sciences & Technologies, Shiraz University of Medical Science, Shiraz 71348-14336, Iran
| | - Mahdi Karimi
- Cellular & Molecular Research Center, Iran University of Medical Sciences, Tehran 14496-14535, Iran
- Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14496-14535, Iran
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA
- Harvard – MIT Division of Health Sciences & Technology, Cambridge, MA 02139, USA
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Hosoya M, Saeki T, Saegusa C, Matsunaga T, Okano H, Fujioka M, Ogawa K. Estimating the concentration of therapeutic range using disease-specific iPS cells: Low-dose rapamycin therapy for Pendred syndrome. Regen Ther 2018; 10:54-63. [PMID: 30581897 PMCID: PMC6299162 DOI: 10.1016/j.reth.2018.11.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 10/28/2018] [Accepted: 11/12/2018] [Indexed: 01/31/2023] Open
Abstract
Introduction Pendred syndrome is an autosomal-recessive disease characterized by congenital hearing loss and thyroid goiter. Previously, cell stress susceptibilities were shown to increase in patient-derived cells with intracellular aggregation using an in vitro acute cochlear cell model derived from patient-specific pluripotent stem (iPS) cells. Moreover, we showed that rapamycin can relieve cell death. However, studies regarding long-term cell survival without cell stressors that mimic the natural course of disease or the rational minimum concentration of rapamycin that prevents cell death are missing. Methods In this report, we first investigated the rational minimum concentration of rapamycin using patient-specific iPS cells derived-cochlear cells with three different conditions of acute stress. We next confirmed the effects of rapamycin in long-term cell survival and phenotypes by using cochlear cells derived from three different patient-derived iPS cells. Results We found that inner ear cells derived from Pendred syndrome patients are more vulnerable than those from healthy individuals during long-term culturing; however, this susceptibility was relieved via treatment with low-dose rapamycin. The slow progression of hearing loss in patients may be explained, in part, by the vulnerability observed in patient cells during long-term culturing. We successfully evaluated the rational minimum concentration of rapamycin for treatment of Pendred syndrome. Conclusion Our results suggest that low-dose rapamycin not only decreases acute symptoms but may prevent progression of hearing loss in Pendred syndrome patients.
In vitro chronic disorder model of Pendred syndrome is established. The vulnerability observed during long-term culturing explains progression of PDS. Low-dose rapamycin relief the cell vulnerability observed in PDS patients. PDS iPSCs reveal a rational treatment strategy for chronic progressive hearing loss.
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Affiliation(s)
- Makoto Hosoya
- Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan
| | - Tsubasa Saeki
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan
| | - Chika Saegusa
- Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan
| | - Tatsuo Matsunaga
- The Laboratory of Auditory Disorders and Division of Hearing and Balance Research, National Institute of Sensory Organs, National Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan.,Medical Genetics Center, National Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masato Fujioka
- Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan
| | - Kaoru Ogawa
- Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan
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Tan P, Lau B, Krishnasamy G, Ng M, Husin L, Ruslan N, Song D, Velaithan V, Okuda K, Patel V. Zebrafish embryonic development-interfering macrolides from Streptomyces californicus impact growth and mitochondrial function in human colorectal cancer cells. Process Biochem 2018. [DOI: 10.1016/j.procbio.2018.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Cross Talk Networks of Mammalian Target of Rapamycin Signaling With the Ubiquitin Proteasome System and Their Clinical Implications in Multiple Myeloma. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 343:219-297. [PMID: 30712673 DOI: 10.1016/bs.ircmb.2018.06.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy and results from the clonal amplification of plasma cells. Despite recent advances in treatment, MM remains incurable with a median survival time of only 5-6years, thus necessitating further insights into MM biology and exploitation of novel therapeutic approaches. Both the ubiquitin proteasome system (UPS) and the PI3K/Akt/mTOR signaling pathways have been implicated in the pathogenesis, and treatment of MM and different lines of evidence suggest a close cross talk between these central cell-regulatory signaling networks. In this review, we outline the interplay between the UPS and mTOR pathways and discuss their implications for the pathophysiology and therapy of MM.
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The impact of metabolic reprogramming on dendritic cell function. Int Immunopharmacol 2018; 63:84-93. [PMID: 30075432 DOI: 10.1016/j.intimp.2018.07.031] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 07/24/2018] [Accepted: 07/25/2018] [Indexed: 12/12/2022]
Abstract
Dendritic cells (DCs) are antigen-presenting cells with the ability to activate naïve T cells and direct the adaptive cellular immune response toward a specific profile. This is important, as different pathogens demand specific "profiles" of immune responses for their elimination. Such a goal is achieved depending on the maturation/activation status of DCs by the time of antigen presentation to T cells. Notwithstanding this, recent studies have shown that DCs alter their metabolic program to accommodate the functional changes in gene expression and protein synthesis that follow antigen recognition. In this review, we aim to summarize the data in the literature regarding the metabolic pathways involved with DC phenotypes and their functions.
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