LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 7 of total 7

Search options

  1. Article ; Online: Aging modulates homeostatic leukocyte trafficking to the peritoneal cavity in a sex-specific manner.

    Hopkin, Sophie J / Pezhman, Laleh / Begum, Jenefa / Kavanagh, Dean / McGettrick, Helen M / Iqbal, Asif J / Chimen, Myriam

    Journal of leukocyte biology

    2023  Volume 114, Issue 4, Page(s) 301–314

    Abstract: Aging is associated with exacerbated systemic inflammation (inflammaging) and the progressive loss of immune system function (immunosenescence). Leukocyte migration is necessary for effective immunity; however, dysregulated trafficking of leukocytes into ...

    Abstract Aging is associated with exacerbated systemic inflammation (inflammaging) and the progressive loss of immune system function (immunosenescence). Leukocyte migration is necessary for effective immunity; however, dysregulated trafficking of leukocytes into tissue contributes to inflammaging and the development of age-related inflammatory diseases. Aging modulates leukocyte trafficking under inflammatory conditions; however, whether aging modulates leukocyte trafficking under homeostatic conditions remains to be elucidated. Although immune responses are evidently sexually dimorphic, limited studies have investigated the effect of sex on age-related changes to leukocyte trafficking processes. Here, we investigated age-related and sex-specific changes to the leukocyte populations within the peritoneal cavity of young (3-mo), middle-aged (18-mo) and old (21-mo) male and female wild-type mice in the steady state. We found an age-related increase in the number of leukocytes within the peritoneal cavity of female mice, predominantly B cells, which may reflect increased trafficking through this tissue with age. This was accompanied by an increased inflammatory environment within the aged cavity, including increased levels of chemoattractants, including B cell chemoattractants CXCL13 and CCL21, soluble adhesion molecules, and proinflammatory cytokines, which was more pronounced in aged female mice. Intravital microscopy techniques revealed altered vascular structure and increased vascular permeability within the peritoneal membrane of aged female mice, which may support increased leukocyte trafficking to the cavity with age. Together, these data indicate that aging affects homeostatic leukocyte trafficking processes in a sex-specific fashion.
    MeSH term(s) Male ; Female ; Animals ; Mice ; Peritoneal Cavity ; Leukocytes ; Inflammation ; Peritoneum ; Chemotactic Factors
    Chemical Substances Chemotactic Factors
    Language English
    Publishing date 2023-06-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1093/jleuko/qiad053
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 603: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  2. Article ; Online: PEPITEM modulates leukocyte trafficking to reduce obesity-induced inflammation.

    Pezhman, Laleh / Hopkin, Sophie J / Begum, Jenefa / Heising, Silke / Nasteska, Daniela / Wahid, Mussarat / Ed Rainger, G / Hodson, David J / Iqbal, Asif J / Chimen, Myriam / McGettrick, Helen M

    Clinical and experimental immunology

    2023  Volume 212, Issue 1, Page(s) 1–10

    Abstract: Dysregulation of leukocyte trafficking, lipid metabolism, and other metabolic processes are the hallmarks that underpin and drive pathology in obesity. Current clinical management targets alternations in lifestyle choices (e.g. exercise, weight loss) to ... ...

    Abstract Dysregulation of leukocyte trafficking, lipid metabolism, and other metabolic processes are the hallmarks that underpin and drive pathology in obesity. Current clinical management targets alternations in lifestyle choices (e.g. exercise, weight loss) to limit the impact of the disease. Crucially, re-gaining control over the pathogenic cellular and molecular processes may offer an alternative, complementary strategy for obese patients. Here we investigate the impact of the immunopeptide, PEPITEM, on pancreas homeostasis and leukocyte trafficking in mice on high-fed obesogenic diet (HFD). Both prophylactic and therapeutic treatment with PEPITEM alleviated the effects of HFD on the pancreas, reducing pancreatic beta cell size. Moreover, PEPITEM treatment also limited T-cell trafficking (CD4+ T-cells and KLRG1+ CD3+ T-cells) to obese visceral, but not subcutaneous, adipose tissue. Similarly, PEPITEM treatment reduced macrophage numbers within the peritoneal cavity of mice on HFD diet at both 6 and 12 weeks. By contrast, PEPITEM therapy elevated numbers of T and B cells were observed in the secondary lymphoid tissues (e.g. spleen and inguinal lymph node) when compared to the untreated HFD controls. Collectively our data highlights the potential for PEPITEM as a novel therapy to combat the systemic low-grade inflammation experienced in obesity and minimize the impact of obesity on pancreatic homeostasis. Thus, offering an alternative strategy to reduce the risk of developing obesity-related co-morbidities, such as type 2 diabetes mellitus, in individuals at high risk and struggling to control their weight through lifestyle modifications.
    MeSH term(s) Mice ; Animals ; Diabetes Mellitus, Type 2/metabolism ; Obesity/complications ; Obesity/metabolism ; Obesity/pathology ; Inflammation/pathology ; Diet ; CD4-Positive T-Lymphocytes/metabolism ; Mice, Inbred C57BL ; Adipose Tissue
    Language English
    Publishing date 2023-03-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218531-3
    ISSN 1365-2249 ; 0009-9104 ; 0964-2536
    ISSN (online) 1365-2249
    ISSN 0009-9104 ; 0964-2536
    DOI 10.1093/cei/uxad022
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.B 337: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  3. Article ; Online: Galectin-9 supports primary T cell transendothelial migration in a glycan and integrin dependent manner.

    Mansour, Adel Abo / Raucci, Federica / Sevim, Mustafa / Saviano, Anella / Begum, Jenefa / Zhi, Zhaogong / Pezhman, Laleh / Tull, Samantha / Maione, Francesco / Iqbal, Asif Jilani

    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

    2022  Volume 151, Page(s) 113171

    Abstract: Adaptive immunity relies on the efficient recruitment of T cells from the blood into peripheral tissues. However, the current understanding of factor(s) coordinating these events is incomplete. Previous studies on galectin-9 (Gal-9), have proposed a ... ...

    Abstract Adaptive immunity relies on the efficient recruitment of T cells from the blood into peripheral tissues. However, the current understanding of factor(s) coordinating these events is incomplete. Previous studies on galectin-9 (Gal-9), have proposed a functionally significant role for this lectin in mediating leukocyte adhesion and transmigration. However, very little is known about its function in T cell migration. Here, we have investigated the role of the Gal-9 on the migration behaviour of both human primary CD4
    MeSH term(s) Animals ; CD8-Positive T-Lymphocytes ; Galectins ; Integrins ; Mice ; Polysaccharides ; Transendothelial and Transepithelial Migration
    Chemical Substances Galectins ; Integrins ; Polysaccharides
    Language English
    Publishing date 2022-05-25
    Publishing country France
    Document type Journal Article
    ZDB-ID 392415-4
    ISSN 1950-6007 ; 0753-3322 ; 0300-0893
    ISSN (online) 1950-6007
    ISSN 0753-3322 ; 0300-0893
    DOI 10.1016/j.biopha.2022.113171
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Ud II Zs.198: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  4. Article ; Online: A reverse translational approach reveals the protective roles of Mangifera indica in inflammatory bowel disease.

    Saviano, Anella / Schettino, Anna / Iaccarino, Nunzia / Mansour, Adel Abo / Begum, Jenefa / Marigliano, Noemi / Raucci, Federica / Romano, Francesca / Riccardi, Gelsomina / Mitidieri, Emma / d'Emmanuele di Villa Bianca, Roberta / Bello, Ivana / Panza, Elisabetta / Smimmo, Martina / Vellecco, Valentina / Rimmer, Peter / Cheesbrough, Jonathan / Zhi, Zhaogong / Iqbal, Tariq H /
    Pieretti, Stefano / D'Amore, Vincenzo Maria / Marinelli, Luciana / La Pietra, Valeria / Sorrentino, Raffaella / Costa, Luisa / Caso, Francesco / Scarpa, Raffaele / Cirino, Giuseppe / Randazzo, Antonio / Bucci, Mariarosaria / McGettrick, Helen Michelle / Iqbal, Asif Jilani / Maione, Francesco

    Journal of autoimmunity

    2024  Volume 144, Page(s) 103181

    Abstract: Inflammatory bowel diseases (IBDs) are chronic intestinal disorders often characterized by a dysregulation of T cells, specifically T helper (Th) 1, 17 and T regulatory (Treg) repertoire. Increasing evidence demonstrates that dietary polyphenols from ... ...

    Abstract Inflammatory bowel diseases (IBDs) are chronic intestinal disorders often characterized by a dysregulation of T cells, specifically T helper (Th) 1, 17 and T regulatory (Treg) repertoire. Increasing evidence demonstrates that dietary polyphenols from Mangifera indica L. extract (MIE, commonly known as mango) mitigate intestinal inflammation and splenic Th17/Treg ratio. In this study, we aimed to dissect the immunomodulatory and anti-inflammatory properties of MIE using a reverse translational approach, by initially using blood from an adult IBD inception cohort and then investigating the mechanism of action in a preclinical model of T cell-driven colitis. Of clinical relevance, MIE modulates TNF-α and IL-17 levels in LPS spiked sera from IBD patients as an ex vivo model of intestinal barrier breakdown. Preclinically, therapeutic administration of MIE significantly reduced colitis severity, pathogenic T-cell intestinal infiltrate and intestinal pro-inflammatory mediators (IL-6, IL-17A, TNF-α, IL-2, IL-22). Moreover, MIE reversed colitis-induced gut permeability and restored tight junction functionality and intestinal metabolites. Mechanistic insights revealed MIE had direct effects on blood vascular endothelial cells, blocking TNF-α/IFN-γ-induced up-regulation of COX-2 and the DP2 receptors. Collectively, we demonstrate the therapeutic potential of MIE to reverse the immunological perturbance during the onset of colitis and dampen the systemic inflammatory response, paving the way for its clinical use as nutraceutical and/or functional food.
    MeSH term(s) Adult ; Humans ; Animals ; Mangifera ; Tumor Necrosis Factor-alpha/metabolism ; Endothelial Cells/metabolism ; Inflammatory Bowel Diseases ; Colitis ; Intestinal Mucosa ; Disease Models, Animal
    Chemical Substances Tumor Necrosis Factor-alpha
    Language English
    Publishing date 2024-03-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639452-8
    ISSN 1095-9157 ; 0896-8411
    ISSN (online) 1095-9157
    ISSN 0896-8411
    DOI 10.1016/j.jaut.2024.103181
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 2368: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  5. Article ; Online: S100A8/A9 drives the formation of procoagulant platelets through GPIbα.

    Colicchia, Martina / Schrottmaier, Waltraud C / Perrella, Gina / Reyat, Jasmeet S / Begum, Jenefa / Slater, Alexandre / Price, Joshua / Clark, Joanne C / Zhi, Zhaogong / Simpson, Megan J / Bourne, Joshua H / Poulter, Natalie S / Khan, Abdullah O / Nicolson, Phillip L R / Pugh, Matthew / Harrison, Paul / Iqbal, Asif J / Rainger, George E / Watson, Steve P /
    Thomas, Mark R / Mutch, Nicola J / Assinger, Alice / Rayes, Julie

    Blood

    2022  Volume 140, Issue 24, Page(s) 2626–2643

    Abstract: S100A8/A9, also known as "calprotectin" or "MRP8/14," is an alarmin primarily secreted by activated myeloid cells with antimicrobial, proinflammatory, and prothrombotic properties. Increased plasma levels of S100A8/A9 in thrombo-inflammatory diseases are ...

    Abstract S100A8/A9, also known as "calprotectin" or "MRP8/14," is an alarmin primarily secreted by activated myeloid cells with antimicrobial, proinflammatory, and prothrombotic properties. Increased plasma levels of S100A8/A9 in thrombo-inflammatory diseases are associated with thrombotic complications. We assessed the presence of S100A8/A9 in the plasma and lung autopsies from patients with COVID-19 and investigated the molecular mechanism by which S100A8/A9 affects platelet function and thrombosis. S100A8/A9 plasma levels were increased in patients with COVID-19 and sustained high levels during hospitalization correlated with poor outcomes. Heterodimeric S100A8/A9 was mainly detected in neutrophils and deposited on the vessel wall in COVID-19 lung autopsies. Immobilization of S100A8/A9 with collagen accelerated the formation of a fibrin-rich network after perfusion of recalcified blood at venous shear. In vitro, platelets adhered and partially spread on S100A8/A9, leading to the formation of distinct populations of either P-selectin or phosphatidylserine (PS)-positive platelets. By using washed platelets, soluble S100A8/A9 induced PS exposure but failed to induce platelet aggregation, despite GPIIb/IIIa activation and alpha-granule secretion. We identified GPIbα as the receptor for S100A8/A9 on platelets inducing the formation of procoagulant platelets with a supporting role for CD36. The effect of S100A8/A9 on platelets was abolished by recombinant GPIbα ectodomain, platelets from a patient with Bernard-Soulier syndrome with GPIb-IX-V deficiency, and platelets from mice deficient in the extracellular domain of GPIbα. We identified the S100A8/A9-GPIbα axis as a novel targetable prothrombotic pathway inducing procoagulant platelets and fibrin formation, in particular in diseases associated with high levels of S100A8/A9, such as COVID-19.
    MeSH term(s) Animals ; Mice ; Blood Platelets/metabolism ; Calgranulin A/metabolism ; COVID-19/metabolism ; Fibrin/metabolism ; Phosphatidylserines/metabolism ; Platelet Aggregation ; Humans ; Calgranulin B/metabolism ; Autopsy ; Platelet Glycoprotein GPIb-IX Complex/metabolism
    Chemical Substances Calgranulin A ; Fibrin (9001-31-4) ; Phosphatidylserines ; S100A9 protein, human ; Calgranulin B ; adhesion receptor ; Platelet Glycoprotein GPIb-IX Complex
    Language English
    Publishing date 2022-08-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2021014966
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.140: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 364: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  6. Article ; Online: New biologic (Ab-IPL-IL-17) for IL-17-mediated diseases: identification of the bioactive sequence (nIL-17) for IL-17A/F function.

    Saviano, Anella / Manosour, Adel Abo / Raucci, Federica / Merlino, Francesco / Marigliano, Noemi / Schettino, Anna / Wahid, Mussarat / Begum, Jenefa / Filer, Andrew / Manning, Julia E / Casillo, Gian Marco / Piccolo, Marialuisa / Ferraro, Maria Grazia / Marzano, Simona / Russomanno, Pasquale / Bellavita, Rosa / Irace, Carlo / Amato, Jussara / Alfaifi, Mohammed /
    Rimmer, Peter / Iqbal, Tariq / Pieretti, Stefano / Vellecco, Valentina / Caso, Francesco / Costa, Luisa / Giacomelli, Roberto / Scarpa, Raffaele / Cirino, Giuseppe / Bucci, Mariarosaria / McGettrick, Helen M / Grieco, Paolo / Iqbal, Asif Jilani / Maione, Francesco

    Annals of the rheumatic diseases

    2023  Volume 82, Issue 11, Page(s) 1415–1428

    Abstract: Objectives: Interleukin (IL) 17s cytokines are key drivers of inflammation that are functionally dysregulated in several human immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), psoriasis and inflammatory bowel disease ( ... ...

    Abstract Objectives: Interleukin (IL) 17s cytokines are key drivers of inflammation that are functionally dysregulated in several human immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), psoriasis and inflammatory bowel disease (IBD). Targeting these cytokines has some therapeutic benefits, but issues associated with low therapeutic efficacy and immunogenicity for subgroups of patients or IMIDs reduce their clinical use. Therefore, there is an urgent need to improve the coverage and efficacy of antibodies targeting IL-17A and/or IL-17F and IL-17A/F heterodimer.
    Methods and results: Here, we initially identified a bioactive 20 amino acid IL-17A/F-derived peptide (nIL-17) that mimics the pro-inflammatory actions of the full-length proteins. Subsequently, we generated a novel anti-IL-17 neutralising monoclonal antibody (Ab-IPL-IL-17) capable of effectively reversing the pro-inflammatory, pro-migratory actions of both nIL-17 and IL-17A/F. Importantly, we demonstrated that Ab-IPL-IL-17 has less off-target effects than the current gold-standard biologic, secukinumab. Finally, we compared the therapeutic efficacy of Ab-IPL-IL-17 with reference anti-IL-17 antibodies in preclinical murine models and samples from patients with RA and IBD. We found that Ab-IPL-IL-17 could effectively reduce clinical signs of arthritis and neutralise elevated IL-17 levels in IBD patient serum.
    Conclusions: Collectively, our preclinical and in vitro clinical evidence indicates high efficacy and therapeutic potency of Ab-IPL-IL-17, supporting the rationale for large-scale clinical evaluation of Ab-IPL-IL-17 in patients with IMIDs.
    MeSH term(s) Humans ; Mice ; Animals ; Interleukin-17 ; Immunomodulating Agents ; Arthritis, Rheumatoid ; Cytokines ; Inflammatory Bowel Diseases/drug therapy ; Biological Products/pharmacology ; Biological Products/therapeutic use
    Chemical Substances Interleukin-17 ; Immunomodulating Agents ; Cytokines ; Biological Products
    Language English
    Publishing date 2023-08-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 7090-7
    ISSN 1468-2060 ; 0003-4967
    ISSN (online) 1468-2060
    ISSN 0003-4967
    DOI 10.1136/ard-2023-224479
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.114: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 167: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  7. Article ; Online: Distinct fibroblast subsets drive inflammation and damage in arthritis.

    Croft, Adam P / Campos, Joana / Jansen, Kathrin / Turner, Jason D / Marshall, Jennifer / Attar, Moustafa / Savary, Loriane / Wehmeyer, Corinna / Naylor, Amy J / Kemble, Samuel / Begum, Jenefa / Dürholz, Kerstin / Perlman, Harris / Barone, Francesca / McGettrick, Helen M / Fearon, Douglas T / Wei, Kevin / Raychaudhuri, Soumya / Korsunsky, Ilya /
    Brenner, Michael B / Coles, Mark / Sansom, Stephen N / Filer, Andrew / Buckley, Christopher D

    Nature

    2019  Volume 570, Issue 7760, Page(s) 246–251

    Abstract: The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs) ...

    Abstract The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs)
    MeSH term(s) Animals ; Arthritis, Rheumatoid/pathology ; Bone and Bones/pathology ; Endopeptidases ; Female ; Fibroblasts/classification ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Gelatinases/metabolism ; Humans ; Inflammation/pathology ; Joints/pathology ; Male ; Membrane Proteins/metabolism ; Mice ; RNA-Seq ; Serine Endopeptidases/metabolism ; Single-Cell Analysis ; Synovial Membrane/pathology ; Thy-1 Antigens/metabolism
    Chemical Substances Membrane Proteins ; Thy-1 Antigens ; Endopeptidases (EC 3.4.-) ; Serine Endopeptidases (EC 3.4.21.-) ; fibroblast activation protein alpha (EC 3.4.21.-) ; Gelatinases (EC 3.4.24.-)
    Language English
    Publishing date 2019-05-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-019-1263-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 26: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 9: Show issues
    Zs.MO 244: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

To top