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  • 1
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    Online Resource
    Abstract 3232: In vitro cell based cytotoxicity and T cell activation assays to assess safety and efficacy of engineered T cell therapies
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3232-3232
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3232-3232
    Abstract: Chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells are part of a big wave of immunotherapies showing great promise in cancer clinical trials. With the first T cell based therapies targeting hematological malignances now approved, their next challenge is solid tumors. Solid tumors create an additional challenge due to the lack of tumor specific target antigens, posing significant safety risks, i.e. on-target on-tumor, on-target off-tumor and off-target toxicities. Toxic effects previously reported vary from mild-severe cytokine release syndrome (CRS) to neurotoxicity and death. We have developed in vitro assays utilizing primary human cells from healthy tissue and/or differentiated iPCS-derived cells to assess on-target off-tumor and/or off-target cytotoxicity for engineered T cell therapies. The presence of CAR-T cell mediated cytotoxicity was measured through co-culture with healthy human primary cells to assess unwanted CAR-T reactivity as well as a high target antigen expressing control cancer cell line to confirm CAR-T functionality. The human primary cell type was selected based on its potential safety risk by establishing low level protein expression of the target antigen. Readouts included IFNγ production determined by MesoScale Discovery platform as a measure of T cell activation and Hoechst/PI staining of target cells by flow cytometry. Our study generated high quality data of the CAR-T cell, confirming functionality by showing consistent T cell activation and killing against a positive control cell line. Moreover, we were able establish a clear absence of activity against the primary human cells thus providing insight into the safety of the CAR-T therapy. The developed safety assays provide a robust and rapid platform to assess on-target off-tumor and off-target effects within immuno-oncology therapies, either TCR or CAR-T cells, in both early stage development or late stage testing of the therapeutic product. Through inclusion of a wide range of human primary cells, both high risk tissues and major organs at risk of off-target toxicity, a clear safety profile can be generate in vitro for these novel T cell therapies. Safety risks associated with cell based IO-therapies is the biggest challenge for the success of these therapies, performing a thorough safety screen on healthy primary human tissues is therefore crucial. Citation Format: Sanne Holt, Sophie Vermond, Monique Hazenoot Hazenoot, Jeroen Overman, Jamil Aarbiou Aarbiou, Jeroen DeGroot DeGroot. In vitro cell based cytotoxicity and T cell activation assays to assess safety and efficacy of engineered T cell therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3232.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-3232
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
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    Biochemical markers of bone turnover and their association with bone marrow lesions
    Springer Science and Business Media LLC ; 2008
    In:  Arthritis Research & Therapy Vol. 10, No. 4 ( 2008), p. R102-
    Details
    In: Arthritis Research & Therapy, Springer Science and Business Media LLC, Vol. 10, No. 4 ( 2008), p. R102-
    Type of Medium: Online Resource
    ISSN: 1478-6354
    URL: Article
    DOI: 10.1186/ar2494
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2008
    detail.hit.zdb_id: 2041668-4
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  • 3
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    Profiling of Endogenous Peptides in Human Synovial Fluid by NanoLC-MS: Method Validation and Peptide Identification
    American Chemical Society (ACS) ; 2007
    In:  Journal of Proteome Research Vol. 6, No. 11 ( 2007-11-01), p. 4388-4396
    Details
    In: Journal of Proteome Research, American Chemical Society (ACS), Vol. 6, No. 11 ( 2007-11-01), p. 4388-4396
    Type of Medium: Online Resource
    ISSN: 1535-3893 , 1535-3907
    URL: Article
    URL: Article
    DOI: 10.1021/pr0704534
    DOI: 10.1021/pr0704534.s001
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2007
    detail.hit.zdb_id: 2065254-9
    SSG: 12
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  • 4
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    Comprehensive LC–MS E Lipidomic Analysis using a Shotgun Approach and Its Application to Biomarker Detection and Identification in Osteoarthritis Patients
    American Chemical Society (ACS) ; 2011
    In:  Journal of Proteome Research Vol. 10, No. 7 ( 2011-07-01), p. 3303-3308
    Details
    In: Journal of Proteome Research, American Chemical Society (ACS), Vol. 10, No. 7 ( 2011-07-01), p. 3303-3308
    Type of Medium: Online Resource
    ISSN: 1535-3893 , 1535-3907
    URL: Article
    DOI: 10.1021/pr200420k
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2011
    detail.hit.zdb_id: 2065254-9
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  • 5
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    Age-related accumulation of Maillard reaction products in human articular cartilage collagen
    Portland Press Ltd. ; 2000
    In:  Biochemical Journal Vol. 350, No. 2 ( 2000-09-01), p. 381-387
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 350, No. 2 ( 2000-09-01), p. 381-387
    Abstract: Non-enzymic modification of tissue proteins by reducing sugars, the so-called Maillard reaction, is a prominent feature of aging. In articular cartilage, relatively high levels of the advanced glycation end product (AGE) pentosidine accumulate with age. Higher pentosidine levels have been associated with a stiffer collagen network in cartilage. However, even in cartilage, pentosidine levels themselves represent & lt; 1 cross-link per 20 collagen molecules, and as such cannot be expected to contribute substantially to the increase in collagen network stiffness. In the present study, we investigated a broad range of Maillard reaction products in cartilage collagen in order to determine whether pentosidine serves as an adequate marker for AGE levels. Not only did the well-characterized AGEs pentosidine, Nε-(carboxymethyl)lysine, and Nε-(carboxyethyl)lysine increase with age in cartilage collagen (all P & lt; 0.0001), but also general measures of AGE cross-linking, such as browning and fluorescence (both P & lt; 0.0001), increased. The levels of these AGEs are all higher in cartilage collagen than in skin collagen. As a functional measure of glycation the digestibility of articular collagen by bacterial collagenase was investigated; digestibility decreased linearly with age, proportional to the extent of glycation. Furthermore, the arginine content and the sum of the hydroxylysine and lysine content of cartilage collagen decrease significantly with age (P & lt; 0.0001 and P & lt; 0.01 respectively), possibly due to modification by the Maillard reaction. The observed relationship between glycation and amino acid modification has not been reported previously in vivo. Our present results indicate that extensive accumulation of a variety of Maillard reaction products occurs in cartilage collagen with age. Altogether our results support the hypothesis that glycation contributes to stiffer and more brittle cartilage with advancing age.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj3500381
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2000
    detail.hit.zdb_id: 1473095-9
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  • 6
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    Elevation of cartilage AGEs does not accelerate initiation of canine experimental osteoarthritis upon mild surgical damage
    Wiley ; 2012
    In:  Journal of Orthopaedic Research Vol. 30, No. 9 ( 2012-09), p. 1398-1404
    Details
    In: Journal of Orthopaedic Research, Wiley, Vol. 30, No. 9 ( 2012-09), p. 1398-1404
    Abstract: Osteoarthritis is a highly prevalent disease, age being the main risk factor. The age‐related accumulation of advanced‐glycation‐endproducts (AGEs) adversely affects the mechanical and biochemical properties of cartilage. The hypothesis that accumulation of cartilage AGEs in combination with surgically induced damage predisposes to the development of osteoarthritis was tested in vivo in a canine model. To artificially increase cartilage AGEs, right knee joints of eight dogs were repeatedly injected with ribose/threose (AGEd‐joints). Left joints with vehicle alone served as control. Subsequently, minimal surgically applied cartilage damage was induced and loading restrained as much as possible. Thirty weeks after surgery, joint tissues of all dogs were analyzed for biochemical and histological features of OA. Cartilage pentosidine levels were ∼5‐fold enhanced ( p  = 0.001 vs. control‐joints). On average, no statistically significant differences in joint degeneration were found between AGEd and control‐joints. Enhanced cartilage pentosidine levels did correlate with less cartilage proteoglycan release ( R  = −0.762 and R  = −0.810 for total and newly‐formed proteoglycans, respectively; p  = 0.028 and 0.015 for both). The current data support the diminished cartilage turnover, but only a tendency towards enhanced cartilage damage in AGEd articular cartilage was observed. As such, elevated AGEs do not unambiguously accelerate the development of early canine OA upon minimal surgical damage. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1398–1404, 2012
    Type of Medium: Online Resource
    ISSN: 0736-0266 , 1554-527X
    URL: Issue
    URL: Article
    DOI: 10.1002/jor.v30.9
    DOI: 10.1002/jor.22092
    Language: English
    Publisher: Wiley
    Publication Date: 2012
    detail.hit.zdb_id: 2050452-4
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  • 7
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    Age-related accumulation of pentosidine in aggrecan and collagen from normal and degenerate human intervertebral discs
    Portland Press Ltd. ; 2006
    In:  Biochemical Journal Vol. 399, No. 1 ( 2006-10-01), p. 29-35
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 399, No. 1 ( 2006-10-01), p. 29-35
    Abstract: During aging and degeneration, many changes occur in the structure and composition of human cartilaginous tissues, which include the accumulation of the AGE (advanced glycation end-product), pentosidine, in long-lived proteins. In the present study, we investigated the accumulation of pentosidine in constituents of the human IVD (intervertebral disc), i.e. collagen, aggrecan-derived PG (proteoglycan) (A1) and its fractions (A1D1–A1D6) in health and pathology. We found that, after maturity, pentosidine accumulates with age. Over the age range studied, a linear 6-fold increase was observed in pentosidine accumulation for A1 and collagen with respective rates of 0.12 and 0.66 nmol·(g of protein)−1·year−1. Using previously reported protein turnover rate constants (kT) obtained from measurements of the D-isomer of aspartic residue in collagen and aggrecan of human IVD, we could calculate the pentosidine formation rate constants (kF) for these constituents [Sivan, Tsitron, Wachtel, Roughley, Sakkee, van der Ham, DeGroot, Roberts and Maroudas (2006) J. Biol. Chem. 281, 13009–13014; Tsitron (2006) MSc Thesis, Technion-Israel Institute of Technology, Haifa, Israel]. In spite of the comparable formation rate constants obtained for A1D1 and collagen [1.81±0.25 compared with 3.71±0.26 μmol of pentosidine·(mol of lysine)−1·year−1 respectively] , the higher pentosidine accumulation in collagen is consistent with its slower turnover (0.005 year−1 compared with 0.134 year−1 for A1D1). Pentosidine accumulation increased with decreasing buoyant density and decreasing turnover of the proteins from the most glycosaminoglycan-rich PG components (A1D1) to the least (A1D6), with respective kF values of 1.81±0.25 and 3.18±0.37 μmol of pentosidine·(mol of lysine)−1·year−1. We concluded that protein turnover is an important determinant of pentosidine accumulation in aggrecan and collagen of human IVD, as was found for articular cartilage. Correlation of pentosidine accumulation with protein half-life in both normal and degenerate discs further supports this finding.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20060579
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2006
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 8
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    Similarities and discrepancies in subchondral bone structure in two differently induced canine models of osteoarthritis
    Wiley ; 2010
    In:  Journal of Bone and Mineral Research Vol. 25, No. 7 ( 2010-07), p. 1650-1657
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 25, No. 7 ( 2010-07), p. 1650-1657
    Abstract: In osteoarthritis (OA), cartilage degradation is accompanied by subchondral bone changes. The pathogenesis and physiology of bone changes in OA are still unclear. The changes in subchondral bone architecture and cartilage damage were compared in differently induced experimental models of OA. Experimental OA was induced bilaterally by anterior cruciate ligament transection (ACLT) or by cartilage trauma (Groove model); bilateral sham surgery served as control. Lysylpyridinoline (LP, bone resorption) and C‐telopeptide of type II collagen (CTX‐II, cartilage breakdown) were measured over time. At 20 weeks after surgery, the subchondral cortical plate and trabecular bone of the tibia were analyzed by micro–computed tomography (µCT) and cartilage degeneration was analyzed histologically and biochemically. In both models, cartilage degeneration and cortical subchondral plate thinning were present. CTX‐II levels were elevated over time in both models. Subchondral trabecular bone changes were observed only in the ACLT model, not in the Groove model. Correspondingly, LP levels were elevated over time in the ACLT model and not in the Groove model. Interestingly, the trabecular bone changes in the ACLT model were extended to the metaphyseal area. The early decrease in plate thickness, present in both models, as was cartilage damage, suggests that plate thinning is a phenomenon that is intrinsic to the process of OA independent of the cause/induction of OA. On the other hand, trabecular changes in subchondral and metaphyseal bone are not part of a common pathway of OA development and may be induced biomechanically in the destabilized and less loaded ACLT joint. © 2010 American Society for Bone and Mineral Research
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 1523-4681
    URL: Issue
    URL: Article
    DOI: 10.1002/jbmr.v25:7
    DOI: 10.1002/jbmr.39
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 2010
    detail.hit.zdb_id: 2008867-X
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  • 9
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    Corticosteroids Reduce the Tensile Strength of Isolated Collagen Fascicles
    SAGE Publications ; 2006
    In:  The American Journal of Sports Medicine Vol. 34, No. 12 ( 2006-12), p. 1992-1997
    Details
    In: The American Journal of Sports Medicine, SAGE Publications, Vol. 34, No. 12 ( 2006-12), p. 1992-1997
    Abstract: Overuse tendon injuries are frequent. Corticosteroid injections are commonly used as treatment, although their direct effects on the material properties of the tendon are poorly understood. Purpose To examine the influence of corticosteroids on the tensile strength of isolated collagen fascicles. Study Design Controlled laboratory study. Methods Single strands (300-500 [.mu]m) of rat-tail collagen fascicles were incubated in either high (1 mL of 40 mgmL-1 mixed with 0.5 mL saline 9%) or low (1 mL of 40 mgmL-1 mixed with 2 mL saline 9%) concentration of methylprednisolone acetate (Depomedrol) for 3 or 7 days, while the control segment from the same fascicle was kept in saline (N = 64). After the incubation period, the fascicles underwent displacement to failure in a mechanical test rig at 0.13 mm/s, and thereafter hydroxylysyl pyridinoline and lysyl pyridinoline cross-link content was evaluated in a high-performance liquid chromatography system. Data for each group were analyzed with a 2-way analysis of variance (time × incubation) for ultimate stress (mean ± standard deviation). Results In the high-concentration groups, strength was reduced after 3 (16.6 ± 4.6 MPa) and 7 (8.6 ± 1.7 MPa) days compared to the controls (30.2 ± 5.0 MPa and 25.6 ± 4.6 MPa, respectively; P 〈 . 05). In the low-concentration groups, strength was reduced after 3 (12.0 ± 3.1 MPa) and 7 days (10.9 ± 2.5 MPa) compared to the controls (31.5 ± 5.0 MPa and 32.4 ± 5.6 MPa, respectively; P 〈 . 05). The amount of cross-linking was unaffected by the intervention. Conclusion Data show that the tensile strength of isolated fascicles is markedly reduced after 3-and 7-day incubation in both high and low concentration of corticosteroids, although the observed effect on whole tendon remains unknown. Clinical Relevance Corticosteroids may weaken specific regions of the injected tendon and leave it more prone to rupture. This weakening effect is manifested in the individual collagen fascicles that constitute the tendon.
    Type of Medium: Online Resource
    ISSN: 0363-5465 , 1552-3365
    URL: Article
    DOI: 10.1177/0363546506290402
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2006
    detail.hit.zdb_id: 2063945-4
    SSG: 31
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  • 10
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    Achilles Tendinosis : Changes in Biochemical Composition and Collagen Turnover Rate
    SAGE Publications ; 2007
    In:  The American Journal of Sports Medicine Vol. 35, No. 9 ( 2007-09), p. 1549-1556
    Details
    In: The American Journal of Sports Medicine, SAGE Publications, Vol. 35, No. 9 ( 2007-09), p. 1549-1556
    Abstract: Understanding biochemical and structural changes of the extracellular matrix in Achilles tendinosis might be important for developing mechanism-based therapies. Hypothesis In Achilles tendinosis, changes occur in biochemical composition and collagen turnover rate. Study Design Descriptive laboratory study. Methods From 10 patients undergoing surgery for Achilles tendinopathy, 1 tendinosis biopsy specimen and 1 biopsy specimen of macroscopically healthy tendon tissue adjacent to the lesion were collected. Furthermore, biopsy samples were collected from 3 donors with asymptomatic Achilles tendons. Water content, collagen content, percentage of denatured collagen, amount of lysine hydroxylation, number of enzymatic and nonenzymatic crosslinks, matrix metalloproteinase activity, and matrix metalloproteinase and collagen gene-expression levels were analyzed. Results In tendinotic lesions, the water content was highest, and collagen content was subnormal with higher amounts of denatured/damaged collagen. Low pentosidine levels in tendinotic tissue indicated the presence of relatively young collagenous matrix. More hydroxylated lysine residues were present in tendinotic samples, but enzymatic crosslinks revealed no differences between tendinotic, adjacent, and healthy samples. In tendinotic specimens, matrix metalloproteinase activity was higher, matrix metalloproteinase gene-expression profile was altered, and collagen type I and III gene expression were upregulated. Conclusion In Achilles tendinosis, the collagen turnover rate is increased, and the natural biochemical composition of the collagenous matrix is compromised. Clinical Relevance Although tendon tissue directly adjacent to an Achilles tendinosis lesion looks macroscopically healthy, histological and biochemical degenerative changes in adjacent tissue are evident, which may have implications for surgical interventions.
    Type of Medium: Online Resource
    ISSN: 0363-5465 , 1552-3365
    URL: Article
    DOI: 10.1177/0363546507301885
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2007
    detail.hit.zdb_id: 2063945-4
    SSG: 31
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