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  • 1
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 165.13-165.13
    Abstract: The activity of linsitinib, a small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF-1R), was assessed in a mouse model of Graves’ orbitopathy (GO). GO is the most common extra-thyroidal manifestation of Graves’ disease (GD), which is caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR). Methods: GD was induced in mice by immunization with a human TSHR A-subunit encoding plasmid. Linsitinib was administered orally for four weeks either in parallel to or after disease induction. Endocrine orbitopathy and inflammation were determined by histology and MRI. Results: Immunization with the TSHR A-subunit induced hyperthyroidism, as well as CD3+ T-cell infiltration and macrophage infiltration into orbital muscle/adipose tissue. Linsitinib reduced these effects by up to 80% whether given prophylactically or after disease induction. In addition, linsitinib reduced the formation of brown adipose tissue in the orbit and displayed an additional effect on the immune system. An MRI using F19 imaging confirmed marked orbital inflammation, significant muscle edema and formation of brown fat in experimental GO, events that were abrogated upon application of linsitinib. Linsitinib’s pharmacologic effects were observed at a dose that did not impact the concentration of plasma glucose. Conclusion: Linsitinib improved GO-related endpoints in a TSHR autoantibody dependent mouse model of Graves’ disease. Both prophylactic and therapeutic intervention with linsitinib improved clinically relevant endpoints in the orbita and thyroid gland. Our results are consistent with the therapeutic hypothesis being evaluated in an ongoing Phase 2b clinical study (NCT05276063). This work was funded by Sling Therapeutics, Inc.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    RVK:
    RVK:
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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  • 2
    In: Endocrine Abstracts, Bioscientifica, ( 2022-09-02)
    Type of Medium: Online Resource
    ISSN: 1479-6848
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2022
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  • 3
    In: Frontiers in Endocrinology, Frontiers Media SA, Vol. 14 ( 2023-6-26)
    Abstract: Graves’ disease (GD) is an autoimmune disorder caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR) leading to overstimulation of the thyroid gland. Thyroid eye disease (TED) is the most common extra thyroidal manifestation of GD. Therapeutic options to treat TED are very limited and novel treatments need to be developed. In the present study we investigated the effect of linsitinib, a dual small-molecule kinase inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) and the Insulin receptor (IR) on the disease outcome of GD and TED. Methods Linsitinib was administered orally for four weeks with therapy initiating in either the early (“active”) or the late (“chronic”) phases of the disease. In the thyroid and the orbit, autoimmune hyperthyroidism and orbitopathy were analyzed serologically (total anti-TSHR binding antibodies, stimulating anti TSHR antibodies, total T4 levels), immunohistochemically (H & amp;E-, CD3-, TNFa- and Sirius red staining) and with immunofluorescence (F4/80 staining). An MRI was performed to quantify in vivo tissue remodeling inside the orbit. Results Linsitinib prevented autoimmune hyperthyroidism in the early state of the disease, by reducing morphological changes indicative for hyperthyroidism and blocking T-cell infiltration, visualized by CD3 staining. In the late state of the disease linsitinib had its main effect in the orbit. Linsitinib reduced immune infiltration of T-cells (CD3 staining) and macrophages (F4/80 and TNFa staining) in the orbita in experimental GD suggesting an additional, direct effect of linsitinib on the autoimmune response. In addition, treatment with linsitinib normalized the amount of brown adipose tissue in both the early and late group. An in vivo MRI of the late group was performed and revealed a marked decrease of inflammation, visualized by 19 F MR imaging, significant reduction of existing muscle edema and formation of brown adipose tissue. Conclusion Here, we demonstrate that linsitinib effectively prevents development and progression of thyroid eye disease in an experimental murine model for Graves’ disease. Linsitinib improved the total disease outcome, indicating the clinical significance of the findings and providing a path to therapeutic intervention of Graves’ Disease. Our data support the use of linsitinib as a novel treatment for thyroid eye disease.
    Type of Medium: Online Resource
    ISSN: 1664-2392
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2592084-4
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  • 4
    In: Endocrinology, The Endocrine Society, Vol. 164, No. 2 ( 2022-12-19)
    Abstract: The inflammatory eye disease Graves’ orbitopathy (GO) is the main complication of autoimmune Graves’ disease. In previous studies we have shown that hypoxia plays an important role for progression of GO. Hypoxia can maintain inflammation by attracting inflammatory cells such as macrophages (MQ). Herein, we investigated the interaction of MQ and orbital fibroblasts (OF) in context of inflammation and hypoxia. We detected elevated levels of the hypoxia marker HIF-1α, the MQ marker CD68, and inflammatory cytokines TNFα, CCL2, CCL5, and CCL20 in GO biopsies. Hypoxia stimulated GO tissues to release TNFα, CCL2, and CCL20 as measured by multiplex enzyme-linked immunosorbent assay (ELISA). Further, TNFα and hypoxia stimulated the expression of HIF-1α, CCL2, CCL5, and CCL20 in OF derived from GO tissues. Immunofluorescence confirmed that TNFα-positive MQ were present in the GO tissues. Thus, interaction of M1-MQ with OF under hypoxia also induced HIF-1α, CCL2, and CCL20 in OF. Inflammatory inhibitors etanercept or dexamethasone prevented the induction of HIF-1α and release of CCL2 and CCL20. Moreover, co-culture of M1-MQ/OF under hypoxia enhanced adipogenic differentiation and adiponectin secretion. Dexamethasone and HIF-1α inhibitor PX-478 reduced this effect. Our findings indicate that GO fat tissues are characterized by an inflammatory and hypoxic milieu where TNFα-positive MQ are present. Hypoxia and interaction of M1-MQ with OF led to enhanced secretion of chemokines, elevated hypoxic signaling, and adipogenesis. In consequence, M1-MQ/OF interaction results in constant inflammation and tissue remodeling. A combination of anti-inflammatory treatment and HIF-1α reduction could be an effective treatment option.
    Type of Medium: Online Resource
    ISSN: 1945-7170
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2022
    detail.hit.zdb_id: 2011695-0
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  • 5
    Online Resource
    Online Resource
    Frontiers Media SA ; 2023
    In:  Frontiers in Endocrinology Vol. 14 ( 2023-4-4)
    In: Frontiers in Endocrinology, Frontiers Media SA, Vol. 14 ( 2023-4-4)
    Abstract: Severity of Graves’ orbitopathy (GO) shows wide individual differences. For optimal treatment, it is important to be able to predict the natural course of the disease as accurate as possible to counteract with anti-inflammatory and surgical treatment. Therefore, we aimed to further elucidate the impact of sex, age and smoking on GO. Methods We collected the clinical and demographic data of all patients of our tertiary referral center from January 2008 till December 2018 and analyzed it with descriptive statistics. Only patients with a complete data set were included in the further analysis. Odds ratio’s for moderate-to-severe and sight-threatening GO in relation to age, sex and smoking were calculated by means of multivariate logistic regression models. Results We evaluated the data of 4260 patient with GO and complete data sets. Most of these were women (83%). There were no significant differences between male and female patients regarding smoking habits and thyroid treatment. Men were significantly older at initial manifestation of TED (51.8 vs. 49.9y, p & lt;0.01) and showed significant more often severe stages (61% vs. 53%, p & lt;0.0001). Therefore, they needed significantly more intense treatment with steroids, irradiation, orbital decompression and muscle surgery. In multivariate logistic regression analyses age (OR 0.97, 95% CI:0.97-0.98, p & lt;0.0001), male sex (OR 1.64, 95% CI:1.38-1.9, p & lt;0.0001), smoking (OR 1.19, 95% CI:1.04-1.36, p=0.01), Grave’s disease (OR 1.55, 95% CI:1.26-1.90, p & lt;0.0001) and history of radioiodine treatment (RAI) (OR 2.44, 95% CI:2.10-2.86, p & lt;0.0001) showed an significant association with severe stages of GO. Discussion Our retrospective analysis showed once more that women are more often afflicted by GO. In contrast, men seem to be more severely afflicted and in need of anti-inflammatory and surgical treatments. This might be due to a different approach to the health system and resilience to GO specific symptoms, as well as previously described worse thyroid control. Estrogen mediated effects might also play a role as in other autoimmune diseases and should be subject of further trials. Besides the biological sex, smoking could again be confirmed as serious risk factor for severe GO. Of note, RAI was associated with more severe stages of GO, which should be subject to further investigation.
    Type of Medium: Online Resource
    ISSN: 1664-2392
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2592084-4
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  • 6
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 7, No. Supplement_1 ( 2023-10-05)
    Abstract: Disclosure: A. Gulbins: Grant Recipient; Self; Sling therapeutics, Inc. M. Horstmann: Grant Recipient; Self; Sling therapeutics, Inc. A. Daser: None. U. Flögel: None. M. Oeverhaus: Grant Recipient; Self; Sling therapeutics, Inc. B.E. Nikolaos: None. J.P. Banga: None. G. Krause: None. G.D. Hammer: Research Investigator; Self; Sling therapeutics, Inc. A.G. Spencer: Research Investigator; Self; Sling therapeutics, Inc. R. Zeidan: Research Investigator; Self; Sling therapeutics, Inc. A. Eckstein: Grant Recipient; Self; Sling therapeutics, Inc. S. Philipp: Grant Recipient; Self; Sling therapeutics, Inc. G. Görtz: Grant Recipient; Self; Sling therapeutics, Inc. Study objective: We investigated the effect of linsitinib, a small molecule inhibitor of the Insulin like growth factor 1 receptor (IGF-1R), on Graves’ disease and thyroid eye disease. Graves‘ disease (GD), also known as “Basedow's disease“, is the most common cause for hyperthyroidism, typically presenting in patients between 40-60 years. GD is an autoimmune condition of the thyroid which is caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR). Thyroid eye disease (TED) is the most common extra thyroidal manifestation of GD and occurs in about 50% of the clinical cases. Methods: To induce Graves’ Disease in mice we immunized mice 3-times with a plasmid encoding for the A-subunit of the TSHR. During each active (early) and chronic (late) states of the autoimmune disease, linsitinib was administered orally for four weeks. Endocrine orbitopathy and inflammation were determined by histology and MRI. Results: As seen in the histology, linsitinib prevented autoimmune hyperthyroidism, morphological changes, formation of brown adipose tissue in the orbita and orbital T-cell and macrophage infiltration into the orbit in the active state as well as the chronic phase. To evaluate the effect of linsitinib during the course of therapy, living mice were examined via MRI. A distinctive migration of immune cells in the orbit with consecutive inflammation can be seen in the TSHR-immunized group, which is completely blocked by treatment with linsitinib. In addition, the orbital inflammation was partnered with the onset of muscle edema and formation of brown adipose tissue in TSHR-immunized mice, effects that were abrogated upon application of linsitinib. Conclusion: In summary, we demonstrate the development of GD and TED in a mouse model upon immunization against the TSHR. The IGF-1R antagonist linsitinib blocks the development of the local pathologies of GD and TED in an early and late phase of the autoimmune disorder and also prevents development of the autoimmune response. We show that treatment of immunized mice with linsitinib after disease onset significantly limited the severity of the disease, indicating the clinical significance of the findings and providing a path to therapeutic intervention of Graves’ Disease. Our data support the use of linsitinib as a novel first line treatment of thyroid eye disease. Presentation: Saturday, June 17, 2023
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
    detail.hit.zdb_id: 2881023-5
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  • 7
    In: Endocrine Abstracts, Bioscientifica, ( 2023-08-24)
    Type of Medium: Online Resource
    ISSN: 1479-6848
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2023
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  • 8
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2022
    In:  European Archives of Oto-Rhino-Laryngology Vol. 279, No. 5 ( 2022-05), p. 2401-2407
    In: European Archives of Oto-Rhino-Laryngology, Springer Science and Business Media LLC, Vol. 279, No. 5 ( 2022-05), p. 2401-2407
    Abstract: To determine the outcome after orbital decompression using a graduated technique, adapting the surgical technique according to individual patients’ disease characteristics. Methods We retrospectively examined the postoperative outcome in patients treated with a graduated balanced orbital decompression regarding reduction of proptosis, new onset diplopia and improvement in visual function. 542 patients (1018 orbits) were treated between 2012 and 2020 and included in the study. Clinical examinations including visual acuity, exophthalmometry (Hertel) and orthoptic evaluation were performed preoperatively and at minimum 6 weeks postoperatively. Mean follow-up was 22.9 weeks. Results Mean proptosis values have significantly decreased after surgery ( p   〈  0.01). In 83.3% of the patients Hertel measurement normalized (≤ 18 mm) after surgery, New onset diplopia within 20° of primary position occurred in 33.0% of patients, of whom 16.0% had preoperative double vision in secondary gaze. Patients suffering from dysthyroid optic neuropathy (DON) had a significant increase in visual acuity ( p   〈  0.01). Conclusion We demonstrated that individually adapted graduated orbital decompression successfully improves key disease parameters of Graves’ orbitopathy with low morbidity.
    Type of Medium: Online Resource
    ISSN: 0937-4477 , 1434-4726
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1459042-6
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  • 9
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Ophthalmic Plastic & Reconstructive Surgery Vol. 37, No. 6 ( 2021-11), p. 564-570
    In: Ophthalmic Plastic & Reconstructive Surgery, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. 6 ( 2021-11), p. 564-570
    Abstract: The aim of the study was to identify possible risk factors for new onset diplopia in 20° of primary position (NOD PP) after orbital decompression. A predisposition for NOD has been established for patients with pre-existing diplopia in secondary gaze; therefore, the authors focused on patients without preoperative diplopia. Methods: Retrospective chart review of patients who underwent balanced orbital decompression between 2012 and 2019 due to Graves orbitopathy at the authors’ institution. Exclusion criteria were incomplete clinical data set, revision surgery, and medial or lateral decompression only. The following clinical parameters were evaluated preoperatively and postoperatively: Hertel exophthalmometry, objective measurement of misalignment using the prism-cover-test, assessment of the field of binocular single vision, and measurement of monocular excursions. In addition, the diameter of the extraocular eye muscles was measured in all preoperative CT scans. Results: We included 327 patients (612 orbits), 126 patients (242 orbits) had no preoperative diplopia. In patients with NOD PP (34%, n = 43/126), enlargement of the medial rectus muscle and restriction of abduction and elevation were significantly more frequent than in patients with no NOD PP. The degree of exophthalmos decrease positively correlated with postoperative squint angle. Conclusion: We were able to identify the diameter of the medial rectus muscle, restriction of abduction, and elevation as well as an extensive reduction of exophthalmos as risk factors for NOD PP in patients with no preoperative diplopia.
    Type of Medium: Online Resource
    ISSN: 0740-9303
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2070654-6
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