scholarly journals Lessons Learned from Targeting IGF-I Receptor in Thyroid-Associated Ophthalmopathy

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 383
Author(s):  
Joseph A.M.J.L. Janssen ◽  
Terry J. Smith
Keyword(s):  
Paradigm Shift ◽  
Human Monoclonal Antibody ◽  
Lessons Learned ◽  
Graves Disease ◽  
Immunological Mechanisms ◽  
Thyroid Associated Ophthalmopathy ◽  
Igf I ◽  
Attractive Therapeutic Target ◽  
Functional Complex ◽  
Autoimmune Reactivity

Complex immunological mechanisms underlie the pathogenesis of thyroid-associated ophthalmopathy (TAO). Historical models of Graves’ disease and TAO have focused almost entirely on autoimmune reactivity directed against the thyrotropin receptor (TSHR). The insulin-like growth factor-I receptor (IGF-IR) has been proposed as a second participating antigen in TAO by virtue of its interactions with IGFs and anti-IGF-IR antibodies generated in Graves’ disease. Furthermore, the IGF-IR forms with TSHR a physical and functional complex which is involved in signaling downstream from both receptors. Inhibition of IGF-IR activity results in attenuation of signaling initiated at either receptor. Based on the aggregate of findings implicating IGF-IR in TAO, the receptor has become an attractive therapeutic target. Recently, teprotumumab, a human monoclonal antibody IGF-IR inhibitor was evaluated in two clinical trials of patients with moderate to severe, active TAO. Those studies revealed that teprotumumab was safe and highly effective in reducing disease activity and severity. Targeting IGF-IR with specific biologic agents may result in a paradigm shift in the therapy of TAO.

Lessons Learned from ISIS Recruitment in Turkey: A Paradigm Shift in Counterterrorism Is Needed

2021 ◽  
Author(s):  
Suleyman Ozeren ◽  
Suat Cubukcu ◽  
Mehmet F. Bastug
Keyword(s):  
Human Resources ◽  
Open Source ◽  
Paradigm Shift ◽  
Lessons Learned ◽  
Islamic State ◽  
Face To Face ◽  
Rehabilitation Programs ◽  
Transit Country ◽  
Different Levels

The Islamic State of Iraq and Syria (ISIS) has been unprecedentedly effective in recruiting foreign terrorist fighters (FTFs). While Turkey has been a transit country and a major hub for ISIS’s logistical and human resources, it also has become a prolific hotbed for its recruitment. Based on face-to-face interviews and open-source reports, this paper provides an in-depth assessment of ISIS’s recruitment structure and the challenges that Turkey faces in relation to ISIS’s activities and FTFs. We conclude with a set of recommendations and a roadmap for pursuing effective and sustainable policies against ISIS. Overall, Turkey should adopt a paradigm shift on counterterrorism, transform the security and intelligence apparatus, and develop rehabilitation programs that consider the specificity of individuals’ radicalization at different levels.

Polymorphisms of IRAK1 Gene on X Chromosome Is Associated with Hashimoto Thyroiditis in Korean Children

Endocrinology ◽  
2020 ◽  
Vol 161 (8) ◽  
Author(s):  
Hye-Ri Shin ◽  
Won Kyoung Cho ◽  
In-Cheol Baek ◽  
Na Yeong Lee ◽  
Yoon Ji Lee ◽  
...  
Keyword(s):  
X Chromosome ◽  
Hashimoto Thyroiditis ◽  
Categorical Variables ◽  
Graves Disease ◽  
Strong Linkage Disequilibrium ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Korean Children ◽  
Autoimmune Thyroid ◽  
Thyroid Associated Ophthalmopathy

Abstract Autoimmune thyroid disease (AITD) is predominant in females and has been focused on the sexual diploid in immune response. The IL-1 receptor-associated kinase 1 (IRAK1) gene on the X chromosome was recently suggested as strong autoimmune disease-susceptible loci, second to the major histocompatibility complex region. We investigated the frequency of IRAK1 single-nucleotide polymorphisms (SNPs) in children with AITD. In this study, we observed that SNPs of IRAK1 including rs3027898, rs1059703, and rs1059702 in 115 Korean AITD pediatric patients (Graves’ disease = 74 [females = 52/males = 22]; Hashimoto disease [HD] = 41 [females = 38/males = 3]; thyroid-associated ophthalmopathy [TAO] = 40 (females = 27/males = 13); without TAO = 75 (females = 63/males = 12); total males = 25, total females = 90; mean age = 11.9 years) and 204 healthy Korean individuals (males = 104/females = 100). The data from cases and controls were analyzed from separate sex-stratified or all combined by χ 2 test for categorical variables and Student t test for numerical variables. Our study revealed that SNPs of IRAK1-associated HD and without TAO but Graves’ disease and TAO were not found significant. When cases and controls were analyzed by separate sex, we found that rs3027898 AA, rs1059703 AA, and rs1059702 GG showed disease susceptibility in female AITD, HD, and without TAO. Also, all rs3027898, rs1059703, and rs1059702 were found to be in strong linkage disequilibrium (D′ = 0.96-0.98, r2 = 0.83–0.97). The haplotype of 3 SNPs was higher in AITD than in controls (CGA, r2 = 5.42, P = 0.019). Our results suggest that IRAK1 polymorphisms may contribute to the pathogenesis of HD, AITD, and without thyroid-associated ophthalmopathy for females.

scholarly journals Cytokines, Graves' Disease, and Thyroid-Associated Ophthalmopathy

Thyroid ◽  
2008 ◽  
Vol 18 (9) ◽  
pp. 953-958 ◽  
Author(s):  
Andrew G. Gianoukakis ◽  
Nicole Khadavi ◽  
Terry J. Smith
Keyword(s):  
Graves Disease ◽  
Thyroid Associated Ophthalmopathy

Application of New Therapies in Graves' Disease and Thyroid-Associated Ophthalmopathy: Animal Models and Translation to Human Clinical Trials

Thyroid ◽  
2008 ◽  
Vol 18 (9) ◽  
pp. 973-981 ◽  
Author(s):  
J. Paul Banga ◽  
Claus H. Nielsen ◽  
Jacqueline A. Gilbert ◽  
Daniel El Fassi ◽  
Laszlo Hegedus
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Graves Disease ◽  
New Therapies ◽  
Thyroid Associated Ophthalmopathy

Thyroid-Associated Ophthalmopathy in Black South Africans with Graves' Disease

Endocrine ◽  
2000 ◽  
Vol 13 (3) ◽  
pp. 325-328 ◽  
Author(s):  
Barry I. Joffe ◽  
Vanessa R. Panz ◽  
Masayo Yamada ◽  
Jack R. Wall
Keyword(s):  
Graves Disease ◽  
South Africans ◽  
Thyroid Associated Ophthalmopathy ◽  
Black South Africans

scholarly journals 40 YEARS OF IGF1: IGF1 receptor and thyroid-associated ophthalmopathy

2018 ◽  
Vol 61 (1) ◽  
pp. T29-T43 ◽  
Author(s):  
Michelle Mohyi ◽  
Terry J Smith
Keyword(s):  
Graves Disease ◽  
Physical Interaction ◽  
Therapeutic Trial ◽  
Thyrotropin Receptor ◽  
Autoimmune Process ◽  
The Past ◽  
Thyroid Associated Ophthalmopathy ◽  
Upper Face ◽  
Igf1 Receptor ◽  
Orbital Fibroblasts

Thyroid-associated ophthalmopathy (TAO) is a vexing and poorly understood autoimmune process involving the upper face and tissues surrounding the eyes. In TAO, the orbit can become inflamed and undergo substantial remodeling that is disfiguring and can lead to loss of vision. There are currently no approved medical therapies for TAO, the consequence of its uncertain pathogenic nature. It usually presents as a component of the syndrome known as Graves’ disease where loss of immune tolerance to the thyrotropin receptor (TSHR) results in the generation of activating antibodies against that protein and hyperthyroidism. The role for TSHR and these antibodies in the development of TAO is considerably less well established. We have reported over the past 2 decades evidence that the insulin-like growth factorI receptor (IGF1R) may also participate in the pathogenesis of TAO. Activating antibodies against IGF1R have been detected in patients with GD. The actions of these antibodies initiate signaling in orbital fibroblasts from patients with the disease. Further, we have identified a functional and physical interaction between TSHR and IGF1R. Importantly, it appears that signaling initiated from either receptor can be attenuated by inhibiting the activity of IGF1R. These findings underpin the rationale for therapeutically targeting IGF1R in active TAO. A recently completed therapeutic trial of teprotumumab, a human IGF1R inhibiting antibody, in patients with moderate to severe, active TAO, indicates the potential effectiveness and safety of the drug. It is possible that other autoimmune diseases might also benefit from this treatment strategy.

scholarly journals Sepsis—Pathophysiology and Therapeutic Concepts

2021 ◽  
Vol 8 ◽  
Author(s):  
Dominik Jarczak ◽  
Stefan Kluge ◽  
Axel Nierhaus
Keyword(s):  
Paradigm Shift ◽  
Host Response ◽  
Disease Burden ◽  
Therapeutic Approaches ◽  
Immunological Mechanisms ◽  
Therapeutic Concepts ◽  
Threatening Condition ◽  
Life Threatening ◽  
Sepsis And Septic Shock ◽  
Evidence Based Therapy

Sepsis is a life-threatening condition and a global disease burden. Today, the heterogeneous syndrome is defined as severe organ dysfunction caused by a dysregulated host response to infection, with renewed emphasis on immune pathophysiology. Despite all efforts of experimental and clinical research during the last three decades, the ability to positively influence course and outcome of the syndrome remains limited. Evidence-based therapy still consists of basic causal and supportive measures, while adjuvant interventions such as blood purification or targeted immunotherapy largely remain without proof of effectiveness so far. With this review, we aim to provide an overview of sepsis immune pathophysiology, to update the choice of therapeutic approaches targeting different immunological mechanisms in the course of sepsis and septic shock, and to call for a paradigm shift from the pathogen to the host response as a potentially more promising angle.

scholarly journals Teprotumumab Treatment for Thyroid-Associated Ophthalmopathy

2020 ◽  
Vol 9 (Suppl. 1) ◽  
pp. 31-39
Author(s):  
Terry J. Smith
Keyword(s):  
Paradigm Shift ◽  
Vision Loss ◽  
Standard Of Care ◽  
Autoimmune Process ◽  
First Line ◽  
Thyroid Associated Ophthalmopathy ◽  
The Us ◽  
Fundamental Research ◽  
Line Standard

<b><i>Background:</i></b> Thyroid-associated ophthalmopathy (TAO), an autoimmune process affecting the tissues surrounding the eye, most commonly develops in individuals with Graves’ disease. It is disfiguring, can cause vision loss, and dramatically lessens the quality of life in patients. There has been an absence of approved medical therapies for TAO with proven effectiveness and safety in multicenter, placebo-controlled, and adequately powered clinical trials. <b><i>Summary:</i></b> The following is a brief overview of the rationale for developing a monoclonal antibody inhibitor of the insulin-like growth factor-I receptor into a treatment for TAO. This area of fundamental research has yielded an effective and safe medication, namely teprotumumab, based on two multicenter, placebo-controlled trials. Teprotumumab, marketed as Tepezza, has been approved recently by the US Food and Drug Administration for the treatment of TAO. Given its remarkable effectiveness, Tepezza is poised to become the first-line standard of care for TAO. <b><i>Key Messages:</i></b> Introduction of Tepezza into our armamentarium of therapeutic strategies for TAO represents a paradigm shift in the management of the disease. I proffer that the drug will replace glucocorticoids as a first-line treatment for TAO.

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