Developing Novel Therapeutic Strategies Against Ring Finger Protein 213 Vasculopathy: Is It an Achievable Goal?
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ABSTRACT:
SUBMITTER: Liu M
PROVIDER: S-EPMC6818045 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
Publications
Developing Novel Therapeutic Strategies Against Ring Finger Protein 213 Vasculopathy: Is It an Achievable Goal?
Liu Minghua M Gutierrez Jose J
Journal of the American Heart Association 20191008 20
See Article Choi et al. ...[more]
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Project description:The aim of this study was to help people comprehensively understand the research advances related to ring finger protein 213 (RNF213) in moyamoya disease (MMD) and to understand the disease at the molecular level to provide a new perspective of the diagnosis of the disease.This review was based on data in articles published between 2005 and 2015 that were retrieved from the PubMed database. The search terms included RNF213, MMD, intracranial major artery stenosis /occlusion (ICASO), genotype, phenotype, mutant and variants, and the combinations of these terms.Articles related to MMD and RNF213 were selected for review, and we also reviewed publications related to ICASO.RNF213 is not only associated with MMD but also associated with intracranial major artery stenosis. In addition, RNF213 variants exhibit apparent ethnic diversity; specifically, the c.14576G>A variant is mainly detected in Korean, Chinese, and Japanese populations, particularly the latter population. The genotypes of RNF213 correlate with the phenotypes of MMD; for example, the homozygous c.14576G>A variant is associated with early-onset, severe symptoms, and an unfavorable prognosis. Furthermore, the RNF213 c.14576G>A variant should be considered during the diagnosis of MMD because no patients with quasi-MMD have been reported to carry the RNF213 c.14576G>A variant whereas 66 of 78 patients with definite MMD have been found to carry this variant.The growing literature demonstrates that MMD is primarily caused by the synergy of genetic and environmental factors, and unknown genetic modifiers might play roles in the etiology of MMD. Further research should be conducted to clarify the pathogenic mechanism of MMD.
| S-EPMC5072264 | biostudies-other
Project description:Recently, thyroid autoantibodies were found to be associated with moyamoya disease (MMD). The ring finger protein 213 (RNF213) p.R4810K variant represents the most important susceptibility genotype of this disease, but its relationship with thyroid autoantibodies remains to be elucidated. Thus, in this study, we aimed to evaluate the clinical relevance of thyroid autoantibodies in each RNF213 genotype in patients with MMD. Included in this study were patients with MMD without a thyroid disease history and in euthyroid status; they were then classified into the mutated or nonmutated based on the RNF213 p.R4810K genotype and positive or negative based on thyroid autoantibody (thyroperoxidase and thyroglobulin) levels. Clinical data of each group were thereafter evaluated. Among the 209 patients, the mutated RNF213 p.R4810K variant and positive thyroid autoantibodies were detected in 155 and 41 patients, respectively. Positive thyroid autoantibodies were found to be more common in the nonmutated patients than in the mutated patients (31.5% vs. 15.5%; P = 0.011). In the mutated patients, as compared to autoantibody-negative patients, autoantibody-positive patients were determined to be more likely to have advanced disease with posterior cerebral artery involvement (54.2% vs. 29.0%; P = 0.017), white matter infarction (58.3% vs. 37.6%; P = 0.046), and a higher modified Rankin Scale at last visit (16.7% vs. 3.1%; P = 0.021). These results suggest that thyroid autoantibodies can act as an immunity inducer in patients with MMD lacking the susceptibility gene RNF213 p.R4810K variant. Moreover, the simultaneous presence of thyroid autoantibodies and the variant seems to aggravate the disease, which indicates synergy between thyroid autoantibodies and the variant.
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Project description:ISG15 is an interferon-stimulated, ubiquitin-like protein that can conjugate to substrate proteins (ISGylation) to counteract microbial infection, but the underlying mechanisms remain elusive. Here, we use a virus-like particle trapping technology to identify ISG15-binding proteins and discover Ring Finger Protein 213 (RNF213) as an ISG15 interactor and cellular sensor of ISGylated proteins. RNF213 is a poorly characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. We report that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We show that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting infection with Listeria monocytogenes, herpes simplex virus 1, human respiratory syncytial virus and coxsackievirus B3, and we observe a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector.
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Project description:Selective estrogen receptor modulators (SERMs), which lack the estrogen steroid moiety yet retain the ability to bind the estrogen receptor (ER), are known to confer mixed ER agonist or antagonist effects depending on the target tissue. The tissue-selective effects of SERMs have led to considerations in the clinical profile of an ideal SERM, which would have ER agonist activity in tissues where mimicking the action of estrogens is desirable, and ER neutral or antagonist activity in tissues estrogens have been shown to adversely stimulate. A number of newer SERMs, including bazedoxifene, lasofoxifene, ospemifene, and arzoxifene, are currently in clinical development for the prevention and treatment of postmenopausal osteoporosis and for other indications. Although the possibility of developing a single agent that has all of the desired characteristics of an ideal SERM seems to be unlikely, progress in the clinical development of SERMs targeted to the ER suggests that these newer compounds may have attributes that represent an improvement relative to existing SERMs. Further clinical investigation will help to clarify the relative benefits and risks of novel SERMs in development within specific indications.
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Project description:The ring finger protein 213 (RNF213) susceptibility gene has been detected in more than 80% of Japanese and Korean patients with moyamoya disease (MMD), a bilateral internal carotid artery (ICA) occlusion. Furthermore, RNF213 has been detected in more than 20% of East Asians with atherosclerotic ICA stenosis. In this study, we evaluated the frequency of RNF213 mutations in congenital occlusive lesions of the ICA system. This case series was conducted jointly at four university hospitals. Patients with a family history of MMD, quasi-MMD, or related diseases were excluded. Ten patients were diagnosed with abnormal ICA or middle cerebral artery (MCA) angiogenesis. Patients with neurofibromatosis were excluded. Finally, nine patients with congenital vascular abnormalities were selected; of these, five had ICA deficiency and four had twig-like MCA. The RNF213 c.14576G > A mutation was absent in all patients. Therefore, the RNF213 c.14576G > A mutation may not be associated with ICA and MCA congenital dysplasia-rare vascular anomalies making it difficult to study a large number of cases. However, an accumulation of cases is required for accurate determination. The results of this study may help differentiate congenital vascular diseases from MMD.
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Project description:BackgroundImmunotherapy has historically been of interest in the management of metastatic renal cell cancer (mRCC) because of its relative chemoresistance and the reproducible but low incidence of spontaneous remission in metastatic disease. Recently, targeted immunotherapies in the form of checkpoint inhibitors have shown durable responses in approximately 20%-30% of patients with solid tumors, with a much more acceptable side-effect profile. Anti-programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 antibodies rely on the presence of host T cells in the tumor microenvironment to be stimulated in order to activate an antitumor response. The presence of tumor antigens augments this stimulation. This has led to further research into combination therapy with anti-PD-1 inhibitors and radiotherapy, chemotherapy, or targeted therapy with the aim of increasing the response rate to these agents.Materials and methodsWe describe three cases of patients with mRCC treated with anti-PD-1 antibody therapy in combination with targeted therapy (bevacizumab), anti-cytotoxic T lymphocyte antigen 4 therapy (ipilimumab), or radiotherapy. We perform a comprehensive literature review on combination immunotherapy and the scope for the future.ResultsTwo patients had a complete clinical response within 3 months of commencing treatment. The third patient had a further significant response to radiotherapy outside the field of treatment after initial response to anti-PD-1 therapy, which lasted for over 12 months.ConclusionWe are now in the era of immunotherapy with promising results in select patients. However, the number of complete remissions with single agents are low. This report demonstrates the potential for combination therapy in mRCC to produce complete responses and improved survival rates. Whether these results equate to cure in a subset of patients requires longer follow-up. Further evaluation of dosing regimens, sequencing methods, and biomarkers to select patient population is required to advance this treatment strategy.Implications for practiceMultiple phase I-III studies exploring the benefit of combination immunotherapy are currently under way. Further research into predictive biomarkers to identify the cohort of patients who gain this benefit is pertinent. This case series demonstrates that the combination of immunotherapy with other treatments can lead to complete responses, even in patients with initially bulky disease. Combination therapy with immunotherapy seems to cause more durable responses in patients with metastatic renal cell cancer compared with monotherapy. Significantly longer follow-up is necessary to determine whether durable complete response confers a cure in a select group of patients.
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Project description:Despite rising interest on the concept of societal resilience and its measurement, little has been done to provide operational indicators. Importantly, an evidence-based approach to assess the suitability of indicators remains unexplored. Furthermore few approaches that exist do not investigate indicators of psychological resilience, which is emerging as an important component of societal resilience to disasters. Disasters are events which overwhelm local capacities, often producing human losses, injury and damage to the affected communities. As climate hazards and disasters are likely to increase in the coming decades, strengthening the capacity of societies to withstand these shocks and recover quickly is vital. In this review, we search the Web of Knowledge to summarize the evidence on indicators of psychological resilience to disasters and provided a qualitative assessment of six selected studies. We find that an evidence-based approach using features from systematic reviews is useful to compile, select and assess the evidence and elucidate robust indicators. We conclude that strong social support received after a disaster is associated with an increased psychological resilience whereas a female gender is connected with a decrease in the likelihood of a resilient outcome. These results are consistent across disaster settings and cultures and are representative of approximately 13 million disaster-exposed civilians of adult age. An approach such as this that collects and evaluates evidence will allow indicators of resilience to be much more revealing and useful in the future. They will provide a robust basis to prioritize indicators to act upon through intersectoral policies and post-disaster public health interventions.
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Project description:Alzheimer's Disease (AD), the most prevalent neurodegenerative disease of aging, affects one in eight older Americans. Nearly all drug treatments tested for AD today have failed to show any efficacy. There is a great need for therapies to prevent and/or slow the progression of AD. The major challenge in AD drug development is lack of clarity about the mechanisms underlying AD pathogenesis and pathophysiology. Several studies support the notion that AD is a multifactorial disease. While there is abundant evidence that amyloid plays a role in AD pathogenesis, other mechanisms have been implicated in AD such as tangle formation and spread, dysregulated protein degradation pathways, neuroinflammation, and loss of support by neurotrophic factors. Therefore, current paradigms of AD drug design have been shifted from single target approach (primarily amyloid-centric) to developing drugs targeted at multiple disease aspects, and from treating AD at later stages of disease progression to focusing on preventive strategies at early stages of disease development. Here, we summarize current strategies and new trends of AD drug development, including pre-clinical and clinical trials that target different aspects of disease (mechanism-based versus non-mechanism based, e.g. symptomatic treatments, lifestyle modifications and risk factor management).
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