UNASSIGNED: Rheumatoid arthritis (RA) is a chronic autoimmune disease affected by genetics and the environment factors. Its early diagnosis and treatment are difficult, and the infection risk is serious. The treatment effects for most patients were not significant, which has become a difficult challenge to overcome. Cell signals play an important role in regulating basic cellular activities such as immunity. Notch signaling is a near secretory signal that can affects many processes of cell normal morphogenesis, including the differentiation of pluripotent progenitor cells, apoptosis, cell proliferation and the formation of cell boundary. In addition, the expression and activation of Notch signaling are increased in the synovial cells and vascular endothelial cells of RA patients. The purpose of this review was to elucidate the related mechanisms of Notch signaling in RA progression, as well as the potential therapeutic value of Notch signaling in a variety of autoimmune diseases.
UNASSIGNED: Literatures about Notch signaling and RA were extensively reviewed to analyze and discuss.
UNASSIGNED: This article briefly reviews the role of Notch signaling in RA. It also summarizes the functional role of Notch signaling in the treatment of RA, with the goal to provide a new treatment option for RA patients.
UNASSIGNED: In this review, the approach we discussed focuses on Notch signaling as a potential therapeutic target against RA, enriching therapeutic strategies for inflammatory diseases including RA.

Cholangiocarcinoma (CCA) is an aggressive type of bile duct cancer that is characterized by a high mortality rate due to its late diagnosis and ineffective treatment. The aim of the present systematic review was to analyze the association between Notch signaling and CCA in terms of its pathogenesis, progression and potential treatment targets. Relevant information was gathered from the PubMed, ScienceDirect and Scopus databases using the search terms \'cholangiocarcinoma\' AND \'Notch signaling\'. Of the 90 articles identified, 28 fulfilled the eligibility criteria and were included in the analysis. It was concluded that overexpression/upregulation of Notch ligands, such as Jagged1 and Notch receptors (Notch1, Notch2 and Notch3), as well as upregulation of the upstream Notch signaling pathway, promoted CCA development and progression. In addition, downregulation of Notch1 signaling through several possible interventions appears to be a promising strategy for inhibition of CCA development and progression. Therefore, the Notch signaling pathway may be considered as a potential target for CCA control.

UNASSIGNED: Vein of Galen malformations (VOGMs) represent a rare pathologic entity with often catastrophic natural history. The advances in endovascular treatment in recent years have allowed for a paradigm shift in the treatment and outcome of these high-flow shunts, even though their pathogenetic mechanisms and evolution remain in part obscure.
UNASSIGNED: The overall management of VOGMs requires a tailored case-to-case approach, starting with in utero detection and reserving endovascular treatment for indicated cases. Lately, the advances in translational research with whole-genome sequencing and the coupling with cellular-level hemodynamics attempt to shed more light in the pathogenesis and evolution of these lesions. At the same time the advances in endovascular techniques allow for more safety and tailored technical strategy planning. Furthermore, the advances in MRI techniques allow a better understanding of their vascular anatomy. In view of these recent advances and by performing a PUBMED literature review of the last 15 years, we attempt a review of the evolutions in the imaging, management, endovascular treatment and understanding of underlying mechanisms for VOGMs.
UNASSIGNED: The progress in the fields detailed in this review appears very promising in better understanding VOGMs and expanding the available therapeutic arsenal.

Notch signaling is an evolutionarily conserved pathway regulating normal embryonic development and homeostasis in a wide variety of tissues. It is also critically involved in carcinogenesis, as well as cancer progression. Activation of the Notch pathway members can be either oncogenic or suppressive, depending on tissue context. The present study is a comprehensive overview, extended with a bioinformatics analysis of TCGA cohorts, including breast, bladder, cervical, colon, kidney, lung, ovary, prostate and rectum carcinomas. We performed global expression profiling of the Notch pathway core components and downstream targets. For this purpose, we implemented the Uniform Manifold Approximation and Projection algorithm to reduce the dimensions. Furthermore, we determined the optimal cutpoint using Evaluate Cutpoint software to established disease-free and overall survival with respect to particular Notch members. Our results demonstrated separation between tumors and their corresponding normal tissue, as well as between tumors in general. The differentiation of the Notch pathway, at its various stages, in terms of expression and survival resulted in distinct profiles of biological processes such as proliferation, adhesion, apoptosis and epithelial to mesenchymal transition. In conclusion, whether oncogenic or suppressive, Notch signaling is proven to be associated with various types of malignancies, and thus may be of interest as a potential therapeutic target.

The Notch pathway involves evolutionarily conserved signaling regulating the development of the female tract organs such as breast, ovary, cervix, and uterine endometrium. A great number of studies revealed Notch aberrancies in association with their carcinogenesis and disease progression, the management of which is still challenging. The present study is a comprehensive review of the available literature on Notch signaling during the normal development and carcinogenesis of the female tract organs. The review has been enriched with our analyses of the TCGA data including breast, cervical, ovarian, and endometrial carcinomas concerning the effects of Notch signaling at two levels: the core components and downstream effectors, hence filling the lack of global overview of Notch-driven carcinogenesis and disease progression. Phenotype heterogeneity regarding Notch signaling was projected in two uniform manifold approximation and projection algorithm dimensions, preceded by the principal component analysis step reducing the data burden. Additionally, overall and disease-free survival analyses were performed with the optimal cutpoint determination by Evaluate Cutpoints software to establish the character of particular Notch components in tumorigenesis. In addition to the review, we demonstrated separate models of the examined cancers of the Notch pathway and its targets, although expression profiles of all normal tissues were much more similar to each other than to its cancerous compartments. Such Notch-driven cancerous differentiation resulted in a case of opposite association with DFS and OS. As a consequence, target genes also show very distinct profiles including genes associated with cell proliferation and differentiation, energy metabolism, or the EMT. In conclusion, the observed Notch associations with the female tract malignancies resulted from differential expression of target genes. This may influence a future analysis to search for new therapeutic targets based on specific Notch pathway profiles.

Understanding and targeting Notch signaling effectively has long been valued in the field of cancer and other immune disorders. Here, we discuss key discoveries at the intersection of Notch signaling, cancer and immunology. While there is a plethora of Notch targeting agents tested in vitro, in vivo and in clinic, undesirable off-target effects and therapy-related toxicities have been significant obstacles. We make a case for the clinical application of ligand-derived and affinity modifying compounds as novel therapeutic agents and discuss major research findings with an emphasis on Notch ligand-specific modulation of immune responses.

Alzheimer\'s disease (AD) is a complex neurodegenerative disease that leads to insidious deterioration of brain functions and is considered the sixth leading cause of death in the world. Alzheimer\'s patients suffer from memory loss, cognitive deficit and behavioral changes; thus, they eventually follow a low-quality life. AD is considered as a multifactorial disorder involving different neuropathological mechanisms. Recent research has identified more than 20 pathological factors that are promoting disease progression. Three significant hypotheses are said to be the root cause of disease pathology, which include acetylcholine deficit, the formation of amyloid-beta senile plaques and tau protein hyperphosphorylation. Apart from these crucial factors, pathological factors such as apolipoprotein E (APOE), glycogen synthase kinase 3β, notch signaling pathway, Wnt signaling pathway, etc., are considered to play a role in the advancement of AD and therefore could be used as targets for drug discovery and development. As of today, there is no complete cure or effective disease altering therapies for AD. The current therapy is assuring only symptomatic relief from the disease, and progressive loss of efficacy for these symptomatic treatments warrants the discovery of newer drugs by exploring these novel drug targets. A comprehensive understanding of these therapeutic targets and their neuropathological role in AD is necessary to identify novel molecules for the treatment of AD rationally.

Colorectal cancer (CRC) has one of the highest mortality rates despite the advancement of treatment options. Aggressive CRC remains difficult to treat owing to the activation of oncogenic signaling pathways such as the Notch signaling pathway. The role of Notch receptors varies according to the difference in their structures; in particular, aberrant activation of Notch1 has been attributed to the severity of CRC. Notch1 activation in CRC is inhibited by small molecule inhibitors that target γ-secretase, an enzyme responsible for the third and last cleavage step of Notch receptors. γ-Secretase also produces the intracellular domain that finally carries out cellular functions by activating downstream effectors. However, most inhibitors block γ-secretase non-selectively and cause severe toxicity. Plant-source-derived small molecules, monoclonal antibodies, biological molecules (such as SiRNAs), and compounds targeting the Notch1 receptor itself or the downstream molecules such as HES1 are some of the options that are in advanced stages of clinical trials. The Negative Regulatory Region (NRR), which plays a central role in the transduction of Notch1 signaling in the event of ligand-dependent and ligand-independent Notch1 processing is also being targeted specifically by monoclonal antibodies (mAbs) to prevent aberrant Notch1 activation. In this review, we discuss the role of Notch1 in CRC, particularly its metastatic phenotype, and how mutations in Notch1, specifically in its NRR region, contribute to the aberrant activation of Notch1 signaling, which, in turn, contributes to CRC pathogenesis. We also discuss prevailing and emerging therapies that target the Notch1 receptor and the NRR region, and we highlight the potential of these therapies in abrogating Notch signaling and, thus, CRC development and progression.

The meeting between Rumi and Shams, in the 13th century, was a turning point in the life of Rumi leading to a revolutionary effect in his thoughts, ideas, and poems. This was an ever-inspiring meeting with many results throughout the centuries. This meeting has created some footprints in cellular and molecular medicine: The discovery of two distinct genes in Drosophila, i.e. Rumi and Shams and their role in controlling Notch signaling, which has a critical role in cell biology. This nomination and the interactions between the two genes has led us to a number of novel studies during the last years. This article reviews the interactions between Rumi and Shams and their effects on Notch signaling in order to find potential novel drugs for pain control through drug development studies in the future.

Bicuspid aortic valve (BAV) disease remains the most common congenital cardiac disease and is associated with an increased risk of potentially fatal aortopathy including aortic aneurysm and dissection. Mutations in the NOTCH1 gene are one of only a few genetic anomalies identified in BAV disease; however evidence for defective NOTCH signaling, and its involvement in the characteristic histological changes of VSMC apoptosis and differentiation in ascending aortae of BAV patients is lacking. This review scrutinizes the evidence for the interactions of NOTCH signaling, cellular differentiation and apoptosis in the context of aortic VSMCs and provides focus for future research efforts in the diagnosis of BAV aortopathy and prevention of catastrophic complications through NOTCH signaling manipulation.