scholarly journals Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jan Philipp Delling ◽  
Tobias M. Boeckers
Keyword(s):  
Animal Models ◽  
Treatment Options ◽  
Regulation Of Gene Expression ◽  
Treatment Strategies ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Therapeutic Strategies ◽  
Clinical Severity ◽  
Comprehensive Overview ◽  
Increased Risk

Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. Main text This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Conclusions Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.

Neoplastic meningitis: metastases to the leptomeninges and cerebrospinal fluid

2017 ◽  
Author(s):  
Marc C. Chamberlain ◽  
Stephanie E. Combs ◽  
Soichiro Shibui
Keyword(s):  
Cerebrospinal Fluid ◽  
Treatment Options ◽  
Neurological Complications ◽  
Therapeutic Strategies ◽  
Neoplastic Meningitis ◽  
Meningeal Carcinomatosis ◽  
Leptomeningeal Metastases ◽  
Carcinomatous Meningitis ◽  
Fluid Compartment ◽  
Increased Risk

Carcinomatous meningitis or meningeal carcinomatosis is a term that defines leptomeningeal metastases arising as a result of metastases from systemic solid cancers. Similarly, lymphomatous and leukaemic meningitis result from cerebrospinal fluid dissemination of lymphoma or leukaemia. All three entities are commonly referred to as neoplastic meningitis or leptomeningeal metastases due to involvement of both the cerebrospinal fluid compartment as well as the leptomeninges comprised of the pia and arachnoid. Treatment options are limited for these neurological complications and outcomes are generally poor. New therapeutic strategies are desperately needed as more cancer patients survive longer and are at increased risk for neoplastic meningitis.

scholarly journals Small animal models of heart failure

2019 ◽  
Vol 115 (13) ◽  
pp. 1838-1849 ◽  
Author(s):  
Christian Riehle ◽  
Johann Bauersachs
Keyword(s):  
Heart Failure ◽  
Animal Models ◽  
Surgical Techniques ◽  
Treatment Strategies ◽  
Small Animal ◽  
Therapeutic Strategies ◽  
Genetic Modifications ◽  
Small Animal Models ◽  
New Treatment ◽  
Underlying Mechanisms

Abstract Heart disease is a major cause of death worldwide with increasing prevalence, which urges the development of new therapeutic strategies. Over the last few decades, numerous small animal models have been generated to mimic various pathomechanisms contributing to heart failure (HF). Despite some limitations, these animal models have greatly advanced our understanding of the pathogenesis of the different aetiologies of HF and paved the way to understanding the underlying mechanisms and development of successful treatments. These models utilize surgical techniques, genetic modifications, and pharmacological approaches. The present review discusses the strengths and limitations of commonly used small animal HF models, which continue to provide crucial insight and facilitate the development of new treatment strategies for patients with HF.

scholarly journals Thrombocytosis: Diagnostic Evaluation, Thrombotic Risk Stratification, and Risk-Based Management Strategies

Thrombosis ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Jonathan S. Bleeker ◽  
William J. Hogan
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Diagnostic Evaluation ◽  
Diagnostic Process ◽  
Special Focus ◽  
Thrombotic Risk ◽  
Increased Risk

Thrombocytosis is a commonly encountered clinical scenario, with a large proportion of cases discovered incidentally. The differential diagnosis for thrombocytosis is broad and the diagnostic process can be challenging. Thrombocytosis can be spurious, attributed to a reactive process or due to clonal disorder. This distinction is important as it carries implications for evaluation, prognosis, and treatment. Clonal thrombocytosis associated with the myeloproliferative neoplasms, especially essential thrombocythemia and polycythemia vera, carries a unique prognostic profile, with a markedly increased risk of thrombosis. This risk is the driving factor behind treatment strategies in these disorders. Clinical trials utilizing targeted therapies in thrombocytosis are ongoing with new therapeutic targets waiting to be explored. This paper will outline the mechanisms underlying thrombocytosis, the diagnostic evaluation of thrombocytosis, complications of thrombocytosis with a special focus on thrombotic risk as well as treatment options for clonal processes leading to thrombocytosis, including essential thrombocythemia and polycythemia vera.

scholarly journals Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects

2020 ◽  
Vol 20 (1_suppl) ◽  
pp. 23S-30S ◽  
Author(s):  
Stephen F. Traynelis ◽  
Dennis Dlugos ◽  
David Henshall ◽  
Heather C. Mefford ◽  
Michael A. Rogawski ◽  
...  
Keyword(s):  
Animal Models ◽  
Single Gene ◽  
Treatment Options ◽  
Therapeutic Strategies ◽  
Machine Learning Algorithms ◽  
High Rate ◽  
New Approaches ◽  
Human Epilepsy ◽  
Induced Pluripotent ◽  
New Treatments

The goals of Epilepsy Benchmark Area III involve identifying areas that are ripe for progress in terms of controlling seizures and patient symptoms in light of the most recent advances in both basic and clinical research. These goals were developed with an emphasis on potential new therapeutic strategies that will reduce seizure burden and improve quality of life for patients with epilepsy. In particular, we continue to support the proposition that a better understanding of how seizures are initiated, propagated, and terminated in different forms of epilepsy is central to enabling new approaches to treatment, including pharmacological as well as surgical and device-oriented approaches. The stubbornly high rate of treatment-resistant epilepsy—one-third of patients—emphasizes the urgent need for new therapeutic strategies, including pharmacological, procedural, device linked, and genetic. The development of new approaches can be advanced by better animal models of seizure initiation that represent salient features of human epilepsy, as well as humanized models such as induced pluripotent stem cells and organoids. The rapid advances in genetic understanding of a subset of epilepsies provide a path to new and direct patient-relevant cellular and animal models, which could catalyze conceptualization of new treatments that may be broadly applicable across multiple forms of epilepsies beyond those arising from variation in a single gene. Remarkable advances in machine learning algorithms and miniaturization of devices and increases in computational power together provide an enhanced opportunity to detect and mitigate seizures in real time via devices that interrupt electrical activity directly or administer effective pharmaceuticals. Each of these potential areas for advance will be discussed in turn.

scholarly journals The Communication Between Intestinal Microbiota and Ulcerative Colitis: An Exploration of Pathogenesis, Animal Models, and Potential Therapeutic Strategies

2021 ◽  
Vol 8 ◽  
Author(s):  
Yu Hu ◽  
Zhen Ye ◽  
Mingquan Wu ◽  
Yingqi She ◽  
Linzhen Li ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Animal Models ◽  
Effective Treatment ◽  
Intestinal Microbiota ◽  
Therapeutic Potential ◽  
Treatment Strategies ◽  
Therapeutic Strategies ◽  
Sufficient Evidence ◽  
Chronic Inflammatory Bowel Disease ◽  
Preclinical Research

Ulcerative Colitis (UC) is a chronic inflammatory bowel disease. The prolonged course of UC and the lack of effective treatment management make it difficult to cure, affecting the health and life safety of patients. Although UC has received more attention, the etiology and pathogenesis of UC are still unclear. Therefore, it is urgent to establish an updated and comprehensive understanding of UC and explore effective treatment strategies. Notably, sufficient evidence shows that the intestinal microbiota plays an important role in the pathogenesis of UC, and the treating method aimed at improving the balance of the intestinal microbiota exhibits a therapeutic potential for UC. This article reviews the relationship between the genetic, immunological and microbial risk factors with UC. At the same time, the UC animal models related to intestinal microbiota dysbiosis induced by chemical drugs were evaluated. Finally, the potential value of the therapeutic strategies for restoring intestinal microbial homeostasis and treating UC were also investigated. Comprehensively, this study may help to carry out preclinical research, treatment theory and methods, and health management strategy of UC, and provide some theoretical basis for TCM in the treatment of UC.

scholarly journals Intrauterine Viral Infections: Impact of Inflammation on Fetal Neurodevelopment

2021 ◽  
Vol 15 ◽  
Author(s):  
Sourav Ganguli ◽  
Pavithra L. Chavali
Keyword(s):  
Neurodevelopmental Disorders ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Fetal Brain ◽  
Preterm Births ◽  
Autism Spectrum ◽  
Future Research ◽  
Increased Risk ◽  
Mechanistic Basis ◽  
Simplex Virus

Intrauterine viral infections during pregnancy by pathogens such as Zika virus, Cytomegalovirus, Rubella and Herpes Simplex virus can lead to prenatal as well as postnatal neurodevelopmental disorders. Although maternal viral infections are common during pregnancy, viruses rarely penetrate the trophoblast. When they do cross, viruses can cause adverse congenital health conditions for the fetus. In this context, maternal inflammatory responses to these neurotropic pathogens play a significant role in negatively affecting neurodevelopment. For instance, intrauterine inflammation poses an increased risk of neurodevelopmental disorders such as microcephaly, schizophrenia, autism spectrum disorder, cerebral palsy and epilepsy. Severe inflammatory responses have been linked to stillbirths, preterm births, abortions and microcephaly. In this review, we discuss the mechanistic basis of how immune system shapes the landscape of the brain and how different neurotropic viral pathogens evoke inflammatory responses. Finally, we list the consequences of neuroinflammation on fetal brain development and discuss directions for future research and intervention strategies.

scholarly journals Animal models of regenerative medicine for biological treatment approaches of degenerative disc diseases

2020 ◽  
pp. 153537022096912
Author(s):  
Demissew Shenegelegn Mern ◽  
Tanja Walsen ◽  
Anja Beierfuß ◽  
Claudius Thomé
Keyword(s):  
Animal Models ◽  
Biological Treatment ◽  
Chronic Back Pain ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Disc Disease ◽  
Treatment Approaches ◽  
Degenerative Disc ◽  
And Function

Degenerative disc disease (DDD) is a painful, chronic and progressive disease, which is characterized by inflammation, structural and biological deterioration of the intervertebral disc (IVD) tissues. DDD is specified as cell-, age-, and genetic-dependent degenerative process that can be accelerated by environmental factors. It is one of the major causes of chronic back pain and disability affecting millions of people globally. Current treatment options, such as physical rehabilitation, pain management, and surgical intervention, can provide only temporary pain relief. Different animal models have been used to study the process of IVD degeneration and develop therapeutic options that may restore the structure and function of degenerative discs. Several research works have depicted considerable progress in understanding the biological basis of disc degeneration and the therapeutic potentials of cell transplantation, gene therapy, applications of supporting biomaterials and bioactive factors, or a combination thereof. Since animal models play increasingly significant roles in treatment approaches of DDD, we conducted an electronic database search on Medline through June 2020 to identify, compare, and discuss publications regarding biological therapeutic approaches of DDD that based on intradiscal treatment strategies. We provide an up-to-date overview of biological treatment strategies in animal models including mouse, rat, rabbit, porcine, bovine, ovine, caprine, canine, and primate models. Although no animal model could profoundly reproduce the clinical conditions in humans; animal models have played important roles in specifying our knowledge about the pathophysiology of DDD. They are crucial for developing new therapy approaches for clinical applications.

scholarly journals Maternal iodine status in a multi-ethnic UK birth cohort: associations with autism spectrum disorder

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kirsten Jade Cromie ◽  
Diane Erin Threapleton ◽  
Charles Jonathan Peter Snart ◽  
Elizabeth Taylor ◽  
Dan Mason ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Thyroid Hormones ◽  
Iodine Deficiency ◽  
Urinary Iodine ◽  
Fetal Brain ◽  
First Trimester ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Iodine Status ◽  
Increased Risk

Abstract Background Maternal iodine requirements increase during pregnancy to supply thyroid hormones essential for fetal brain development. Maternal iodine deficiency can lead to hypothyroxinemia, a reduced fetal supply of thyroid hormones which, in the first trimester, has been linked to an increased risk of autism spectrum disorder (ASD) in the child. No study to date has explored the direct link between maternal iodine deficiency and diagnosis of ASD in offspring. Methods Urinary iodine concentrations (UIC) and iodine/creatinine ratios (I:Cr) were measured in 6955 mothers at 26–28 weeks gestation participating in the Born in Bradford (BiB) cohort. Maternal iodine status was examined in relation to the probability of a Read (CTV3) code for autism being present in a child’s primary care records through a series of logistic regression models with restricted cubic splines. Results Median (inter-quartile range) UIC was 76 μg/L (46, 120) and I:Cr was 83 μg/g (59, 121) indicating a deficient population according to WHO guidelines. Ninety two children (1·3%) in our cohort had received a diagnosis of ASD by the census date. Overall, there was no evidence to support an association between I:Cr or UIC and ASD risk in children aged 8–12 years (p = 0·3). Conclusions There was no evidence of an increased clinical ASD risk in children born to mothers with mild-to-moderate iodine deficiency at 26 weeks gestation. Alternative functional biomarkers of exposure and a wider range of conditions may provide further insight.

scholarly journals Targeted Therapies in HER2-Positive Breast Cancer - a Systematic Review

Breast Care ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. 173-178 ◽  
Author(s):  
Amelie Schramm ◽  
Nikolaus De Gregorio ◽  
Peter Widschwendter ◽  
Visnja Fink ◽  
Jens Huober
Keyword(s):  
Breast Cancer ◽  
Targeted Therapies ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Her2 Overexpression ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Increased Risk ◽  
Positive Breast Cancer

About 20% of all breast cancer patients have a human epidermal growth factor receptor 2 (HER2)-positive breast tumor. This entity underwent an impressive change in prognosis, with notable improvement of progression-free survival and overall survival. Due to more aggressive tumors and no specific therapy, HER2 overexpression was historically seen as a negative prognostic marker, with worse prognosis and increased risk of recurrent disease. Trastuzumab, the first anti-HER2 antibody, revolutionized the systemic therapy options in HER2-positive breast cancer and initiated several targeted therapies and more personalized treatment strategies. Over the years, multiple HER2-targeting drugs stepped into clinical practice, for the curative as well as the metastatic situation. This review summarizes the targeted treatment options in HER2-positive breast cancer and their current impact in the clinical routine. Results of the most outstanding trials in HER2-targeted therapies and important ongoing trials are subsequently described for an up-to-date overview.

scholarly journals AB5 Enterotoxin-Mediated Pathogenesis: Perspectives Gleaned from Shiga Toxins

Toxins ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 62
Author(s):  
Erika N. Biernbaum ◽  
Indira T. Kudva
Keyword(s):  
Foodborne Pathogens ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Treatment Strategies ◽  
Antibiotic Use ◽  
Fluid Replacement ◽  
Shiga Toxins ◽  
Increased Risk ◽  
Uremic Syndrome ◽  
Primary Focus

Foodborne diseases affect an estimated 600 million people worldwide annually, with the majority of these illnesses caused by Norovirus, Vibrio, Listeria, Campylobacter, Salmonella, and Escherichia coli. To elicit infections in humans, bacterial pathogens express a combination of virulence factors and toxins. AB5 toxins are an example of such toxins that can cause various clinical manifestations, including dehydration, diarrhea, kidney damage, hemorrhagic colitis, and hemolytic uremic syndrome (HUS). Treatment of most bacterial foodborne illnesses consists of fluid replacement and antibiotics. However, antibiotics are not recommended for infections caused by Shiga toxin-producing E. coli (STEC) because of the increased risk of HUS development, although there are conflicting views and results in this regard. Lack of effective treatment strategies for STEC infections pose a public health threat during outbreaks; therefore, the debate on antibiotic use for STEC infections could be further explored, along with investigations into antibiotic alternatives. The overall goal of this review is to provide a succinct summary on the mechanisms of action and the pathogenesis of AB5 and related toxins, as expressed by bacterial foodborne pathogens, with a primary focus on Shiga toxins (Stx). The role of Stx in human STEC disease, detection methodologies, and available treatment options are also briefly discussed.

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