scholarly journals Glioblastoma: a molecular genetic portrait and modern therapeutic strategies for drug treatment

2021 ◽  
Vol 8 (3) ◽  
pp. 60-76
Author(s):  
G. P. Guens ◽  
V. D. Sanikovich ◽  
V. A. Mileyko ◽  
A. A. Lebedeva
Keyword(s):  
Genetic Disorders ◽  
Antiangiogenic Therapy ◽  
Molecular Genetic ◽  
Gene Mutations ◽  
Clinical Results ◽  
Genetic Changes ◽  
Viral Therapy ◽  
The Central Nervous System ◽  
New Treatment ◽  
Methods Of Treatment

Glioblastoma multiforme is the most common and malignant primary tumor of the central nervous system. Despite the existing modern complex therapy and advances in the study of molecular genetic changes in this tumor, the prognosis for patients with glioblastoma is one of the most unfavorable in oncology. This overview reviews existing therapeutic agents and clinical studies of potential drugs for the treatment of patients with glioblastoma multiforme.Next-generation sequencing has become firmly established in the clinical practice of oncologists and allows detecting gene mutations in tumor cells, some of which can serve as targets for therapy. Glioblastoma is characterized by a large number of potentially targeted molecular genetic disorders. As in the case of other solid tumors, targeted and immunotherapy for glioblastomas is being actively studied, including the combination of drugs with physical methods of exposure. To date, new treatment methods of glioblastoma, including antiangiogenic therapy, immunotherapy, oncolytic viral therapy and gene therapy still have uncertain or very modest clinical results. There are many reasons for the lack of progress in the treatment of glioblastoma – from the banal inability of most molecules to overcome the blood-brain barrier to the wide genetic heterogeneity of these tumors. The most promising direction of studies is immunotherapy. But at this stage, we cannot say that there is an effective monotherapy for glioblastoma. The combination treatment with radiation therapy and chemotherapy increases the mutational load, the expression of stress and other factors, therefore, the researchers pin great hopes on the combined methods of treatment.

Molecular and genetic mechanisms of mastocytosis

2019 ◽  
pp. 127-133
Author(s):  
К.М. Шкурлатовская ◽  
А.С. Орлова ◽  
Е.В. Силина ◽  
Т.Г. Синельникова ◽  
О.Ю. Олисова ◽  
...  
Keyword(s):  
Mast Cells ◽  
Intracellular Signaling ◽  
Molecular Genetic ◽  
Gene Mutations ◽  
Good Prognosis ◽  
New Drugs ◽  
Genetic Changes ◽  
Leading Role ◽  
Genetic Mechanisms ◽  
Almost All

Мастоцитоз - группа редких клональных расстройств, характеризующихся аномальной пролиферацией и накоплением неопластических тучных клеток в коже и/или различных внутренних органах. Несмотря на гетерогенность клинической картины и прогноза подтипов заболевания, ведущее звено в патогенезе мастоцитоза занимают молекулярно-генетические дефекты. Практически у всех пациентов с мастоцитозом обнаруживаются мутации в нуклеотидной последовательности гена KIT, чаще всего в виде замены аспарагиновой кислоты на валин в кодоне 816. Данные дефекты наблюдаются как при формах, характеризующихся благоприятным прогнозом, так и при злокачественных подтипах заболевания. Наличие других мутаций, например, в генах TET2, SRSF2, ASXL1, RUNX1, и молекулярно-генетических изменений, вызванных ими, вносят вклад в клинико-патологическое разнообразие мастоцитоза и ассоциировано с более агрессивным течением заболевания. Понимание сложности молекулярно-генетических изменений при мастоцитозе необходимо для выбора наиболее эффективного метода лечения и разработки новых препаратов, способных улучшить прогноз у пациентов c мастоцитозом. В статье представлены основные патогенетические механизмы мастоцитоза. Рассмотрена роль мутаций в гене KIT, а также индуцированные мутациями изменения в рецепторе с-Kit и внутриклеточных сигнальных путях, ответственных за пролиферацию тучных клеток. Mastocytosis is a group of rare clonal disorders characterized by abnormal proliferation and accumulation of neoplastic mast cells in the skin and/or various internal organs. Molecular genetic defects play the leading role in the pathogenesis of mastocytosis despite a significant clinical and prognostic heterogeneity of different forms of this disease. In almost all forms of mastocytosis, patients carry KIT gene mutations, mostly D816V. However, these defects are observed both in forms with good prognosis and in advanced variants of the disease. Mutations in other genes, such as TET2, SRSF2, ASXL1, RUNX1, and the resulting molecular changes contribute to the clinical and pathological heterogeneity of mastocytosis and are associated with a more aggressive disease. Insight into the complexity of molecular and genetic changes in mastocytosis is essential for choosing an optimum treatment and for developing new drugs to improve the outcome of the treatment. The article described major pathogenetic mechanisms of mastocytosis and focused on the role of KIT mutations, conformation of the c-Kit receptor, and intracellular signaling pathways responsible for the proliferation of mast cells.

Management of thoracic aortic lesions - the future is endovascular

VASA ◽  
2012 ◽  
Vol 41 (3) ◽  
pp. 163-176 ◽  
Author(s):  
Weidenhagen ◽  
Bombien ◽  
Meimarakis ◽  
Geisler ◽  
A. Koeppel
Keyword(s):  
Thoracic Aorta ◽  
Clinical Decision Making ◽  
Treatment Options ◽  
Clinical Decision ◽  
Clinical Results ◽  
Treatment Modalities ◽  
Traumatic Rupture ◽  
Descending Thoracic Aorta ◽  
New Treatment ◽  
Aneurysm Dissection

Open surgical repair of lesions of the descending thoracic aorta, such as aneurysm, dissection and traumatic rupture, has been the “state-of-the-art” treatment for many decades. However, in specialized cardiovascular centers, thoracic endovascular aortic repair and hybrid aortic procedures have been implemented as novel treatment options. The current clinical results show that these procedures can be performed with low morbidity and mortality rates. However, due to a lack of randomized trials, the level of reliability of these new treatment modalities remains a matter of discussion. Clinical decision-making is generally based on the experience of the vascular center as well as on individual factors, such as life expectancy, comorbidity, aneurysm aetiology, aortic diameter and morphology. This article will review and discuss recent publications of open surgical, hybrid thoracic aortic (in case of aortic arch involvement) and endovascular repair in complex pathologies of the descending thoracic aorta.

Oncolytic Coxsackievirus and the Mechanisms of its Effects on Cancer: A Narrative Review

2020 ◽  
Vol 16 ◽  
Author(s):  
Ali Ahmadi ◽  
Hadi Esmaeili Gouvarchin Ghaleh ◽  
Ruhollah Dorostkar ◽  
Mahdieh Farzanehpour ◽  
Masoumeh Bolandian
Keyword(s):  
Genetic Disease ◽  
Control Cell ◽  
Gene Mutations ◽  
Therapeutic Agents ◽  
Cell Penetrating Peptides ◽  
Triggered Release ◽  
New Techniques ◽  
Viral Therapy ◽  
Cell Penetrating ◽  
Cancer Cell Targeting

Abstract:: Cancer is a genetic disease triggered by gene mutations, which control cell growth and their functionality inherited from previous generations. The targeted therapy of some tumors was not especially successful. A host of new techniques can be used to treat aptamer-mediated targeting, cancer immunotherapy, cancer stem cell (CSC) therapy, cell-penetrating peptides (CPPs), hormone therapy, intracellular cancer cell targeting, nanoparticles, and viral therapy. These include chemical-analog conjugation, gene delivery, ligand-receptor-based targeting, prodrug therapies, and triggered release strategies. Virotherapy is a biotechnological technique for turning viruses into therapeutic agents by the reprogramming of viruses to cure diseases. In several tumors, including melanoma, multiple myeloma, bladder cancer, and breast cancer, the oncolytic capacity of oncolytic Coxsackievirus has been studied. The present study aims to assess oncolytic Coxsackievirus and its mechanisms of effect on cancer cells.

A bigger brain for a more complex environment

2020 ◽  
Vol 31 (8) ◽  
pp. 803-816
Author(s):  
Umberto di Porzio
Keyword(s):  
Human Brain ◽  
Cognitive Abilities ◽  
Molecular Genetic ◽  
Adult Size ◽  
Genetic Changes ◽  
Cultural Challenges ◽  
Birth Canal ◽  
Newborn Brain ◽  
Neuronal Interactions ◽  
The Brain

AbstractThe environment increased complexity required more neural functions to develop in the hominin brains, and the hominins adapted to the complexity by developing a bigger brain with a greater interconnection between its parts. Thus, complex environments drove the growth of the brain. In about two million years during hominin evolution, the brain increased three folds in size, one of the largest and most complex amongst mammals, relative to body size. The size increase has led to anatomical reorganization and complex neuronal interactions in a relatively small skull. At birth, the human brain is only about 20% of its adult size. That facilitates the passage through the birth canal. Therefore, the human brain, especially cortex, develops postnatally in a rich stimulating environment with continuous brain wiring and rewiring and insertion of billions of new neurons. One of the consequence is that in the newborn brain, neuroplasticity is always turned “on” and it remains active throughout life, which gave humans the ability to adapt to complex and often hostile environments, integrate external experiences, solve problems, elaborate abstract ideas and innovative technologies, store a lot of information. Besides, hominins acquired unique abilities as music, language, and intense social cooperation. Overwhelming ecological, social, and cultural challenges have made the human brain so unique. From these events, as well as the molecular genetic changes that took place in those million years, under the pressure of natural selection, derive the distinctive cognitive abilities that have led us to complex social organizations and made our species successful.

scholarly journals Novel missense mutation of SASH1 in a Chinese family with dyschromatosis universalis hereditaria

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lu Cao ◽  
Ruixue Zhang ◽  
Liang Yong ◽  
Shirui Chen ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Sequence Alignment ◽  
Multiple Sequence Alignment ◽  
Molecular Genetic ◽  
Family Members ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Mendelian Inheritance ◽  
Chinese Family ◽  
Multiple Sequence

Abstract Background Dyschromatosis universalis hereditaria (DUH) is a pigmentary dermatosis characterized by generalized mottled macules with hypopigmention and hyperpigmention. ABCB6 and SASH1 are recently reported pathogenic genes related to DUH, and the aim of this study was to identify the causative mutations in a Chinese family with DUH. Methods Sanger sequencing was performed to investigate the clinical manifestation and molecular genetic basis of these familial cases of DUH, bioinformatics tools and multiple sequence alignment were used to analyse the pathogenicity of mutations. Results A novel missense mutation, c.1529G>A, in the SASH1 gene was identified, and this mutation was not found in the National Center for Biotechnology Information Database of Short Genetic Variation, Online Mendelian Inheritance in Man, ClinVar, or 1000 Genomes Project databases. All in silico predictors suggested that the observed substitution mutation was deleterious. Furthermore, multiple sequence alignment of SASH1 revealed that the p.S510N mutation was highly conserved during evolution. In addition, we reviewed the previously reported DUH-related gene mutations in SASH1 and ABCB6. Conclusion Although the affected family members had identical mutations, differences in the clinical manifestations of these family members were observed, which reveals the complexity of the phenotype-influencing factors in DUH. Our findings reveal the mutation responsible for DUH in this family and broaden the mutational spectrum of the SASH1 gene.

scholarly journals Genetic Approaches Using Zebrafish to Study the Microbiota–Gut–Brain Axis in Neurological Disorders

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 566
Author(s):  
Jae-Geun Lee ◽  
Hyun-Ju Cho ◽  
Yun-Mi Jeong ◽  
Jeong-Soo Lee
Keyword(s):  
Neurological Disorders ◽  
Genetic Model ◽  
Molecular Genetic ◽  
Autism Spectrum ◽  
Behavioral Abnormalities ◽  
Bidirectional Signaling ◽  
Intestinal Dysbiosis ◽  
The Central Nervous System ◽  
The Brain

The microbiota–gut–brain axis (MGBA) is a bidirectional signaling pathway mediating the interaction of the microbiota, the intestine, and the central nervous system. While the MGBA plays a pivotal role in normal development and physiology of the nervous and gastrointestinal system of the host, its dysfunction has been strongly implicated in neurological disorders, where intestinal dysbiosis and derived metabolites cause barrier permeability defects and elicit local inflammation of the gastrointestinal tract, concomitant with increased pro-inflammatory cytokines, mobilization and infiltration of immune cells into the brain, and the dysregulated activation of the vagus nerve, culminating in neuroinflammation and neuronal dysfunction of the brain and behavioral abnormalities. In this topical review, we summarize recent findings in human and animal models regarding the roles of the MGBA in physiological and neuropathological conditions, and discuss the molecular, genetic, and neurobehavioral characteristics of zebrafish as an animal model to study the MGBA. The exploitation of zebrafish as an amenable genetic model combined with in vivo imaging capabilities and gnotobiotic approaches at the whole organism level may reveal novel mechanistic insights into microbiota–gut–brain interactions, especially in the context of neurological disorders such as autism spectrum disorder and Alzheimer’s disease.

scholarly journals Chronic Alcohol Use Induces Molecular Genetic Changes in the Dorsomedial Thalamus of People with Alcohol-Related Disorders

2021 ◽  
Vol 11 (4) ◽  
pp. 435
Author(s):  
Andreas-Christian Hade ◽  
Mari-Anne Philips ◽  
Ene Reimann ◽  
Toomas Jagomäe ◽  
Kattri-Liis Eskla ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Molecular Genetic ◽  
Brain Structures ◽  
Thalamic Nuclei ◽  
Genetic Changes ◽  
Molecular Changes ◽  
Gabaergic Neurotransmission ◽  
And Control ◽  
Upregulated Genes

The Mediodorsal (MD) thalamus that represents a fundamental subcortical relay has been underrepresented in the studies focusing on the molecular changes in the brains of subjects with alcohol use disorder (AUD). In the current study, MD thalamic regions from AUD subjects and controls were analyzed with Affymetrix Clariom S human microarray. Long-term alcohol use induced a significant (FDR ≤ 0.05) upregulation of 2802 transcripts and downregulation of 1893 genes in the MD thalamus of AUD subjects. A significant upregulation of GRIN1 (glutamate receptor NMDA type 1) and FTO (alpha-ketoglutarate dependent dioxygenase) was confirmed in western blot analysis. Immunohistochemical staining revealed similar heterogenous distribution of GRIN1 in the thalamic nuclei of both AUD and control subjects. The most prevalent functional categories of upregulated genes were related to glutamatergic and GABAergic neurotransmission, cellular metabolism, and neurodevelopment. The prevalent gene cluster among down-regulated genes was immune system mediators. Forty-two differentially expressed genes, including FTO, ADH1B, DRD2, CADM2, TCF4, GCKR, DPP6, MAPT and CHRH1, have been shown to have strong associations (FDR p < 10−8) with AUD or/and alcohol use phenotypes in recent GWA studies. Despite a small number of subjects, we were able to detect robust molecular changes in the mediodorsal thalamus caused by alcohol emphasizing the importance of deeper brain structures such as diencephalon, in the development of AUD-related dysregulation of neurocircuitry.

Molecular Genetic Changes in Alveolar Soft Part Sarcoma

1998 ◽  
Vol 18 (6) ◽  
pp. 529-543
Author(s):  
Agnes S. Chan ◽  
Jeremy A. Squire ◽  
Paul Thorner ◽  
Maria Zielenska
Keyword(s):  
Soft Part ◽  
Molecular Genetic ◽  
Alveolar Soft Part Sarcoma ◽  
Genetic Changes
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