scholarly journals Development of Therapies for Rare Genetic Disorders of GPX4: Roadmap and Opportunities

2021 ◽  
Author(s):  
Dorian Cheff ◽  
Alysson Muotri ◽  
Brent Stockwell ◽  
Edward Schmidt ◽  
Qitao Ran ◽  
...  
Keyword(s):  
Genetic Disorders ◽  
Drug Repurposing ◽  
Genetic Component ◽  
Main Body ◽  
Sequencing Data ◽  
Spondylometaphyseal Dysplasia ◽  
Disease Understanding ◽  
Recent Sequencing ◽  
Support Research

Background: Extremely rare progressive diseases like Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) can be neonatally lethal and therefore go undiagnosed or are difficult to treat. Recent sequencing efforts have linked this disease to mutations in GPX4, with consequences in the resulting enzyme, glutathione peroxidase 4. This offers potential diagnostic and therapeutic avenues for those suffering from this disease, though the steps toward these treatments is often convoluted, expensive, and time-consuming. Main body: The CureGPX4 organization was developed to promote awareness of GPX4-related diseases like SSMD, as well as support research that could lead to essential therapeutics for patients. We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis. We outline in detail the steps CureGPX4 has taken to reach milestones of team creation, disease understanding, drug repurposing, and design of future studies. Conclusion: The primary aim of this review is to provide a roadmap for therapy development for rare, ultra-rare, and difficult to diagnose diseases, as well as increase awareness of the genetic component of SSMD. This work will offer a better understanding of GPx4-related diseases, and help guide researchers, clinicians, and patients interested in other rare diseases find a path towards treatments.

scholarly journals Characterization of symbiotic and associated bacteria from entomopathogenic nematode Heterorhabditis sp. (nematode: Heterorhabditidae) isolated from India

2020 ◽  
Vol 30 (1) ◽  
Author(s):  
Rashid Pervez ◽  
Showkat Ahmad Lone ◽  
Sasmita Pattnaik
Keyword(s):  
Insect Pests ◽  
Entomopathogenic Nematode ◽  
Alcaligenes Faecalis ◽  
Symbiotic Bacteria ◽  
Rrna Gene ◽  
Main Body ◽  
Associated Bacteria ◽  
Molecular Approaches

Abstract Background Entomopathogenic nematodes (EPNs) harboring symbiotic bacteria are one of the safest alternatives to the chemical insecticides for the control of various insect pests. Infective juveniles of EPNs locate a target insect, enter through the openings, and reach the hemocoel, where they release the symbiotic bacteria and the target gets killed by the virulence factors of the bacteria. Photorhabdus with Heterorhabditis spp. are well documented; little is known about the associated bacteria. Main body In this study, we explored the presence of symbiotic and associated bacteria from Heterorhabditis sp. (IISR-EPN 09) and characterized by phenotypic, biochemical, and molecular approaches. Six bacterial isolates, belonging to four different genera, were recovered and identified as follows: Photorhabdus luminescens, one each strain of Providencia vermicola, Pseudomonas entomophila, Alcaligenes aquatilis, and two strains of Alcaligenes faecalis based on the phenotypic, biochemical criteria and the sequencing of 16S rRNA gene. Conclusion P. luminescens is symbiotically associated with Heterorhabditis sp. (IISR-EPN 09), whereas P. vermicola, P. entomophila, A. aquatilis, and A. faecalis are the associated bacteria. Further studies are needed to determine the exact role of the bacterial associates with the Heterorhabditis sp.

scholarly journals The role of neurohormonal blockers in the primary prevention of acute-, early-, and late-onset anthracycline-induced cardiotoxicity

2020 ◽  
Vol 72 (1) ◽  
Author(s):  
Ahmed Ayuna ◽  
Nik Abidin
Keyword(s):  
Primary Prevention ◽  
Myocardial Injury ◽  
Troponin I ◽  
Late Onset ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Main Body ◽  
Converting Enzyme Inhibitors ◽  
Ventricular Ejection Fraction

Abstract Background Anthracycline-induced cardiotoxicity has been classified based on its onset into acute, early, and late. It may have a significant burden on the quality and quantity of life of those exposed to this class of medication. Currently, there are several ongoing debates on the role of different measures in the primary prevention of cardiotoxicity in cancer survivors. Our article aims to focus on the role of neurohormonal blockers in the primary prevention of anthracycline-induced cardiotoxicity, whether it is acute, early, or late onset. Main body of the abstract PubMed and Google Scholar database were searched for the relevant articles; we reviewed and appraised 15 RCTs, and we found that angiotensin-converting enzyme inhibitors (ACEI) and B-blockers were the most commonly used agents. Angiotensin II receptor blockers (ARBs) and mineralocorticoid receptor antagonists (MRAs) were used in a few other trials. The follow-up period was on the range of 1–156 weeks (mode 26 weeks). Left ventricular ejection fraction (LVEF), left ventricular diameters, and diastolic function were assessed by either echocardiogram or occasionally by cardiac magnetic resonance imaging (MRI). The occurrence of myocardial injury was assessed by troponin I. It was obvious that neurohormonal blockers reduced the occurrence of LVEF and myocardial injury in 14/15 RCTs. Short conclusion Beta-blockers, especially carvedilol and ACEI, especially enalapril, should be considered for the primary prevention of acute- and early-onset cardiotoxicity. ARB and MRA are suitable alternatives when patients are intolerant to ACE-I and B-blockers. We recommend further studies to explore and establish the role of neurohormonal blockers in the primary prevention of the acute-, early-, and late-onset cardiotoxicity.

scholarly journals Impact of sex in the prevalence and progression of glioblastomas: the role of gonadal steroid hormones

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Claudia Bello-Alvarez ◽  
Ignacio Camacho-Arroyo
Keyword(s):  
Cell Proliferation ◽  
Steroid Hormones ◽  
Physiological State ◽  
Migration And Invasion ◽  
Low Grade ◽  
Main Body ◽  
Protective Effects ◽  
Gonadal Steroid Hormones ◽  
Gonadal Steroid

Abstract Background As in other types of cancers, sex is an essential factor in the origin and progression of glioblastomas. Research in the field of endocrinology and cancer suggests that gonadal steroid hormones play an important role in the progression and prevalence of glioblastomas. In the present review, we aim to discuss the actions and mechanism triggered by gonadal steroid hormones in glioblastomas. Main body Glioblastoma is the most common malignant primary brain tumor. According to the epidemiological data, glioblastomas are more frequent in men than in women in a 1.6/1 proportion both in children and adults. This evidence, and the knowledge about sex influence over the prevalence of countless diseases, suggest that male gonadal steroid hormones, such as testosterone, promote glioblastomas growth. In contrast, a protective role of female gonadal steroid hormones (estradiol and progesterone) against glioblastomas has been questioned. Several pieces of evidence demonstrate a variety of effects induced by female and male gonadal steroid hormones in glioblastomas. Several studies indicate that pregnancy, a physiological state with the highest progesterone and estradiol levels, accelerates the progression of low-grade astrocytomas to glioblastomas and increases the symptoms associated with these tumors. In vitro studies have demonstrated that progesterone has a dual role in glioblastoma cells: physiological concentrations promote cell proliferation, migration, and invasion while very high doses (out physiological range) reduce cell proliferation and increases cell death. Conclusion Gonadal steroid hormones can stimulate the progression of glioblastomas through the increase in proliferation, migration, and invasion. However, the effects mentioned above depend on the concentrations of these hormones and the receptor involved in hormone actions. Estradiol and progesterone can exert promoter or protective effects while the role of testosterone has been always associated to glioblastomas progression.

scholarly journals Exploring the multiple roles of guardian of the genome: P53

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Wasim Feroz ◽  
Arwah Mohammad Ali Sheikh
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Crucial Role ◽  
Cellular Response ◽  
Genotoxic Stress ◽  
Specific Response ◽  
Main Body ◽  
Repair System ◽  
Tumour Suppression

Abstract Background Cells have evolved balanced mechanisms to protect themselves by initiating a specific response to a variety of stress. The TP53 gene, encoding P53 protein, is one of the many widely studied genes in human cells owing to its multifaceted functions and complex dynamics. The tumour-suppressing activity of P53 plays a principal role in the cellular response to stress. The majority of the human cancer cells exhibit the inactivation of the P53 pathway. In this review, we discuss the recent advancements in P53 research with particular focus on the role of P53 in DNA damage responses, apoptosis, autophagy, and cellular metabolism. We also discussed important P53-reactivation strategies that can play a crucial role in cancer therapy and the role of P53 in various diseases. Main body We used electronic databases like PubMed and Google Scholar for literature search. In response to a variety of cellular stress such as genotoxic stress, ischemic stress, oncogenic expression, P53 acts as a sensor, and suppresses tumour development by promoting cell death or permanent inhibition of cell proliferation. It controls several genes that play a role in the arrest of the cell cycle, cellular senescence, DNA repair system, and apoptosis. P53 plays a crucial role in supporting DNA repair by arresting the cell cycle to purchase time for the repair system to restore genome stability. Apoptosis is essential for maintaining tissue homeostasis and tumour suppression. P53 can induce apoptosis in a genetically unstable cell by interacting with many pro-apoptotic and anti-apoptotic factors. Furthermore, P53 can activate autophagy, which also plays a role in tumour suppression. P53 also regulates many metabolic pathways of glucose, lipid, and amino acid metabolism. Thus under mild metabolic stress, P53 contributes to the cell’s ability to adapt to and survive the stress. Conclusion These multiple levels of regulation enable P53 to perform diversified roles in many cell responses. Understanding the complete function of P53 is still a work in progress because of the inherent complexity involved in between P53 and its target proteins. Further research is required to unravel the mystery of this Guardian of the genome “TP53”.

scholarly journals MiR-146a Regulates Migration and Invasion by Targeting NRP2 in Circulating-Tumor Cell Mimicking Suspension Cells

Genes ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 45
Author(s):  
Yeojin Do ◽  
Jin Gu Cho ◽  
Ji Young Park ◽  
Sumin Oh ◽  
Doyeon Park ◽  
...  
Keyword(s):  
Cancer Metastasis ◽  
Metastatic Cancer ◽  
Molecular Networks ◽  
Migration And Invasion ◽  
Integrated Analysis ◽  
Molecular Characteristics ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Suspension Cells

Cancer metastasis is the primary cause of cancer-related death and metastatic cancer has circulating-tumor cells (CTCs), which circulate in the bloodstream before invading other organs. Thus, understanding the precise role of CTCs may provide new insights into the metastasis process and reduce cancer mortality. However, the molecular characteristics of CTCs are not well understood due to a lack of number of CTCs. Therefore, suspension cells were generated from MDA-MB-468 cells to mimic CTCs, and we investigate the microRNA (miRNA)-dependent molecular networks and their role in suspension cells. Here, we present an integrated analysis of mRNA and miRNA sequencing data for suspension cell lines, through comparison with adherent cells. Among the differentially regulated miRNA–mRNAs axes, we focus on the miR-146a-Neuropilin2 (NRP2) axis, which is known to influence tumor aggressiveness. We show that miR-146a directly regulates NRP2 expression and inhibits Semaphorin3C (SEMA3C) signaling. Functional studies reveal that miR-146a represses SEMA3C-induced invasion and proliferation by targeting NRP2. Finally, high-NRP2 is shown to be associated with poor outcomes in breast cancer patients. This study identifies the key role of the miR-146a–NRP2 signaling axis that is critical for the regulation of migration and invasion in CTC-mimicking cells.

Cultural diplomacy: symbiosis of cultural and legal potential

2021 ◽  
pp. 89-95
Author(s):  
Oksana Stasevska ◽  
Illia Malanchuk
Keyword(s):  
Foreign Policy ◽  
Cultural Heritage ◽  
Cultural Diplomacy ◽  
Armed Forces ◽  
Legal Framework ◽  
Legal Aspects ◽  
Modern World ◽  
Main Body ◽  
Cultural Images

Problem setting. The study of the potential of cultural diplomacy has been growing rapidly in recent times. This is due to the realization of the failures of traditional and «force» diplomacy, which often demonstrate the inability to ensure the successful solution of important international problems. Researchers note the need to use cultural diplomacy to intensify and increase the effectiveness of international cooperation. Target of research. Understanding the actualization of cultural diplomacy of Ukraine in the modern world, an attempt to analyze its legal basis. Analysis of resent researches and publications. The concep «cultural diplomacy» is more common in scientific discourse. Scientists such as D. Vedeneev, V. Kostrov, T. Peresunko, N. Musienko, V. Tsyvaty, M. Kulinich, O. Rozumna, and others have contributed to the development of the role of cultural diplomacy in the foreign policy vector of the Ukraine. Political science works predominate among the researches. Few works analyze the legal aspects of cultural diplomacy. Article’s main body. In the context of globalization there is a loss of national origins. Therefore, states must use all their potential to preserve and enhance their own and the world’s cultural heritage, mutual understanding and support of interethnic harmony. International legal thought defines the concept of «diplomacy» in different ways, sometimes identifying it with international law or foreign policy. However, diplomacy is one of the most important tools of foreign policy, along with its components such as the armed forces, intelligence, economic ties, and so on. Cultural diplomacy is a type of diplomacy that uses the country’s cultural heritage as a means to an end. The role of cultural potential in international relations is highly valued. It is cultural diplomacy, not the use of force to impose political, ideological ideas, which aims to unite countries. Ukraine is returning to the active use of cultural diplomacy tools in the XXI century, when there was an urgent need for broad international support for the implementation of ambitious European integration plans. The system of coordination, stimulation and organization of cultural activities at the international level allows identifying the tasks of cultural diplomacy of Ukraine. Ukrainian cultural diplomacy based on international legal instruments ratified by Ukraine and acts of national legislation. The analysis of the problem allows determining the urgent task of creating a favorable legislative framework for the maximum effectiveness of cultural diplomacy. Conclusions and prospects for the development. The filling of legal gaps in cultural diplomacy should take place in the vector of recognition of culture as a subject of foreign policy, awareness of its reputational and social potential. Ukraine faces the task of updating old and finding new cultural images and symbols to create a decent image of the country, as well as to create an appropriate legal framework for the effective implementation of the tasks of cultural diplomacy.

Abstract WMP40: Cervical Internal Carotid Artery Tortuosity as a Marker of Non-Atherosclerotic Aging: Results From the Northern Manhattan Study (NOMAS)

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Farid Khasiyev ◽  
Tatjana Rundek ◽  
Chensy Marquez ◽  
Clinton B. Wright ◽  
Ralph Sacco ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Internal Carotid Artery ◽  
Internal Carotid ◽  
Genetic Disorders ◽  
Matrix Remodeling ◽  
Plaque Area ◽  
Blood Pressures ◽  
The Right ◽  
Cervical Internal Carotid Artery

Background: Cervical internal carotid artery (ICA) tortuosity has been associated with vascular risk and stroke as well as genetic disorders related to abnormal extracellular matrix remodeling. It is plausible that dystrophic or aberrant arterial remodeling may therefore relate to cervical ICA tortuosity. We hypothesized that cervical ICA tortuosity relates to carotid dilatation, but not to traditional ultrasound (US) markers of atherosclerosis. Methods: Subjects of the NOMAS with available time-of-flight MRA were included in our study. Cervical ICA tortuosity was defined as a bend in the distal cervical ICA of > 90° as seen on MRA. We excluded subjects with < 5 cm of the cervical ICA visualized. Distensibility was calculated as the percentage excursion of the right CCA diastolic diameter during systole, which was assessed by high-resolution B-mode US of the right common carotid artery (CCA). We used multivariable logistic regression analyses to estimate odds ratios for the association of cervical ICA tortuosity and Doppler measures of carotid wall aging. Results: We visualized cervical ICA tortuosity in 468 NOMAS participants (mean age 64±8 years, 70% women, 70% Hispanic). It was present in 23% of subjects. In unadjusted models, cervical ICA tortuosity was more common in women (OR 2.34, 95% CI 1.34-4.11), Hispanics (OR 1.85, 95%CI 1.06-3.25) and those with higher diastolic blood pressures (OR per mm Hg 1.04, 95%CI 1.01-1.06), and less common among smokers (OR 0.23, 95%CI 0.07-0.78). In models adjusted for demographic and vascular risks, right CCA tortuosity was associated with ipsilateral larger CCA DD (OR 1.42, 95%CI 1.02-1.96) and borderline associated with lower distensibility (OR 0.94, 95%CI 0.87-1.01, P=0.06) but not with ipsilateral ICA IMT (OR 0.26, 95%CI 0.14-4.77), number of plaques (OR 1.08, 95%CI 0.76-1.53), maximum plaque thickness (OR 0.96, 95%CI 0.73-1.27), or plaque area (1.00, 95%CI 0.97-1.05). Conclusions: Cervical ICA tortuosity associates with ipsilateral cervical ICA dilatation and lower distensibility, but not with traditional US markers of atherosclerosis. The association with diastolic blood pressure suggests a role of steady, rather than pulsatile, hemodynamics in aberrant cervical ICA remodeling.

Genetic Disorders, Genotyping Techniques and the Emerging Role of Tetra-ARMS-PCR as a Diagnostic Tool

Resonance ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 1229-1240
Author(s):  
Motiur Rahaman ◽  
Mandrita Mukherjee ◽  
Nishant Chakravorty
Keyword(s):  
Diagnostic Tool ◽  
Genetic Disorders ◽  
Arms Pcr

Reaching Future Scientists, Consumers, & Citizens

2014 ◽  
Vol 76 (6) ◽  
pp. 379-383 ◽  
Author(s):  
Melissa A. Hicks ◽  
Rebecca J. Cline ◽  
Angela M. Trepanier
Keyword(s):  
Personalized Medicine ◽  
Genetic Basis ◽  
Genetic Disorders ◽  
Single Gene ◽  
Personal Health ◽  
Adult Onset ◽  
Biology Textbooks ◽  
Multifactorial Diseases ◽  
Single Gene Disorders

An understanding of how genomics information, including information about risk for common, multifactorial disease, can be used to promote personal health (personalized medicine) is becoming increasingly important for the American public. We undertook a quantitative content analysis of commonly used high school textbooks to assess how frequently the genetic basis of common multifactorial diseases was discussed compared with the “classic” chromosomal–single gene disorders historically used to teach the concepts of genetics and heredity. We also analyzed the types of conditions or traits that were discussed. We identified 3957 sentences across 11 textbooks that addressed multifactorial and “classic” genetic disorders. “Classic” gene disorders were discussed relatively more frequently than multifactorial diseases, as was their genetic basis, even after we enriched the sample to include five adult-onset conditions common in the general population. Discussions of the genetic or hereditary components of multifactorial diseases were limited, as were discussions of the environmental components of these conditions. Adult-onset multifactorial diseases are far more common in the population than chromosomal or single-gene disorders; many are potentially preventable or modifiable. As such, they are targets for personalized medical approaches. The limited discussion in biology textbooks of the genetic basis of multifactorial conditions and the role of environment in modifying genetic risk may limit the public’s understanding and use of personalized medicine.

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