T. Markova, Aysylu Murtazina, V. Kenis, E. Melchenko, M. Ampleeva, T. Nagornova, A. Alieva, E. Dadali, S. Kutsev
Multiple epiphyseal dysplasia type 1 is one of the most common autosomal dominant types of the genetically heterogeneous group of skeletal dysplasias characterized by impaired ossification of the epiphyses of long bones. To date, it is known that the disease is caused by heterozygous variants in the COMP gene and is characterized by a significant variability in the clinical manifestations. We report the first case of a patient with MED 1 caused by novel homozygous single nucleotide variant c.2170dupG (p.Val724Glyfs*20) in the COMP gene identified by whole-exome sequencing. The following segregation analysis in the family found a detected variant in heterozygous state in healthy consanguineous parents of the proband. Clinical and radiological examination revealed the atypical signs of epiphyseal dysplasia including limited range of extension and supination of both forearms, severe bilateral ulnar clubhand, plano-valgus deformity of the feet and generalized muscle weakness with gait disturbances. Among the clinical features, myopathic signs were the most prominent. The radiological and neurophysiological data can be helpful in the differential diagnostics with the congenital myopathies. The novel homozygous variant in the COMP gene that caused multiple epiphyseal dysplasia 1 with autosomal recessive inheritance can contribute to the more detailed description of genotype–phenotype correlations, which will allow research to understand better the role of the C-terminal domain of COMP.
{"title":"A Novel Homozygous Variant in the COMP Gene Causing a Multiple Epiphyseal Dysplasia 1 with Autosomal Recessive Inheritance","authors":"T. Markova, Aysylu Murtazina, V. Kenis, E. Melchenko, M. Ampleeva, T. Nagornova, A. Alieva, E. Dadali, S. Kutsev","doi":"10.3390/ijtm2020019","DOIUrl":"https://doi.org/10.3390/ijtm2020019","url":null,"abstract":"Multiple epiphyseal dysplasia type 1 is one of the most common autosomal dominant types of the genetically heterogeneous group of skeletal dysplasias characterized by impaired ossification of the epiphyses of long bones. To date, it is known that the disease is caused by heterozygous variants in the COMP gene and is characterized by a significant variability in the clinical manifestations. We report the first case of a patient with MED 1 caused by novel homozygous single nucleotide variant c.2170dupG (p.Val724Glyfs*20) in the COMP gene identified by whole-exome sequencing. The following segregation analysis in the family found a detected variant in heterozygous state in healthy consanguineous parents of the proband. Clinical and radiological examination revealed the atypical signs of epiphyseal dysplasia including limited range of extension and supination of both forearms, severe bilateral ulnar clubhand, plano-valgus deformity of the feet and generalized muscle weakness with gait disturbances. Among the clinical features, myopathic signs were the most prominent. The radiological and neurophysiological data can be helpful in the differential diagnostics with the congenital myopathies. The novel homozygous variant in the COMP gene that caused multiple epiphyseal dysplasia 1 with autosomal recessive inheritance can contribute to the more detailed description of genotype–phenotype correlations, which will allow research to understand better the role of the C-terminal domain of COMP.","PeriodicalId":43005,"journal":{"name":"Journal of International Translational Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75671917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
I. Fevraleva, O. Glinshchikova, T. Makarik, A. Sudarikov
Background: Up to 40% of test results for COVID-19 in the presence of clinical manifestations of the disease might be negative. The reason for a false-negative result might originate from any step of the analysis: poor-quality or empty swab, poor RNA isolation, inactivation of reverse transcriptase or Taq polymerase in the test. Methods: Here we describe a PCR approach for SARS-CoV-2 detection with swab quality and integrity controlled by human ABL1 mRNA amplification. Designed primers work with the cDNA of the ABL1 gene, not genomic DNA. Results: The simultaneous appearance of three signals corresponding to the nucleocapsid, spike, and ABL1 gene indicates infection with the Omicron strain. The amplification of ABL1 gene and nucleocapsid only indicate other than Omicron infection. The appearance of ABL1 amplification only indicates a true negative result for SARS-CoV-2. All other variants are null and void. Conclusions: A system has been developed for multiplex PCR diagnostics of SARS-CoV-2, which makes it possible to eliminate errors leading to false-negative and false-positive results at all stages of analysis. This is accomplished by the presence of specific primers for human RNA, controlling proper swab application, handling, and all the stages of RT-PCR.
{"title":"How to Avoid False-Negative and False-Positive COVID-19 PCR Testing","authors":"I. Fevraleva, O. Glinshchikova, T. Makarik, A. Sudarikov","doi":"10.3390/ijtm2020018","DOIUrl":"https://doi.org/10.3390/ijtm2020018","url":null,"abstract":"Background: Up to 40% of test results for COVID-19 in the presence of clinical manifestations of the disease might be negative. The reason for a false-negative result might originate from any step of the analysis: poor-quality or empty swab, poor RNA isolation, inactivation of reverse transcriptase or Taq polymerase in the test. Methods: Here we describe a PCR approach for SARS-CoV-2 detection with swab quality and integrity controlled by human ABL1 mRNA amplification. Designed primers work with the cDNA of the ABL1 gene, not genomic DNA. Results: The simultaneous appearance of three signals corresponding to the nucleocapsid, spike, and ABL1 gene indicates infection with the Omicron strain. The amplification of ABL1 gene and nucleocapsid only indicate other than Omicron infection. The appearance of ABL1 amplification only indicates a true negative result for SARS-CoV-2. All other variants are null and void. Conclusions: A system has been developed for multiplex PCR diagnostics of SARS-CoV-2, which makes it possible to eliminate errors leading to false-negative and false-positive results at all stages of analysis. This is accomplished by the presence of specific primers for human RNA, controlling proper swab application, handling, and all the stages of RT-PCR.","PeriodicalId":43005,"journal":{"name":"Journal of International Translational Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75978912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Point-of-care detection of viral infection is required for effective contact-tracing, epidemiological surveillance, and linkage to care. Traditional diagnostic platforms relying on either antigen detection or nucleic amplification are limited by sensitivity and the need for costly laboratory infrastructure, respectively. Recently, CRISPR-based diagnostics have emerged as an alternative, combining equipment light workflows with high specificity and sensitivity. However, as a nascent technology, several outstanding challenges to widespread field deployment remain. These include the need for pre-detection amplification of target molecules, the lack of standardization in sample preparation and reagent composition, and only equivocal assessments of the unit-economics relative to traditional antigen or polymerase chain reaction-based diagnostics. This review summarizes recent advances with the potential to overcome existing translational barriers, describes the events in CRISPR-based detection of target molecules, and offers perspective on how multiple approaches can be combined to decrease the limit of detection without introducing pre-amplification.
{"title":"CRISPR-Based Diagnostics for Point-of-Care Viral Detection","authors":"Alexander I. Mosa","doi":"10.3390/ijtm2020017","DOIUrl":"https://doi.org/10.3390/ijtm2020017","url":null,"abstract":"Point-of-care detection of viral infection is required for effective contact-tracing, epidemiological surveillance, and linkage to care. Traditional diagnostic platforms relying on either antigen detection or nucleic amplification are limited by sensitivity and the need for costly laboratory infrastructure, respectively. Recently, CRISPR-based diagnostics have emerged as an alternative, combining equipment light workflows with high specificity and sensitivity. However, as a nascent technology, several outstanding challenges to widespread field deployment remain. These include the need for pre-detection amplification of target molecules, the lack of standardization in sample preparation and reagent composition, and only equivocal assessments of the unit-economics relative to traditional antigen or polymerase chain reaction-based diagnostics. This review summarizes recent advances with the potential to overcome existing translational barriers, describes the events in CRISPR-based detection of target molecules, and offers perspective on how multiple approaches can be combined to decrease the limit of detection without introducing pre-amplification.","PeriodicalId":43005,"journal":{"name":"Journal of International Translational Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88581044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
V. Giardini, C. Gambacorti-Passerini, M. Casati, Andrea Carrer, P. Vergani
COVID-19 has been primarily identified as a respiratory infection characterized by signs and symptoms associated with the dysfunction of the renin-angiotensin system (RAS). This is attributed to the SARS-CoV-2 virus invading the respiratory mucosa via angiotensin-converting enzyme 2 (ACE2), which is an important element of the RAS. Meanwhile, preeclampsia is an obstetric pathology that, surprisingly, resembles the pathology of COVID-19. It is a systemic syndrome that occurs during the second half of pregnancy and is determined to be a major cause of maternal and perinatal morbidity and mortality. This disease typically presents with new-onset hypertension and proteinuria or other specific end-organ dysfunctions. RAS-mediated mechanisms may explain its primary clinical-pathological features, which are suggestive of an underlying microvascular dysfunction in both diseases, with induction of vasculopathy, coagulopathy, and inflammation. In this report, we review the medical literature on this subject. Further, the underlying similarities between the two conditions are discussed to assess preeclampsia as a model for COVID-19. These considerations are valid in the case of original SARS-CoV-2 primary infection. Emerging SARS-CoV-2 variants as well as the vaccination could alter various aspects of the virus biology, including human ACE-2 receptor binding affinity and therefore the RAS mediated consequences.
{"title":"Can Similarities between the Pathogenesis of Preeclampsia and COVID-19 Increase the Understanding of COVID-19?","authors":"V. Giardini, C. Gambacorti-Passerini, M. Casati, Andrea Carrer, P. Vergani","doi":"10.3390/ijtm2020016","DOIUrl":"https://doi.org/10.3390/ijtm2020016","url":null,"abstract":"COVID-19 has been primarily identified as a respiratory infection characterized by signs and symptoms associated with the dysfunction of the renin-angiotensin system (RAS). This is attributed to the SARS-CoV-2 virus invading the respiratory mucosa via angiotensin-converting enzyme 2 (ACE2), which is an important element of the RAS. Meanwhile, preeclampsia is an obstetric pathology that, surprisingly, resembles the pathology of COVID-19. It is a systemic syndrome that occurs during the second half of pregnancy and is determined to be a major cause of maternal and perinatal morbidity and mortality. This disease typically presents with new-onset hypertension and proteinuria or other specific end-organ dysfunctions. RAS-mediated mechanisms may explain its primary clinical-pathological features, which are suggestive of an underlying microvascular dysfunction in both diseases, with induction of vasculopathy, coagulopathy, and inflammation. In this report, we review the medical literature on this subject. Further, the underlying similarities between the two conditions are discussed to assess preeclampsia as a model for COVID-19. These considerations are valid in the case of original SARS-CoV-2 primary infection. Emerging SARS-CoV-2 variants as well as the vaccination could alter various aspects of the virus biology, including human ACE-2 receptor binding affinity and therefore the RAS mediated consequences.","PeriodicalId":43005,"journal":{"name":"Journal of International Translational Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79240723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Chemically exposed veterans of the 1991 Gulf War have few options for treatment of conditions and symptoms related to their chemical exposures. Membrane Lipid Replacement (MLR) with oral membrane glycerolphospholipids is a safe and effective method for slowly removing hydrophobic organic molecules from tissues, while enhancing mitochondrial function and decreasing the severity of certain signs and symptoms associated with multi-symptom illnesses. Methods: A preliminary open-label study utilizing 20 male veterans who were deployed to combat areas, exposed to environmental toxic chemicals and subsequently diagnosed with Gulf War Illnesses (GWI) were utilized. These subjects took 6 g per day oral glycerolphospholipids for 6 months, and the severities of over 100 signs and symptoms were self-reported at various times using illness survey forms. Results: In the sixteen patients that fully complied and completed the study, there were gradual and significant reductions of symptom severities in categories related to fatigue, pain, musculoskeletal, nasopharyngeal, breathing, vision, sleep, balance, and urinary, gastrointestinal and chemical sensitivities. There were no adverse incidents during the study, and the all-natural oral study supplement was extremely well tolerated. Conclusions: MLR with oral glycerolphospholipids appears to be a simple, safe and potentially effective method of slowly reducing the severities of multiple symptoms in chemically exposed veterans.
{"title":"Membrane Lipid Replacement with Glycerolphospholipids Slowly Reduces Self-Reported Symptom Severities in Chemically Exposed Gulf War Veterans","authors":"G. Nicolson, P. C. Breeding","doi":"10.3390/ijtm2020014","DOIUrl":"https://doi.org/10.3390/ijtm2020014","url":null,"abstract":"Background: Chemically exposed veterans of the 1991 Gulf War have few options for treatment of conditions and symptoms related to their chemical exposures. Membrane Lipid Replacement (MLR) with oral membrane glycerolphospholipids is a safe and effective method for slowly removing hydrophobic organic molecules from tissues, while enhancing mitochondrial function and decreasing the severity of certain signs and symptoms associated with multi-symptom illnesses. Methods: A preliminary open-label study utilizing 20 male veterans who were deployed to combat areas, exposed to environmental toxic chemicals and subsequently diagnosed with Gulf War Illnesses (GWI) were utilized. These subjects took 6 g per day oral glycerolphospholipids for 6 months, and the severities of over 100 signs and symptoms were self-reported at various times using illness survey forms. Results: In the sixteen patients that fully complied and completed the study, there were gradual and significant reductions of symptom severities in categories related to fatigue, pain, musculoskeletal, nasopharyngeal, breathing, vision, sleep, balance, and urinary, gastrointestinal and chemical sensitivities. There were no adverse incidents during the study, and the all-natural oral study supplement was extremely well tolerated. Conclusions: MLR with oral glycerolphospholipids appears to be a simple, safe and potentially effective method of slowly reducing the severities of multiple symptoms in chemically exposed veterans.","PeriodicalId":43005,"journal":{"name":"Journal of International Translational Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91327511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This is the world’s first tutorial article on Python programing on set operations for beginners and practitioners in translational medicine or medicine in general. This tutorial will allow researchers to demonstrate and showcase their tools on PyPI packages around the world. Via the PyPI packaging, a Python application with a single source code can run on Windows, MacOS, and Linux operating systems. In addition to the PyPI packaging, the reproducibility and quality of the source code must be guaranteed. This paper shows how to publish the Python application in Code Ocean after the PyPI packaging. Code Ocean is used in IEEE, Springer, and Elsevier for software reproducibility validation. First, programmers must understand how to scrape a dataset over the Internet. Second, the dataset files must be read in Python. Third, a program must be built to compute the target values using set operations. Fourth, the Python program must be converted to the PyPI package. Finally, the PyPI package is uploaded. Code Ocean plays a key role in publishing validation for software reproducibility. This paper depicts a vaers executable package as an example for calculating the number of deaths due to COVID-19 vaccines. Calculations were based on gender (male and female), age group, and vaccine group (Moderna, Pfizer, and Novartis), respectively.
{"title":"Set Operations in Python for Translational Medicine","authors":"Yoshiyasu Takefuji","doi":"10.3390/ijtm2020015","DOIUrl":"https://doi.org/10.3390/ijtm2020015","url":null,"abstract":"This is the world’s first tutorial article on Python programing on set operations for beginners and practitioners in translational medicine or medicine in general. This tutorial will allow researchers to demonstrate and showcase their tools on PyPI packages around the world. Via the PyPI packaging, a Python application with a single source code can run on Windows, MacOS, and Linux operating systems. In addition to the PyPI packaging, the reproducibility and quality of the source code must be guaranteed. This paper shows how to publish the Python application in Code Ocean after the PyPI packaging. Code Ocean is used in IEEE, Springer, and Elsevier for software reproducibility validation. First, programmers must understand how to scrape a dataset over the Internet. Second, the dataset files must be read in Python. Third, a program must be built to compute the target values using set operations. Fourth, the Python program must be converted to the PyPI package. Finally, the PyPI package is uploaded. Code Ocean plays a key role in publishing validation for software reproducibility. This paper depicts a vaers executable package as an example for calculating the number of deaths due to COVID-19 vaccines. Calculations were based on gender (male and female), age group, and vaccine group (Moderna, Pfizer, and Novartis), respectively.","PeriodicalId":43005,"journal":{"name":"Journal of International Translational Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85776773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Colya N. Englisch, Daniel Röhricht, M. Walz, K. Junker, Anja Beckmann, C. Meier, F. Paulsen, M. Jung, T. Tschernig
In the context of renal proteinuric diseases, TRPC6 has been shown to play an important role in ultrafiltration associated with the slit diaphragm through the control of the intracellular Ca2+ concentration in the podocytes of glomeruli. However, to date, the properties of TRPC6 have been studied mainly in cell lines or in animal models. Therefore, the aim of the study presented here was to investigate the presence and distribution of TRPC6 in human kidneys in order to possibly verify the applicability of the results previously obtained in nonhuman experiments. For this purpose, kidneys from nine cadavers were prepared for immunohistochemical staining and were supplemented with a fresh human kidney obtained by nephrectomy. TRPC6 was detected in glomeruli and in the parietal epithelial cells of Bowman’s capsule. Larger amounts were detected in the tubular system and collecting ducts. In contrast to the peritubular capillary bed, which showed no immune reaction, the cortical resistance vessels showed mild TRPC6 staining. In conclusion, our studies on the expression of TRPC6 in human kidney tissue support the translational concept of the involvement of TRPC6 in various renal diseases and reveal new aspects of the distribution of TRPC6 in the human kidney.
{"title":"TRPC6 Is Found in Distinct Compartments of the Human Kidney","authors":"Colya N. Englisch, Daniel Röhricht, M. Walz, K. Junker, Anja Beckmann, C. Meier, F. Paulsen, M. Jung, T. Tschernig","doi":"10.3390/ijtm2020013","DOIUrl":"https://doi.org/10.3390/ijtm2020013","url":null,"abstract":"In the context of renal proteinuric diseases, TRPC6 has been shown to play an important role in ultrafiltration associated with the slit diaphragm through the control of the intracellular Ca2+ concentration in the podocytes of glomeruli. However, to date, the properties of TRPC6 have been studied mainly in cell lines or in animal models. Therefore, the aim of the study presented here was to investigate the presence and distribution of TRPC6 in human kidneys in order to possibly verify the applicability of the results previously obtained in nonhuman experiments. For this purpose, kidneys from nine cadavers were prepared for immunohistochemical staining and were supplemented with a fresh human kidney obtained by nephrectomy. TRPC6 was detected in glomeruli and in the parietal epithelial cells of Bowman’s capsule. Larger amounts were detected in the tubular system and collecting ducts. In contrast to the peritubular capillary bed, which showed no immune reaction, the cortical resistance vessels showed mild TRPC6 staining. In conclusion, our studies on the expression of TRPC6 in human kidney tissue support the translational concept of the involvement of TRPC6 in various renal diseases and reveal new aspects of the distribution of TRPC6 in the human kidney.","PeriodicalId":43005,"journal":{"name":"Journal of International Translational Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73425658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Correia, Diana Duarte, Vera Miranda-Gonçalves, N. Vale
Protein aggregation is a common characteristic of several human diseases such as Alzheimer’s disease. Recent evidence has indicated that the aggregation of peptides such as p53 is also marked in cancer cells. The aim of this study was to correlate Thioflavin T (ThT) data with different cellular viability assays (Neutral Red and MTT) in SH-SY5Y neuroblastoma cells and HT-29 colon cancer cells treated with doxorubicin, a classical antineoplastic agent. We also studied the effects of the well-known peptide Aβ42 on the aggregation process in these cells. Our data suggest that both cancer cell lines are responsive to doxorubicin and formed aggregates, highlighting a relationship between ThT and cellular viability methodologies. We observed that lower values of cell viability corresponded with pronounced aggregation. Thus, these results indicated that the ThT methodology used in cells may complement the cell viability assays. In addition, this methodology may be of interest to evaluate the role of protein aggregation in other cancer cells.
{"title":"Potential Translational Thioflavin T Methodology as a Complement of Cell-Based Assays and after Drug Exposition","authors":"A. Correia, Diana Duarte, Vera Miranda-Gonçalves, N. Vale","doi":"10.3390/ijtm2020011","DOIUrl":"https://doi.org/10.3390/ijtm2020011","url":null,"abstract":"Protein aggregation is a common characteristic of several human diseases such as Alzheimer’s disease. Recent evidence has indicated that the aggregation of peptides such as p53 is also marked in cancer cells. The aim of this study was to correlate Thioflavin T (ThT) data with different cellular viability assays (Neutral Red and MTT) in SH-SY5Y neuroblastoma cells and HT-29 colon cancer cells treated with doxorubicin, a classical antineoplastic agent. We also studied the effects of the well-known peptide Aβ42 on the aggregation process in these cells. Our data suggest that both cancer cell lines are responsive to doxorubicin and formed aggregates, highlighting a relationship between ThT and cellular viability methodologies. We observed that lower values of cell viability corresponded with pronounced aggregation. Thus, these results indicated that the ThT methodology used in cells may complement the cell viability assays. In addition, this methodology may be of interest to evaluate the role of protein aggregation in other cancer cells.","PeriodicalId":43005,"journal":{"name":"Journal of International Translational Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77310515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Valluri, Logan Lawrence, K. Denning, J. Cuda, G. Zhu
Glioblastomas (GBMs) are a form of malignant gliomas characterized by a dismal prognosis. Standard treatment for glioblastoma patients is combined maximal surgical removal of the tumor with postoperative radiotherapy and concomitant chemotherapy with Temozolomide (TMZ). Among the histological characteristics that contribute to GBM progression are the rapid proliferation and neo-angiogenetic processes. The Na+/K+-ATPase is a transporter that promotes the migration of cancer cells, and its aberrant expression and activity have been associated with several cancers, including GBM. Using cardiac glycosides, we examined the effects of direct inhibition of the Na+/K+-ATPase in glioblastoma cells in vitro. We found that cardiac glycoside Digoxin is an effective anticancer agent on several glioma cell lines via Na+/K+-ATPase inhibition. Drug cytotoxicity assays showed that Digoxin as monotherapy significantly increased cell death and increased the efficacy of Temozolomide (TMZ) in the glioma cell lines T98G, U-97 MG, and primary GBM cells BNC-6. Additionally, Digoxin exhibited important anti-migratory effects on the highly aggressive and chemotherapy-resistant T98G glioma cell-line, demonstrating a potential therapeutic role for cardiac glycosides.
{"title":"Cardiac Glycosides Increase Temozolomide Anticancer Activity in Therapy Resistant Glioblastoma Cells","authors":"A. Valluri, Logan Lawrence, K. Denning, J. Cuda, G. Zhu","doi":"10.3390/ijtm2020012","DOIUrl":"https://doi.org/10.3390/ijtm2020012","url":null,"abstract":"Glioblastomas (GBMs) are a form of malignant gliomas characterized by a dismal prognosis. Standard treatment for glioblastoma patients is combined maximal surgical removal of the tumor with postoperative radiotherapy and concomitant chemotherapy with Temozolomide (TMZ). Among the histological characteristics that contribute to GBM progression are the rapid proliferation and neo-angiogenetic processes. The Na+/K+-ATPase is a transporter that promotes the migration of cancer cells, and its aberrant expression and activity have been associated with several cancers, including GBM. Using cardiac glycosides, we examined the effects of direct inhibition of the Na+/K+-ATPase in glioblastoma cells in vitro. We found that cardiac glycoside Digoxin is an effective anticancer agent on several glioma cell lines via Na+/K+-ATPase inhibition. Drug cytotoxicity assays showed that Digoxin as monotherapy significantly increased cell death and increased the efficacy of Temozolomide (TMZ) in the glioma cell lines T98G, U-97 MG, and primary GBM cells BNC-6. Additionally, Digoxin exhibited important anti-migratory effects on the highly aggressive and chemotherapy-resistant T98G glioma cell-line, demonstrating a potential therapeutic role for cardiac glycosides.","PeriodicalId":43005,"journal":{"name":"Journal of International Translational Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86310756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sachithra Gunasekara, Miruthula Tamil Selvan, Craig A. Miller, Jennifer M. Rudd
The ongoing COVID-19 pandemic continues to affect the lives, wellbeing, and stability of communities worldwide. The race to save human lives is critical, and the development of useful translational animal models to elucidate disease pathogenesis and prevention, and to test therapeutic interventions, is essential to this response. However, significant limitations exist with the currently employed animal models that slow our ability to respond to the pandemic. Non-human primates serve as an excellent animal model for SARS-CoV-2 disease and interventions, but the availability of these animals is scarce, and few facilities are able to house and utilize this model. Adapted murine models are accessible and improving but lack natural hACE-2 receptors and are only moderate representatives of human COVID-19 disease, transmission, and immune responses. On the other hand, there are several animal species that are both naturally and experimentally infected, such as domestic cats, hamsters, ferrets, and mink. Several of these have proven animal-to-animal transmission and evidence of significant clinical and histopathologic disease that mimics acute COVID-19 in humans. Mobilizing these nontraditional animal models could have a crucial role in SARS-CoV-2 research efficiency and impact. This review focuses on what is known about these nontraditional animal models, including their immune responses to SARS-CoV-2 infection, evidence of clinical and histopathologic disease, transmission potential, and the practicality of each model in a research setting. Comparative insight into these animal models for COVID-19 can strengthen the efforts to mitigate this pandemic.
{"title":"Thinking Outside the Box: Utilizing Nontraditional Animal Models for COVID-19 Research","authors":"Sachithra Gunasekara, Miruthula Tamil Selvan, Craig A. Miller, Jennifer M. Rudd","doi":"10.3390/ijtm2010010","DOIUrl":"https://doi.org/10.3390/ijtm2010010","url":null,"abstract":"The ongoing COVID-19 pandemic continues to affect the lives, wellbeing, and stability of communities worldwide. The race to save human lives is critical, and the development of useful translational animal models to elucidate disease pathogenesis and prevention, and to test therapeutic interventions, is essential to this response. However, significant limitations exist with the currently employed animal models that slow our ability to respond to the pandemic. Non-human primates serve as an excellent animal model for SARS-CoV-2 disease and interventions, but the availability of these animals is scarce, and few facilities are able to house and utilize this model. Adapted murine models are accessible and improving but lack natural hACE-2 receptors and are only moderate representatives of human COVID-19 disease, transmission, and immune responses. On the other hand, there are several animal species that are both naturally and experimentally infected, such as domestic cats, hamsters, ferrets, and mink. Several of these have proven animal-to-animal transmission and evidence of significant clinical and histopathologic disease that mimics acute COVID-19 in humans. Mobilizing these nontraditional animal models could have a crucial role in SARS-CoV-2 research efficiency and impact. This review focuses on what is known about these nontraditional animal models, including their immune responses to SARS-CoV-2 infection, evidence of clinical and histopathologic disease, transmission potential, and the practicality of each model in a research setting. Comparative insight into these animal models for COVID-19 can strengthen the efforts to mitigate this pandemic.","PeriodicalId":43005,"journal":{"name":"Journal of International Translational Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74574451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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