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Article ; Online: A Review on Anaplastic Lymphoma Kinase (ALK) Rearrangements and Mutations: Implications for Gastric Carcinogenesis and Target Therapy.

Mesquita, Felipe Pantoja / Lima, Luina Benevides / Silva, Emerson Lucena da / Souza, Pedro Filho Noronha / Moraes, Maria Elisabete Amaral de / Burbano, Rommel Mario Rodrigues / Montenegro, Raquel Carvalho

Current protein & peptide science

2024

Abstract: Gastric adenocarcinoma is a complex disease with diverse genetic modifications, including Anaplastic Lymphoma Kinase (ALK) gene changes. The ALK gene is located on chromosome 2p23 and encodes a receptor tyrosine kinase that plays a crucial role in ... ...

Abstract	Gastric adenocarcinoma is a complex disease with diverse genetic modifications, including Anaplastic Lymphoma Kinase (ALK) gene changes. The ALK gene is located on chromosome 2p23 and encodes a receptor tyrosine kinase that plays a crucial role in embryonic development and cellular differentiation. ALK alterations can result from gene fusion, mutation, amplification, or overexpression in gastric adenocarcinoma. Fusion occurs when the ALK gene fuses with another gene, resulting in a chimeric protein with constitutive kinase activity and promoting oncogenesis. ALK mutations are less common but can also result in the activation of ALK signaling pathways. Targeted therapies for ALK variations in gastric adenocarcinoma have been developed, including ALK inhibitors that have shown promising results in pre-clinical studies. Future studies are needed to elucidate the ALK role in gastric cancer and to identify predictive biomarkers to improve patient selection for targeted therapy. Overall, ALK alterations are a relevant biomarker for gastric adenocarcinoma treatment and targeted therapies for ALK may improve patients' overall survival.
Language	English
Publishing date	2024-02-28
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	2045662-1
ISSN	1875-5550 ; 1389-2037
ISSN (online)	1875-5550
ISSN	1389-2037
DOI	10.2174/0113892037291318240130103348
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Article ; Online: Mebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death.

da Silva, Emerson Lucena / Mesquita, Felipe Pantoja / Aragão, Dyane Rocha / de Sousa Portilho, Adrhyann Jullyanne / Marinho, Aline Diogo / de Oliveira, Lais Lacerda Brasil / Lima, Luina Benevides / de Moraes, Maria Elisabete Amaral / Souza, Pedro Filho Noronha / Montenegro, Raquel Carvalho

Toxicology and applied pharmacology

2023 Volume 475, Page(s) 116630

Abstract: Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the importance of metabolic reprogramming for the development and cancer progression, inhibitors ... ...

Abstract	Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the importance of metabolic reprogramming for the development and cancer progression, inhibitors of cell metabolism have been studied as potential candidates for chemotherapy in oncology. Mebendazole (MBZ), an antihelminthic approved by FDA, has shown antitumoral activity against cancer cell lines. However, its potential in the modulation of tumoral metabolism remains unclear. Results evidenced that the antitumoral and cytotoxic mechanism of MBZ in GC cells is related to the modulation of the mRNA expression of glycolic targets SLC2A1, HK1, GAPDH, and LDHA. Moreover, in silico analysis has shown that these genes are overexpressed in GC samples, and this increase in expression is related to decreased overall survival rates. Molecular docking revealed that MBZ modifies the protein structure of these targets, which may lead to changes in their protein function. In vitro studies also showed that MBZ induces alterations in glucose uptake, LDH's enzymatic activity, and ATP production. Furthermore, MBZ induced morphologic and intracellular alterations typical of the apoptotic cell death pathway. Thus, this data indicated that the cytotoxic mechanism of MBZ is related to an initial modulation of the tumoral metabolism in the GC cell line. Altogether, our results provide more evidence about the antitumoral mechanism of action of MBZ towards GC cells and reveal metabolic reprogramming as a potential area in the discovery of new pharmacological targets for GC chemotherapy.
MeSH term(s)	Humans ; Mebendazole/pharmacology ; Mebendazole/therapeutic use ; Stomach Neoplasms/drug therapy ; Cell Line, Tumor ; Molecular Docking Simulation ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Glucose
Chemical Substances	Mebendazole (81G6I5V05I) ; Antineoplastic Agents ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2023-07-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2023.116630
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Article ; Online: Effect of CYB2B6 (c.516G>T), CYP2C9 (c.1075A>C) and UGT1A9 (c.98T>C) polymorphisms on propofol pharmacokinetics in patients submitted to colonoscopy: a cohort study.

Poma, Mara Aparecida Maricato / Ribeiro Junior, Howard Lopes / Costa, Eugênio Araújo / Paier, Carlos Roberto Koscky / Brasil, Laís Lacerda / Lima, Luína Benevides / Nobre, Livia Maria Soares / Leite, Tayales Tavares / Lima-Júnior, Roberto César Pereira / Quidute, Ana Rosa Pinto / de Moraes, Maria Elisabete Amaral / de Moraes Filho, Manoel Odorico

Postgraduate medical journal

2023 Volume 99, Issue 1170, Page(s) 286–295

Abstract: Background: The aim of this study was to investigate the effect of CYB2B6 (c.516G>T, rs3745274), CYP2C9 (c.1075A>C, rs1057910) and UGT1A9 (c.98T>C, rs72551330) polymorphisms on the pharmacokinetics of single-drug propofol in adult patients undergoing ... ...

Abstract	Background: The aim of this study was to investigate the effect of CYB2B6 (c.516G>T, rs3745274), CYP2C9 (c.1075A>C, rs1057910) and UGT1A9 (c.98T>C, rs72551330) polymorphisms on the pharmacokinetics of single-drug propofol in adult patients undergoing intravenous sedation. Methods: In this prospective clinical study, a total of 124 patients undergoing anaesthesia with propofol, as a single drug, were evaluated when undergoing colonoscopy procedure. Clinical variables were obtained from the patient's anamnesis prior to performing the anaesthetic procedure, in the moment of the patient's loss of consciousness, during the colonoscopy exam (recorded every 5 min) and in the awakening time. Results: Polymorphic genotypes for the rs3745274 and rs1057910 polymorphisms were associated with bispectral index, target-controlled infusion (TCI)/effector concentration of propofol and TCI/plasma concentration of propofol values. Based on multivariate analysis, it was observed that weight, age, surgery time, systolic blood pressure and the rs1057910 polymorphism corresponded to predictive values for the dose of propofol used. Weight (B = 4.807±0.897), age (B = 1.834±0.834) and duration of surgery (B = 8.164±1.624) corresponded to factors associated with increased propofol dose, while systolic blood pressure (B = -1.892±0.679) and the genotypes (AA vs CA) of the single nucleotide polymorphism (SNP) rs1057910 CYPP2C9 gene (B = -74.161±26.820) decreased the total dose of propofol used. Conclusion: We concluded that the rs1057910 and rs3745274 polymorphisms affect the metabolism of propofol in patients exclusively submitted to this drug. Thus, the knowledge of the polymorphic genotypes of the CYPP2C9 and CYB2B6 genes may be predictive of different metabolising phenotypes, suggesting expected behaviours of BIS parameter in the anaesthetic procedure, which contributes to safer monitoring by anaesthesiologists during the clinical intervention.
MeSH term(s)	Humans ; Cohort Studies ; Cytochrome P-450 CYP2C9/genetics ; Electroencephalography ; Polymorphism, Single Nucleotide ; Propofol/pharmacokinetics ; Propofol/therapeutic use ; Prospective Studies ; Cytochrome P-450 CYP2B6/genetics ; UDP-Glucuronosyltransferase 1A9/genetics
Chemical Substances	CYP2C9 protein, human (EC 1.14.13.-) ; Cytochrome P-450 CYP2C9 (EC 1.14.13.-) ; Propofol (YI7VU623SF) ; Cytochrome P-450 CYP2B6 (EC 1.14.14.1) ; UDP-Glucuronosyltransferase 1A9 (EC 2.4.1.17)
Language	English
Publishing date	2023-05-25
Publishing country	England
Document type	Journal Article
ZDB-ID	80325-x
ISSN	1469-0756 ; 0032-5473
ISSN (online)	1469-0756
ISSN	0032-5473
DOI	10.1136/postgradmedj-2021-141375
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Article: Kinase Inhibitor Screening Displayed

Mesquita, Felipe Pantoja / Souza, Pedro Filho Noronha / da Silva, Emerson Lucena / Lima, Luina Benevides / de Oliveira, Lais Lacerda Brasil / Moreira-Nunes, Caroline Aquino / Zuercher, William J / Burbano, Rommel Mario Rodríguez / de Moraes, Maria Elisabete Amaral / Montenegro, Raquel Carvalho

Pharmaceutics

2022 Volume 14, Issue 9

Abstract: Despite advances in cancer chemotherapy, gastric cancer (GC) continues to have high recurrence rates and poor prognosis with limited treatment options. Understanding the etiology of GC and developing more effective, less harmful therapeutic approaches ... ...

Abstract	Despite advances in cancer chemotherapy, gastric cancer (GC) continues to have high recurrence rates and poor prognosis with limited treatment options. Understanding the etiology of GC and developing more effective, less harmful therapeutic approaches are vital and urgent. Therefore, this work describes a novel kinase target in malignant gastric cells as a potential therapeutic strategy. Our results demonstrate that among 147 kinase inhibitors (KI), only three molecules were significantly cytotoxic for the AGP-01 cell line. Hence, these three molecules were further characterized in their cellular mode of action. There was significant cell cycle impairment due to the expression modulation of genes such as
Language	English
Publishing date	2022-09-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14091841
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Article ; Online: True or false: what are the factors that influence COVID-19 diagnosis by RT-qPCR?

Benevides Lima, Luina / Mesquita, Felipe Pantoja / Brasil de Oliveira, Lais Lacerda / Andréa da Silva Oliveira, Francisca / Elisabete Amaral de Moraes, Maria / Souza, Pedro F N / Montenegro, Raquel Carvalho

Expert review of molecular diagnostics

2022 Volume 22, Issue 2, Page(s) 157–167

Abstract: Introduction: The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease has had a catastrophic impact on the world resulting in several deaths. Since World Health Organization declared the pandemic status of the disease, several molecular ...

Abstract	Introduction: The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease has had a catastrophic impact on the world resulting in several deaths. Since World Health Organization declared the pandemic status of the disease, several molecular diagnostic kits have been developed to help the tracking of viruses spread. Areas covered: This review aims to describe and evaluate the currently reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) diagnosis kit. Several processes used in COVID-19 diagnostic procedures are detailed in further depth to demonstrate optimal practices. Therefore, we debate the main factors that influence the viral detection of SARS-COV-2 and how they can affect the diagnosis of patients. Expert opinion: Here is highlighted and discussed several factors that can interfere in the RT-PCR analysis, such as the viral load of the sample, collection site, collection methodology, sample storage, transport, primer, and probe mismatch/dimerization in different brand kits. This is a pioneer study to discuss the factor that could lead to the wrong interpretation of RT-qPCR diagnosis of SARS-CoV-2. This study aimed to help the readers to understand what very likely is behind a bad result of SARS-CoV-2 detection by RT-PCR and what could be done to reach a reliable diagnosis.
MeSH term(s)	COVID-19/diagnosis ; COVID-19 Testing ; Humans ; RNA, Viral/analysis ; RNA, Viral/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; SARS-CoV-2/genetics ; Sensitivity and Specificity
Chemical Substances	RNA, Viral
Language	English
Publishing date	2022-02-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2112530-2
ISSN	1744-8352 ; 1473-7159
ISSN (online)	1744-8352
ISSN	1473-7159
DOI	10.1080/14737159.2022.2037425
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Article: Anticancer potential of mebendazole against chronic myeloid leukemia:

Daniel, Julio Paulino / Mesquita, Felipe Pantoja / Da Silva, Emerson Lucena / de Souza, Pedro Filho Noronha / Lima, Luina Benevides / de Oliveira, Lais Lacerda Brasil / de Moraes, Maria Elisabete Amaral / Moreira-Nunes, Caroline de Fátima Aquino / Burbano, Rommel Mario Rodríguez / Zanatta, Geancarlo / Montenegro, Raquel Carvalho

Frontiers in pharmacology

2022 Volume 13, Page(s) 952250

Abstract: Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, ... ...

Abstract	Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cause resistance in patients. As a result, broad-spectrum ABL1 medicines are desperately needed. In order to screen potential drugs targeting CML, mebendazole (MBZ) was subjected to the
Language	English
Publishing date	2022-08-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2022.952250
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Article ; Online: Effect of CYB2B6 (c.516G>T), CYP2C9 (c.1075A>C) and UGT1A9 (c.98T>C) polymorphisms on propofol pharmacokinetics in patients submitted to colonoscopy: a cohort study.

Postgraduate medical journal

2022

Abstract	Background: The aim of this study was to investigate the effect of CYB2B6 (c.516G>T, rs3745274), CYP2C9 (c.1075A>C, rs1057910) and UGT1A9 (c.98T>C, rs72551330) polymorphisms on the pharmacokinetics of single-drug propofol in adult patients undergoing intravenous sedation. Methods: In this prospective clinical study, a total of 124 patients undergoing anaesthesia with propofol, as a single drug, were evaluated when undergoing colonoscopy procedure. Clinical variables were obtained from the patient's anamnesis prior to performing the anaesthetic procedure, in the moment of the patient's loss of consciousness, during the colonoscopy exam (recorded every 5 min) and in the awakening time. Results: Polymorphic genotypes for the rs3745274 and rs1057910 polymorphisms were associated with bispectral index, target-controlled infusion (TCI)/effector concentration of propofol and TCI/plasma concentration of propofol values. Based on multivariate analysis, it was observed that weight, age, surgery time, systolic blood pressure and the rs1057910 polymorphism corresponded to predictive values for the dose of propofol used. Weight (B = 4.807±0.897), age (B = 1.834±0.834) and duration of surgery (B = 8.164±1.624) corresponded to factors associated with increased propofol dose, while systolic blood pressure (B = -1.892±0.679) and the genotypes (AA vs CA) of the single nucleotide polymorphism (SNP) rs1057910 CYPP2C9 gene (B = -74.161±26.820) decreased the total dose of propofol used. Conclusion: We concluded that the rs1057910 and rs3745274 polymorphisms affect the metabolism of propofol in patients exclusively submitted to this drug. Thus, the knowledge of the polymorphic genotypes of the CYPP2C9 and CYB2B6 genes may be predictive of different metabolising phenotypes, suggesting expected behaviours of BIS parameter in the anaesthetic procedure, which contributes to safer monitoring by anaesthesiologists during the clinical intervention.
Language	English
Publishing date	2022-02-15
Publishing country	England
Document type	Journal Article
ZDB-ID	80325-x
ISSN	1469-0756 ; 0032-5473
ISSN (online)	1469-0756
ISSN	0032-5473
DOI	10.1136/postmj/postgradmedj-2021-141375
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Article ; Online: Genomic surveillance: Circulating lineages and genomic variation of SARS-CoV-2 in early pandemic in Ceará state, Northeast Brazil.

Oliveira, Francisca Andréa da Silva / de Holanda, Maísa Viana / Lima, Luína Benevides / Dantas, Mariana Brito / Duarte, Igor Oliveira / de Castro, Luzia Gabrielle Zeferino / de Oliveira, Laís Lacerda Brasil / Paier, Carlos Roberto Koscky / Moreira-Nunes, Caroline de Fátima Aquino / Lima, Nicholas Costa Barroso / de Moraes, Maria Elisabete Amaral / de Moraes Filho, Manoel Odorico / Melo, Vânia Maria Maciel / Montenegro, Raquel Carvalho

Virus research

2022 Volume 321, Page(s) 198908

Abstract: In the Northeast of Brazil, Ceará was the second state most impacted by COVID-19 in number of cases and death rate. Despite that, the early dynamics of the pandemic in Ceará was not yet well understood due the low genomic surveillance of SARS-CoV-2 in ... ...

Abstract	In the Northeast of Brazil, Ceará was the second state most impacted by COVID-19 in number of cases and death rate. Despite that, the early dynamics of the pandemic in Ceará was not yet well understood due the low genomic surveillance of SARS-CoV-2 in 2020. In this study, we analyze the circulating lineages and the genomic variation of the virus in Ceará state. Thirty-four genomes were sequenced and combined with sequences available in GISAID database from March 2020 to June 2021 to compose the study dataset. The most prevalent lineages detected were B.1.1.33, in 2020, and P.1, in 2021. Other lineages were found, such as P.2, sublineages of P.1, B.1, B.1.1, B.1.1.28 and B.1.212. Analyzing the mutations, a total of 202 single-nucleotide polymorphisms (SNPs) were identified among the 34 genomes sequenced, of which 127 were missense, 74 synonymous, and one was a nonsense mutation. Among the missense mutations, C14408T, A23403G, T27299C, G28881A G28883C, and T29148C were the most prevalent within the dataset. Although SARS-CoV-2 sequencing data was limited in 2020, our results could provide insights to better understand the genetic diversity of the circulating lineages in Ceará.
MeSH term(s)	Humans ; Brazil/epidemiology ; Codon, Nonsense ; COVID-19/epidemiology ; Genome, Viral ; Genomics ; Mutation ; Pandemics ; Phylogeny ; SARS-CoV-2/genetics
Chemical Substances	Codon, Nonsense
Language	English
Publishing date	2022-08-31
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2022.198908
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Article ; Online: Mebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death

Toxicology and Applied Pharmacology. 2023 Sept., v. 475 p.116630-

2023

Abstract	Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the importance of metabolic reprogramming for the development and cancer progression, inhibitors of cell metabolism have been studied as potential candidates for chemotherapy in oncology. Mebendazole (MBZ), an antihelminthic approved by FDA, has shown antitumoral activity against cancer cell lines. However, its potential in the modulation of tumoral metabolism remains unclear. Results evidenced that the antitumoral and cytotoxic mechanism of MBZ in GC cells is related to the modulation of the mRNA expression of glycolic targets SLC2A1, HK1, GAPDH, and LDHA. Moreover, in silico analysis has shown that these genes are overexpressed in GC samples, and this increase in expression is related to decreased overall survival rates. Molecular docking revealed that MBZ modifies the protein structure of these targets, which may lead to changes in their protein function. In vitro studies also showed that MBZ induces alterations in glucose uptake, LDH's enzymatic activity, and ATP production. Furthermore, MBZ induced morphologic and intracellular alterations typical of the apoptotic cell death pathway. Thus, this data indicated that the cytotoxic mechanism of MBZ is related to an initial modulation of the tumoral metabolism in the GC cell line. Altogether, our results provide more evidence about the antitumoral mechanism of action of MBZ towards GC cells and reveal metabolic reprogramming as a potential area in the discovery of new pharmacological targets for GC chemotherapy.
Keywords	apoptosis ; cell lines ; computer simulation ; cytotoxicity ; death ; drug therapy ; energy metabolism ; enzyme activity ; gene expression ; glucose ; mebendazole ; mechanism of action ; neoplasm cells ; neoplasm progression ; pharmacology ; protein structure ; stomach neoplasms ; toxicology ; Antitumoral ; Drug repurposing ; Glycolytic pathway ; Metabolic reprogramming ; Molecular docking ; Pharmacologic targets
Language	English
Dates of publication	2023-09
Publishing place	Elsevier Inc.
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2023.116630
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Article: Genomic surveillance: Circulating lineages and genomic variation of SARS-CoV-2 in early pandemic in Ceará state, Northeast Brazil

Virus research. 2022 Nov., v. 321

2022

Abstract	In the Northeast of Brazil, Ceará was the second state most impacted by COVID-19 in number of cases and death rate. Despite that, the early dynamics of the pandemic in Ceará was not yet well understood due the low genomic surveillance of SARS-CoV-2 in 2020. In this study, we analyze the circulating lineages and the genomic variation of the virus in Ceará state. Thirty-four genomes were sequenced and combined with sequences available in GISAID database from March 2020 to June 2021 to compose the study dataset. The most prevalent lineages detected were B.1.1.33, in 2020, and P.1, in 2021. Other lineages were found, such as P.2, sublineages of P.1, B.1, B.1.1, B.1.1.28 and B.1.212. Analyzing the mutations, a total of 202 single-nucleotide polymorphisms (SNPs) were identified among the 34 genomes sequenced, of which 127 were missense, 74 synonymous, and one was a nonsense mutation. Among the missense mutations, C14408T, A23403G, T27299C, G28881A G28883C, and T29148C were the most prevalent within the dataset. Although SARS-CoV-2 sequencing data was limited in 2020, our results could provide insights to better understand the genetic diversity of the circulating lineages in Ceará.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; data collection ; databases ; genetic variation ; genome ; genomics ; monitoring ; mortality ; nonsense mutation ; pandemic ; research ; viruses ; Brazil
Language	English
Dates of publication	2022-11
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2022.198908
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