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Fundamental Research May 2024Coronavirus disease 2019 (COVID-19) is a severe global public health emergency that has caused a major crisis in the safety of human life, health, global economy, and...
Coronavirus disease 2019 (COVID-19) is a severe global public health emergency that has caused a major crisis in the safety of human life, health, global economy, and social order. Moreover, COVID-19 poses significant challenges to healthcare systems worldwide. The prediction and early warning of infectious diseases on a global scale are the premise and basis for countries to jointly fight epidemics. However, because of the complexity of epidemics, predicting infectious diseases on a global scale faces significant challenges. In this study, we developed the second version of Global Prediction System for Epidemiological Pandemic (GPEP-2), which combines statistical methods with a modified epidemiological model. The GPEP-2 introduces various parameterization schemes for both impacts of natural factors (seasonal variations in weather and environmental impacts) and human social behaviors (government control and isolation, personnel gathered, indoor propagation, virus mutation, and vaccination). The GPEP-2 successfully predicted the COVID-19 pandemic in over 180 countries with an average accuracy rate of 82.7%. It also provided prediction and decision-making bases for several regional-scale COVID-19 pandemic outbreaks in China, with an average accuracy rate of 89.3%. Results showed that both anthropogenic and natural factors can affect virus spread and control measures in the early stages of an epidemic can effectively control the spread. The predicted results could serve as a reference for public health planning and policymaking.
PubMed: 38933188
DOI: 10.1016/j.fmre.2023.02.030 -
Viruses Jun 2024Experimental evolution studies, in which biological populations are evolved in a specific environment over time, can address questions about the nature of spontaneous... (Review)
Review
Experimental evolution studies, in which biological populations are evolved in a specific environment over time, can address questions about the nature of spontaneous mutations, responses to selection, and the origins and maintenance of novel traits. Here, we review more than 30 years of experimental evolution studies using the bacteriophage (phage) Φ6 cystovirus. Similar to many lab-studied bacteriophages, Φ6 has a high mutation rate, large population size, fast generation time, and can be genetically engineered or cryogenically frozen, which facilitates its rapid evolution in the laboratory and the subsequent characterization of the effects of its mutations. Moreover, its segmented RNA genome, outer membrane, and capacity for multiple phages to coinfect a single host cell make Φ6 a good non-pathogenic model for investigating the evolution of RNA viruses that infect humans. We describe experiments that used Φ6 to address the fitness effects of spontaneous mutations, the consequences of evolution in the presence of coinfection, the evolution of host ranges, and mechanisms and consequences of the evolution of thermostability. We highlight open areas of inquiry where further experimentation on Φ6 could inform predictions for pathogenic viruses.
Topics: Bacteriophage phi 6; Mutation; Host Specificity; Evolution, Molecular; Cystoviridae; Genome, Viral; Humans; Directed Molecular Evolution; Biological Evolution
PubMed: 38932268
DOI: 10.3390/v16060977 -
Viruses Jun 2024Dugbe virus (DUGV) is a tick-borne arbovirus first isolated in Nigeria in 1964. It has been detected in many African countries using such diverse methods as serological...
Dugbe virus (DUGV) is a tick-borne arbovirus first isolated in Nigeria in 1964. It has been detected in many African countries using such diverse methods as serological tests, virus isolation, and molecular detection. In Senegal, reports of DUGV isolates mainly occurred in the 1970s and 1980s. Here, we report a contemporary detection of three novel DUGV isolates upon screening of a total of 2877 individual ticks regrouped into 844 pools. The three positive pools were identified as , the main known vector of DUGV, collected in the southern part of the country (Kolda region). Interestingly, phylogenetic analysis indicates that the newly sequenced isolates are globally related to the previously characterized isolates in West Africa, thus highlighting potentially endemic, unnoticed viral transmission. This study was also an opportunity to develop a rapid and affordable protocol for full-genome sequencing of DUGV using nanopore technology. The results suggest a relatively low mutation rate and relatively conservative evolution of DUGV isolates.
Topics: Animals; Senegal; Phylogeny; Genome, Viral; Ticks; Amblyomma; Arboviruses
PubMed: 38932256
DOI: 10.3390/v16060964 -
Viruses Jun 2024Despite the availability of a vaccine against hepatitis B virus (HBV), this infection still causes public health problems, particularly in susceptible populations. In...
Despite the availability of a vaccine against hepatitis B virus (HBV), this infection still causes public health problems, particularly in susceptible populations. In Portugal, universal free vaccination started in 1994, and most HBV infections are diagnosed in immigrants from high-prevalence countries. Our aim was to assess the pattern of HBV genotypes/subgenotypes in samples collected between 2017 and 2021 from a convenience sample of 70 infected residents in Portugal. The HBV pol/HBsAg region was amplified and sequenced, allowing the analysis of RT sequences submitted to phylogenetic analysis and mutations assessment. A total of 37.1% of samples were from native Portuguese, aged 25-53 years (mean: 36.7 years), and the remaining samples were from individuals born outside of Portugal. A high diversity of HBV was identified: subgenotypes A1-A3 in 41.0% (16/39); D1, D3, and D4 in 30.7% (12/39); E in 23.1% (9/39); and F4 in 2.6% (1/39). Besides genotypes A and D, Portuguese were also infected with genotypes E and F, which are prevalent in Africa and South America, respectively. Resistance mutations in RT sequences were not found. The findings provide valuable insights for updating the HBV molecular epidemiology in Portugal. However, successful strategies to prevent and control the infection are still needed in the country, especially among susceptible and vulnerable populations.
Topics: Humans; Hepatitis B virus; Genotype; Adult; Middle Aged; Phylogeny; Hepatitis B; Female; Male; Portugal; Vaccination; Hepatitis B Vaccines; Mutation; Genetic Variation; Hepatitis B Surface Antigens; DNA, Viral; Young Adult
PubMed: 38932246
DOI: 10.3390/v16060954 -
Medicina (Kaunas, Lithuania) Jun 2024: Malaria continues to be a significant global health challenge. The efficacy of artemisinin-based combination therapies (ACTs) has declined in many parts of the Greater...
: Malaria continues to be a significant global health challenge. The efficacy of artemisinin-based combination therapies (ACTs) has declined in many parts of the Greater Mekong Subregion, including Vietnam, due to the spread of resistant malaria strains. This study was conducted to assess the efficacy of the Dihydroartemisinin (DHA)-Piperaquine (PPQ) regimen in treating uncomplicated malaria and to conduct molecular surveillance of antimalarial drug resistance in Binh Phuoc and Dak Nong provinces. : The study included 63 uncomplicated malaria falciparum patients from therapeutic efficacy studies (TES) treated following the WHO treatment guidelines (2009). Molecular marker analysis was performed on all 63 patients. Methods encompassed Sanger sequencing for mutations and quantitative real-time PCR for the gene. : This study found a marked decrease in the efficacy of the DHA-PPQ regimen, with an increased rate of treatment failures at two study sites. Genetic analysis revealed a significant presence of mutations and amplifications, indicating emerging resistance to artemisinin and its partner drug. : The effectiveness of the standard DHA-PPQ regimen has sharply declined, with rising treatment failure rates. This decline necessitates a review and possible revision of national malaria treatment guidelines. Importantly, molecular monitoring and clinical efficacy assessments together provide a robust framework for understanding and addressing detection drug resistance in malaria.
Topics: Humans; Artemisinins; Quinolines; Vietnam; Antimalarials; Malaria, Falciparum; Male; Female; Adult; Plasmodium falciparum; Drug Resistance; Adolescent; Middle Aged; Drug Therapy, Combination; Young Adult; Protozoan Proteins; Real-Time Polymerase Chain Reaction; Mutation; Piperazines
PubMed: 38929629
DOI: 10.3390/medicina60061013 -
International Journal of Molecular... Jun 2024The association between leukemic stem cells (LSCs) and leukemia development has been widely established in the context of genetic alterations, epigenetic pathways, and... (Review)
Review
The association between leukemic stem cells (LSCs) and leukemia development has been widely established in the context of genetic alterations, epigenetic pathways, and signaling pathway regulation. Hematopoietic stem cells are at the top of the bone marrow hierarchy and can self-renew and progressively generate blood and immune cells. The microenvironment, niche cells, and complex signaling pathways that regulate them acquire genetic mutations and epigenetic alterations due to aging, a chronic inflammatory environment, stress, and cancer, resulting in hematopoietic stem cell dysregulation and the production of abnormal blood and immune cells, leading to hematological malignancies and blood cancer. Cells that acquire these mutations grow at a faster rate than other cells and induce clone expansion. Excessive growth leads to the development of blood cancers. Standard therapy targets blast cells, which proliferate rapidly; however, LSCs that can induce disease recurrence remain after treatment, leading to recurrence and poor prognosis. To overcome these limitations, researchers have focused on the characteristics and signaling systems of LSCs and therapies that target them to block LSCs. This review aims to provide a comprehensive understanding of the types of hematopoietic malignancies, the characteristics of leukemic stem cells that cause them, the mechanisms by which these cells acquire chemotherapy resistance, and the therapies targeting these mechanisms.
Topics: Humans; Hematologic Neoplasms; Neoplastic Stem Cells; Hematopoietic Stem Cells; Leukemia; Signal Transduction; Animals; Tumor Microenvironment; Drug Resistance, Neoplasm; Epigenesis, Genetic; Mutation
PubMed: 38928344
DOI: 10.3390/ijms25126639 -
Cancers Jun 2024Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M...
Lazertinib versus Platinum-Based Chemotherapy with Epidermal Growth Factor Receptor (EGFR)-Positive Non-Small-Cell Lung Cancer after Failing EGFR-Tyrosine Kinase Inhibitor: A Real-World External Comparator Study.
BACKGROUND
Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M mutation in non-small-cell lung cancer (NSCLC) patients. No previous studies have compared lazertinib to platinum-based chemotherapy. We have compared lazertinib with platinum-based chemotherapy in EGFR-mutated NSCLC patients after previous EGFR-TKI therapy.
METHODS
We retrospectively compared 200 patients from LASER201, LASER301, and LASER-PMS studies to 334 patients who were treated with platinum-based chemotherapy after previous EGFR-TKI from the Samsung Medical Center. After propensity score matching (PSM), we selected 156 patients from each group. The primary outcome was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and time to treatment discontinuation (TTD) as secondary outcomes.
RESULTS
The median follow-up of PFS was 15.61 months in the lazertinib group and 21.67 months in the external control group. The PFS was significantly longer in patients who were treated with lazertinib than those treated with platinum-based chemotherapy (10.97 months vs. 5.10 months; adjusted hazard ratio (HR) 0.40; 95% confidence interval (CI), 0.29-0.55; < 0.01) after PSM. Lazertinib showed superior OS (32.23 months vs. 18.73 months; adjusted HR 0.45; 95% CI, 0.29-0.69; < 0.001), ORR (64.1% vs. 47.4%), and TTD (11.66 months vs. 6.73 months; adjusted HR 0.54; 95% CI, 0.39-0.75; < 0.001) compared to platinum-based chemotherapy.
CONCLUSION
Based on this retrospective, external control study, lazertinib has demonstrated significantly better efficacy compared with platinum-based chemotherapy. The external controls provide important context to evaluate efficacy in single-arm studies.
PubMed: 38927875
DOI: 10.3390/cancers16122169 -
Genes Jun 2024Breast cancer (BC) has the highest morbidity rate and the second-highest mortality rate of all cancers among women. Recently, multi-cancer genome profiling (multi-CGP)...
Breast cancer (BC) has the highest morbidity rate and the second-highest mortality rate of all cancers among women. Recently, multi-cancer genome profiling (multi-CGP) tests have become clinically available. In this study, we aimed to clarify the significance of multi-CGP testing of BC by using the large clinical dataset from The Center for Cancer Genomics and Advanced Therapeutics (C-CAT) profiling database in Japan. A total of 3744 BC cases were extracted from the C-CAT database, which enrolled 60,250 patients between June 2019 and October 2023. Of the 3744 BC cases, a total of 3326 cases for which the C-CAT included information on ER, PR, and HER2 status were classified into four subtypes, including TNBC, HR+/HER2-, HR+/HER2+, and HR-/HER2+. Comparisons between groups were performed by the χ test or Fisher's exact test using EZR. Kaplan-Meier curves were created using the log-rank test. : Of all 3326 cases analyzed, 1114 (33.5%) were TNBC cases, HR+/HER2- accounted for 1787 cases (53.7%), HR+/HER2+ for 260 cases (7.8%), and HR-/HER2+ for 165 cases (5.0%). Genetic abnormalities were most frequently detected in (58.0%), (35.5%), (18.7%), (15.5%), and (15.1%) across all BCs. The rate of TMB-High was 12.3%, and the rate of MSI-High was 0.3%, in all BC cases. Therapeutic drugs were proposed for patients with mutations in six genes: , , , , , and . The prognoses of HR+/HER2- cases were significantly ( = 0.044) better in the treated group than in the untreated group. : These findings suggest that cancer gene panel testing is useful for HR+/HER2- cases.
Topics: Humans; Female; Japan; Middle Aged; Breast Neoplasms; Receptor, ErbB-2; Aged; Adult; Retrospective Studies; Biomarkers, Tumor; Receptors, Estrogen; Receptors, Progesterone; Aged, 80 and over; Prognosis; Mutation; Gene Expression Profiling; Class I Phosphatidylinositol 3-Kinases
PubMed: 38927728
DOI: 10.3390/genes15060792 -
Biomedicines Jun 2024Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator...
Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator (ICD) should be considered in patients with an estimated 5-year risk of malignant ventricular arrhythmia (MVA) of ≥10%. The risk prediction score for MVA includes non-missense LMNA mutations, despite their role as an established risk factor for sudden cardiac death (SCD) has been questioned in several studies. The purpose of this study is to investigate cardiac features and find gene-phenotype correlations that would contribute to the evidence on the prognostic implications of non-missense vs. missense mutations in a cohort of LMNA mutant patients. An observational, prospective study was conducted in which 54 patients positive for a Lamin A/C mutation were enrolled, and 20 probands (37%) were included. The median age at first clinical manifestation was 41 (IQR 19) years. The median follow-up was 8 years (IQR 8). The type of gene mutation was distributed as follows: missense in 26 patients (48%), non-frameshift insertions in 16 (30%), frameshift deletions in 5 (9%), and nonsense in 7 (13%). Among the missense mutation carriers, two (8%) died and four (15%) were admitted onto the heart transplant list or underwent transplantation, with a major adverse cardiovascular event (MACE) rate of 35%. No statistically significant differences in MACE prevalence were identified according to the missense and non-missense mutation groups ( value = 0.847). Our data shift the spotlight on this considerable topic and could suggest that some missense mutations may deserve attention regarding SCD risk stratification in real-world clinical settings.
PubMed: 38927500
DOI: 10.3390/biomedicines12061293 -
Biomolecules Jun 2024Lung cancer is a major global health concern with a low survival rate, often due to late-stage diagnosis. Liquid biopsy offers a non-invasive approach to cancer...
Lung cancer is a major global health concern with a low survival rate, often due to late-stage diagnosis. Liquid biopsy offers a non-invasive approach to cancer detection and monitoring, utilizing various features of circulating cell-free DNA (cfDNA). In this study, we established two models based on cfDNA coverage patterns at the transcription start sites (TSSs) from 6X whole-genome sequencing: an Early Cancer Screening Model and an mutation status prediction model. The Early Cancer Screening Model showed encouraging prediction ability, especially for early-stage lung cancer. The mutation status prediction model exhibited high accuracy in distinguishing between -positive and wild-type cases. Additionally, cfDNA coverage patterns at TSSs also reflect gene expression patterns at the pathway level in lung cancer patients. These findings demonstrate the potential applications of cfDNA coverage patterns at TSSs in early cancer screening and in cancer subtyping.
Topics: Humans; ErbB Receptors; Lung Neoplasms; Early Detection of Cancer; Mutation; Cell-Free Nucleic Acids; Female; Male; Middle Aged; Aged; Proof of Concept Study; Biomarkers, Tumor; Liquid Biopsy; Whole Genome Sequencing; Transcription Initiation Site; Circulating Tumor DNA
PubMed: 38927119
DOI: 10.3390/biom14060716