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Pathology, Research and Practice Jun 2024Oral leukoplakia (OLK) is the most common oral potentially malignant disorder (OPMD), which can be malignantly transformed into oral squamous cell carcinoma (OSCC)....
BACKGROUND
Oral leukoplakia (OLK) is the most common oral potentially malignant disorder (OPMD), which can be malignantly transformed into oral squamous cell carcinoma (OSCC). Peroxiredoxin1(Prx1) has been predicted to bind to Prohibitin2 (PHB2), which confers to affect OLK progression; however, the mechanism of Prx1/PHB2 mediated mitophagy involved in OLK remains unclear.
METHODS
This study aimed to explore the mechanism of the Prx1/PHB2 axis on senescence in OLK through mediating mitophagy. The positive rate of Ki67 and the expression of p21, p16, PHB2, and LC3 in human normal, OLK, and OSCC tissues were detected by immunohistochemical staining. The mitophagy and mitochondrial function changes were then analyzed in Prx1 knockdown and Prx1C52S mutations in dysplastic oral keratinocyte (DOK) cells treated with HO. In situ Proximity Ligation Assay combined with co-immunoprecipitation was used to detect the interaction between Prx1 and PHB2.
RESULTS
Clinically, the positive rate of Ki67 progressively increased from normal to OLK, OLK with dysplasia, and OSCC. Higher p21, p16, PHB2, and LC3 expression levels were observed in OLK with dysplasia than in normal and OSCC tissues. In vitro, PHB2 and LC3II expression gradually increased with the degree of DOK cell senescence. Prx1/PHB2 regulated mitophagy and affected senescence in HO-induced DOK cells. Furthermore, Prx1C52S mutation specifically reduced interaction between Prx1 and PHB2. Prx1Cys52 is associated with mitochondrial reactive oxygen species (ROS) accumulated and cell cycle arrest.
CONCLUSION
Prx1Cys52 functions as a redox sensor that binds to PHB2 and regulates mitophagy in the senescence of OLK, suggesting its potential as a clinical target.
PubMed: 38936092
DOI: 10.1016/j.prp.2024.155411 -
JCO Precision Oncology Jun 2024There is limited information about the clinical utility of targeted next-generation sequencing (NGS) panel testing to inform decision making for patients with advanced...
PURPOSE
There is limited information about the clinical utility of targeted next-generation sequencing (NGS) panel testing to inform decision making for patients with advanced solid tumors. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) is a prospective study that enrolled more than 4,500 patients with solid tumor for NGS panel testing. We performed a retrospective survey of medical oncologists to evaluate the impact of NGS testing on treatment decisions.
METHODS
Patients and treating oncologists were identified at the Princess Margaret Cancer Center between 2016 and 2021. Tumor-only sequencing was performed using a gene panel of either 555 or 161 cancer genes. Oncologists were asked to review testing results and complete a survey indicating whether NGS testing affected treatment decisions. The primary outcome of this study was rate of treatment change on the basis of mutation results. Patient, test, and physician factors were evaluated for association with treatment changes using univariate analyses and a mixed-effects model.
RESULTS
Of the 582 surveys sent, 394 (67.7%) were completed. We found that 188 (47.7%) patients had testing results classified as actionable by the oncologist and 62 (15.7%) patients were matched to treatment, of whom 37 (60%) were enrolled in a clinical trial, 13 (21%) received an approved drug, four (6%) were prescribed off-label therapy, and eight (13%) avoided ineffective treatment. Patient, test, and physician characteristics were not significantly associated with treatment change. There was no difference in overall survival between patients who received matched treatment versus those who did not ( = .55, median survival not reached).
CONCLUSION
OCTANE testing led to a change in drug treatment in 15.7% of patients, supporting the clinical utility of NGS panel testing for patients with advanced solid tumors.
Topics: Humans; Neoplasms; High-Throughput Nucleotide Sequencing; Male; Female; Middle Aged; Tertiary Care Centers; Retrospective Studies; Aged; Clinical Decision-Making; Adult; Ontario; Prospective Studies
PubMed: 38935894
DOI: 10.1200/PO.24.00092 -
Molecular Biology and Evolution Jun 2024Plant cells harbor two membrane-bound organelles containing their own genetic material -plastids and mitochondria. Although the two organelles co-exist and co-evolve...
Plant cells harbor two membrane-bound organelles containing their own genetic material -plastids and mitochondria. Although the two organelles co-exist and co-evolve within the same plant cells, they differ in genome copy number, intracellular organization, and mode of segregation. How these attributes affect the time to fixation, or conversely, loss of neutral alleles is currently unresolved. Here we show that mitochondria and plastids share the same mutation rate yet plastid alleles remain in a heteroplasmic state significantly longer compared to mitochondrial alleles. By analyzing genetic variants across populations of the marine flowering plant Zostera marina and simulating organelle allele dynamics, we examine the determinants of allele segregation and allele fixation. Our results suggest that bottlenecks on the cell population, e.g., during branching or seeding, and stratification of the meristematic tissue, are important determinants of mitochondrial allele dynamics. Furthermore, we suggest that the prolonged plastid allele dynamics are due to a yet unknown active plastid partition mechanism. The dissimilarity between plastid and mitochondrial novel allele fixation at different levels of organization may manifest in differences in adaptation processes. Our study uncovers fundamental principles of organelle population genetics that are essential for further investigations of long-term evolution and molecular dating of divergence events.
PubMed: 38934796
DOI: 10.1093/molbev/msae135 -
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