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International Journal of Molecular... Jan 2022Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that have become fixed in the human genome. While HERV genes are typically silenced...
Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that have become fixed in the human genome. While HERV genes are typically silenced in healthy somatic cells, there are numerous reports of HERV transcription and translation across a wide spectrum of cancers, while T and B cell responses against HERV proteins have been detected in cancer patients. This review systematically categorizes the published evidence on the expression of and adaptive immune response against specific HERVs in distinct cancer types. A systematic literature search was performed using Medical Search Headings (MeSH) in the PubMed/Medline database. Papers were included if they described the translational activity of HERVs. We present multiple tables that pair the protein expression of specific HERVs and cancer types with information on the quality of the evidence. We find that HERV-K is the most investigated HERV. HERV-W (syncytin-1) is the second-most investigated, while other HERVs have received less attention. From a therapeutic perspective, HERV-K and HERV-E are the only HERVs with experimental demonstration of effective targeted therapies, but unspecific approaches using antiviral and demethylating agents in combination with chemo- and immunotherapies have also been investigated.
Topics: Animals; Antibody Formation; Endogenous Retroviruses; Host-Pathogen Interactions; Humans; Neoplasms; Retroviridae Infections; Viral Proteins
PubMed: 35163254
DOI: 10.3390/ijms23031330 -
European Review For Medical and... Mar 2021Abnormal DNA methylation plays a critical role in acute myeloid leukemia (AML) pathogenesis and hypomethylating agents (HMAs) such as decitabine (5-aza-29-deoxycytidine)... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Abnormal DNA methylation plays a critical role in acute myeloid leukemia (AML) pathogenesis and hypomethylating agents (HMAs) such as decitabine (5-aza-29-deoxycytidine) and azacitidine (5-azacytidine) are considered efficacious for treating AML. This study aimed to identify if HMAs have therapeutic advantages compared with conventional care regimens (CCR) or placebo in elderly AML patients.
MATERIALS AND METHODS
We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to November July 15, 2020. Randomized controlled trials that compared the efficacy and adverse events associated with HMAs, CCR, or placebo were searched. RevMan 5.3 software was used to calculate the hazard ratio (HR) and risk ratio (RR) with a 95% confidence interval (CI).
RESULTS
Seven trials with a total of 1966 participants were included. Meta-analyses showed that the overall survival of HMAs was better than that of CCR [HR=0.76, 95% CI (0.69-0.85), (p<0.01)], and the complete remission rate of elderly AML patients was increased by HMAs compared with CCR [RR=1.46, 95%CI (1.08-1.99), p=0.01)]. HMA treatment showed higher incidence of neutropenia [RR=1.30 (95%CI 1.07-1.59, p=0.008)], thrombocytopenia [RR=1.14 (95%CI 1.01-1.59, p=0.04)], and pneumonia [RR=1.37 (95%CI 1.06-1.76, p=0.02)] compared with CCR.
CONCLUSIONS
Although HMAs cause a higher incidence of adverse events such as neutropenia, thrombocytopenia, and pneumonia, demethylation drugs are well-tolerated and effective for treating AML in the elderly.
Topics: Aged; Antimetabolites, Antineoplastic; Azacitidine; Humans; Leukemia, Myeloid, Acute; Randomized Controlled Trials as Topic
PubMed: 33829444
DOI: 10.26355/eurrev_202103_25421 -
European Cardiology Jul 2019Acute coronary syndrome (ACS) is characterised by increased effector cells and decreased regulatory T-cells (Tregs). Statins have been shown to be clinically beneficial... (Review)
Review
The Effect of Statins on the Functionality of CD4+CD25+FOXP3+ Regulatory T-cells in Acute Coronary Syndrome: A Systematic Review and Meta-analysis of Randomised Controlled Trials in Asian Populations.
Acute coronary syndrome (ACS) is characterised by increased effector cells and decreased regulatory T-cells (Tregs). Statins have been shown to be clinically beneficial in ACS patients. This effect could be mediated via the induction of Tregs in ACS patients. The aim of this systemic review and meta-analysis was to evaluate whether statin therapy enhances the frequency of Tregs determined by CD4+CD25+FOXP3+ in this subset of patients. A comprehensive search of PubMed and Embase was performed. Studies were restricted to randomised controlled trials that quantified CD4+CD25+FOXP3+ cell frequency by flow cytometric analysis before and after statin treatment in adults diagnosed with ACS. A minimum of at least two of the conventional markers to identify Tregs was compulsory. Four randomised controlled trials studies (439 participants) were included, all with low-to-moderate risk of bias. Pooled data showed a significant increase in Treg frequency after statin therapy in ACS patients. A further meta-regression and subgroup analysis also showed a negative dose-related effect, and a statin type-related effect (rosuvastatin versus atorvastatin), respectively. The results confirmed that statins positively alter the frequency of Tregs, which may indicate a potential mechanism of their therapeutic effect. However, there was a risk of information bias due to the markers used to identify Tregs, which was not fully explored, therefore, further randomised controlled trials should utilise markers of Tregs, such as the FOXP3 locus (Treg-specific demethylated region), for identification.
PubMed: 31360235
DOI: 10.15420/ecr.2019.9.2 -
Cancer Cell International Oct 2022Gene silence via methylation of the CpG islands is cancer's most common epigenetic modification. Given the highly significant role of NIS in thyroid cancer (TC)...
BACKGROUND
Gene silence via methylation of the CpG islands is cancer's most common epigenetic modification. Given the highly significant role of NIS in thyroid cancer (TC) differentiation, this cross-sectional study aimed to investigate the DNA methylation pattern in seven CpG islands (CpG1-7 including +846, +918, +929, +947, +953, +955, and +963, respectively) of the NIS promoter in patients diagnosed with papillary (PTC), follicular (FTC), and multinodular goiter (MNG). Additionally, a systematic review of the literature was conducted to compare our results with studies concerning methylation of the NIS gene promoter.
METHODS
Thyroid specimens from 64 patients met the eligibility criteria, consisting of 28 PTC, 9 FTC, and 27 benign MNG cases. The mRNA of NIS was tested by qRT-PCR. The bisulfite sequencing PCR (BSP) technique was performed to evaluate the promoter methylation pattern of the NIS gene. Sequencing results were received in chromatograph, FASTA, SEQ, and pdf formats and were analyzed using Chromas. The methylation percentage at each position and for each sample was calculated by mC/(mC+C) formula for all examined CpGs; following that, the methylation percentage was also calculated at each CpG site. Besides, a literature search was conducted without restricting publication dates. Nine studies met the eligibility criteria after removing duplicates, unrelated articles, and reviews.
RESULTS
NIS mRNA levels decreased in tumoral tissues of PTC (P = 0.04) and FTC (P = 0.03) patients compared to their matched non-tumoral ones. The methylation of NIS promoter was not common in PTC samples, but it was frequent in FTC (P < 0.05). Significant differences were observed in the methylation levels in the 4th(+ 947), 6th(+ 955), and 7th(+ 963) CpGs sites in the forward strand of NIS promoter between FTC and MNG tissues (76.34 ± 3.12 vs 40.43 ± 8.42, P = 0.004, 69.63 ± 3.03 vs 23.29 ± 6.84, P = 0.001 and 50.33 ± 5.65 vs 24 ± 6.89, P = 0.030, respectively). There was no significant correlation between the expression and methylation status of NIS in PTC and FTC tissues.
CONCLUSION
Perturbation in NIS promoter's methylation individually may have a potential utility in differentiating MNG and FTC tissues. The absence of a distinct methylation pattern implies the importance of other epigenetic processes, which may alter the production of NIS mRNA. In addition, according to the reversibility of DNA methylation, it is anticipated that the design of particular targeted demethylation medicines will lead to a novel cancer therapeutic strategy.
PubMed: 36221112
DOI: 10.1186/s12935-022-02720-w -
The Science of the Total Environment Jan 2024Biological methane, a major source of global methane budget, is traditionally thought to be produced in anaerobic environments. However, the recent reports about methane... (Review)
Review
Biological methane, a major source of global methane budget, is traditionally thought to be produced in anaerobic environments. However, the recent reports about methane supersaturation occurring in oxygenated water layer, termed as "methane paradox", have challenged this prevailing paradigm. Significantly, growing evidence has indicated that phytoplankton including prokaryotic cyanobacteria and eukaryotic algae are capable of generating methane under aerobic conditions. In this regard, a systematic review of aerobic methane production by phytoplankton is expected to arouse the public attention, contributing to the understanding of methane paradox. Here, we comprehensively summarize the widespread phenomena of methane supersaturation in oxic layers. The remarkable correlation relationships between methane concentration and several key indicators (depth, chlorophyll a level and organic sulfide concentration) indicate the significance of phytoplankton in in-situ methane accumulation. Subsequently, four mechanisms of aerobic methane production by phytoplankton are illustrated in detail, including photosynthesis-driven metabolism, reactive oxygen species (ROS)-driven demethylation of methyl donors, methanogenesis catalyzed by nitrogenase and demethylation of phosphonates catalyzed by CP lyase. The first two pathways occur in various phytoplankton, while the latter two have been specially discovered in cyanobacteria. Additionally, the effects of four crucial factors on aerobic methane production by phytoplankton are also discussed, including phytoplankton species, light, temperature and crucial nutrients. Finally, the measures to control global methane emissions from phytoplankton, the precise intracellular mechanisms of methane production and a more complete global methane budget model are definitely required in the future research on methane production by phytoplankton. This review would provide guidance for future studies of aerobic methane production by phytoplankton and emphasize the potential contribution of aquatic ecosystems to global methane budget.
Topics: Phytoplankton; Ecosystem; Chlorophyll A; Methane; Cyanobacteria
PubMed: 37866611
DOI: 10.1016/j.scitotenv.2023.167864 -
Frontiers in Pharmacology 2020Epimutations secondary to gene-environment interactions have a key role in the pathophysiology of major psychiatric disorders. and evidence suggest that mood...
BACKGROUND
Epimutations secondary to gene-environment interactions have a key role in the pathophysiology of major psychiatric disorders. and evidence suggest that mood stabilizers can potentially reverse epigenetic deregulations found in patients with schizophrenia or mood disorders through mechanisms that are not yet fully understood. However, their activity on epigenetic processes has made them a research target for therapeutic approaches.
METHODS
We conducted a comprehensive literature search of PubMed and EMBASE for studies investigating the specific epigenetic changes induced by non-antipsychotic mood stabilizers (valproate, lithium, lamotrigine, and carbamazepine) in animal models, human cell lines, or patients with schizophrenia, bipolar disorder, or major depressive disorder. Each paper was reviewed for the nature of research, the species and tissue examined, sample size, mood stabilizer, targeted gene, epigenetic changes found, and associated psychiatric disorder. Every article was appraised for quality using a modified published process and those who met a quality score of moderate or high were included.
RESULTS
A total of 2,429 records were identified; 1,956 records remained after duplicates were removed and were screened title, abstract and keywords; 129 records were selected for full-text screening and a remaining of 38 articles were included in the qualitative synthesis. Valproate and lithium were found to induce broader epigenetic changes through different mechanisms, mainly DNA demethylation and histones acetylation. There was less literature and hence smaller effects attributable to lamotrigine and carbamazepine could be associated overall with the small number of studies on these agents. Findings were congruent across sample types.
CONCLUSIONS
An advanced understanding of the specific epigenetic changes induced by classic mood stabilizers in patients with major psychiatric disorders will facilitate personalized interventions. Further related drug discovery should target the induction of selective chromatin remodeling and gene-specific expression effects.
PubMed: 32390836
DOI: 10.3389/fphar.2020.00467 -
Contrast Media & Molecular Imaging 2022This study systematically reviewed the effect of DNA methylation in the promoter region of the coagulation factor vWF gene on the risk of unexplained recurrent... (Meta-Analysis)
Meta-Analysis
Correlation Analysis of DNA Methylation in the von Willebrand Factor Promoter Region and the Risk of Unexplained Recurrent Hemophilia: Systematic Review and Meta-Analysis.
This study systematically reviewed the effect of DNA methylation in the promoter region of the coagulation factor vWF gene on the risk of unexplained recurrent hemophilia. PubMed, Medline, Web of Science, and other computers were used to search the database, and the statistical randomized controlled trials of coagulation factor vWF in the risk analysis of unknown recurrent hemophilia were collected. The Cochrane systematic evaluation method was used to evaluate the quality of the included kinds of literature, and Revman5 software was used to sort out and analyze the kinds of literature. Meta-analysis showed that there was a statistical difference between the experimental group and the control group in case fatality rate (OR = 1.76, 95% CI (1.29, 2.39), =0.0003, = 0%, = 3.58), adverse events (OR = 2.38, 95% CI (1.65, 3.45), < 0.00001, = 0%, = 4.60), incidence of joint hemorrhage (OR = 2.52, 95% CI (1.62, 3.91), < 0.00001, = 0%, = 4.12), incidence of subcutaneous stasis (OR = 1.76, 95% CI (1.26, 2.45), =0.0009, = 5%, = 3.33), and hematoma volume (OR = 1.78, 95% CI (1.32, 2.40), =0.0001, = 23%, = 3.80). DNA methylation in the promoter region of the coagulation factor vWF gene was significantly associated with the risk of unexplained recurrent hemophilia. Whether demethylation can improve the bleeding index of patients with recurrent hemophilia remains to be further explored.
Topics: DNA Methylation; Hemophilia A; Humans; Promoter Regions, Genetic; von Willebrand Factor
PubMed: 35711531
DOI: 10.1155/2022/3977289 -
European Review For Medical and... Mar 2024The aim of this study was to evaluate the efficacy and adverse effects of venetoclax in combination with hypomethylating agents in elderly with acute myeloid leukemia. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of this study was to evaluate the efficacy and adverse effects of venetoclax in combination with hypomethylating agents in elderly with acute myeloid leukemia.
MATERIALS AND METHODS
A comprehensive literature search identified related studies from PubMed, Medline, Embase, Scopus, and Cochrane Library. Overall complete remission (CR) and overall response rate (ORR) were applied to evaluate the efficacy of venetoclax in combination with hypomethylating agents in elderly with acute myeloid leukemia, and incidence of grade 3-4 adverse events were used to evaluate the safety.
RESULTS
10 studies, including a total of 930 patients, were identified in our study and analyzed using the random-effects model. Meta-analysis showed the pooled overall CR rate of 70% (95% CI: 63-77%), the pooled ORR rate of 53% (95% CI: 39-67%), and the median overall survival ranged from 7.7 to 16.9 months. A total of 6 studies reported related adverse events, mainly including thrombocytopenia, febrile neutropenia, neutropenia, leukopenia, anemia, and pneumonia. The pooled incidence of overall adverse events was 30% (95% CI: 22-38%), and all adverse events were tolerable and resolved with treatment.
CONCLUSIONS
The combination of venetoclax and demethylating drugs has a good therapeutic effect on elderly patients with acute myeloid leukemia, but it also induces some adverse events. Although this therapy has a small impact on the quality of life, further attention is still needed to reduce the occurrence of such adverse events.
Topics: Aged; Humans; Quality of Life; Bridged Bicyclo Compounds, Heterocyclic; Sulfonamides; Leukemia, Myeloid, Acute; Pathologic Complete Response; Thrombocytopenia
PubMed: 38497866
DOI: 10.26355/eurrev_202403_35597 -
Differential methylation landscape of pancreatic ductal adenocarcinoma and its precancerous lesions.Hepatobiliary & Pancreatic Diseases... Jun 2020Pancreatic cancer is one of the most lethal diseases with an incidence almost equal to the mortality. In addition to having genetic causes, cancer can also be considered...
BACKGROUND
Pancreatic cancer is one of the most lethal diseases with an incidence almost equal to the mortality. In addition to having genetic causes, cancer can also be considered an epigenetic disease. DNA methylation is the premier epigenetic modification and patterns of aberrant DNA methylation are recognized to be a common hallmark of human tumor. In the multistage carcinogenesis of pancreas starting from precancerous lesions to pancreatic ductal adenocarcinoma (PDAC), the epigenetic changes play a significant role.
DATA SOURCES
Relevant studies for this review were derived via an extensive literature search in PubMed via using various keywords such as pancreatic ductal adenocarcinoma, precancerous lesions, methylation profile, epigenetic biomarkers that are relevant directly or closely associated with the concerned area of our interest. The literature search was intensively done considering a time frame of 20 years (1998-2018).
RESULT
In this review we have highlighted the hypermethylation and hypomethylation of the precancerous PDAC lesions (pancreatic intra-epithelial neoplasia, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm and chronic pancreatitis) and PDAC along with the potential biomarkers. We have also achieved the early epigenetic driver that leads to progression from precancerous lesions to PDAC. A bunch of epigenetic driver genes leads to progression of precancerous lesions to PDAC (ppENK, APC, p14/5/16/17, hMLH1 and MGMT) are also documented. We summarized the importance of these observations in therapeutics and diagnosis of PDAC hence identifying the potential use of epigenetic biomarkers in epigenetic targeted therapy. Epigenetic inactivation occurs by hypermethylation of CpG islands in the promoter regions of tumor suppressor genes. We listed all hyper- and hypomethylation of CpG islands of several genes in PDAC including its precancerous lesions.
CONCLUSIONS
The concept of the review would help to understand their biological effects, and to determine whether they may be successfully combined with other epigenetic drugs. However, we need to continue our research to develop more specific DNA-demethylating agents, which are the targets for hypermethylated CpG methylation sites.
Topics: Biomarkers, Tumor; Carcinogenesis; Carcinoma in Situ; Carcinoma, Pancreatic Ductal; DNA Methylation; Epigenesis, Genetic; Humans; Pancreatic Intraductal Neoplasms; Pancreatic Neoplasms; Pancreatitis, Chronic; Precancerous Conditions
PubMed: 32312637
DOI: 10.1016/j.hbpd.2020.03.010 -
International Journal of Molecular... May 2021FLT3-mutated acute myeloid leukemia accounts for around 30% of acute myeloid leukemia (AML). The mutation carried a poor prognosis until the rise of tyrosine kinase...
FLT3-mutated acute myeloid leukemia accounts for around 30% of acute myeloid leukemia (AML). The mutation carried a poor prognosis until the rise of tyrosine kinase inhibitors (TKIs). New potent and specific inhibitors have successfully altered the course of the disease, increasing the complete response rate and the survival of patients with FLT3-mutated AML. The aim of this article is to review all the current knowledge on these game-changing drugs as well as the unsolved issues raised by their use for fit and unfit FLT3-mutated AML patients. To this end, we analyzed the results of phase I, II, III clinical trials evaluating FLT3-TKI both in the first-line, relapse monotherapy or in combination referenced in the PubMed, the American Society of Hematology, the European Hematology Association, and the Clinicaltrials.gov databases, as well as basic science reports on TKI resistance from the same databases. The review follows a chronological presentation of the different trials that allowed the development of first- and second-generation TKI and ends with a review of the current lines of evidence on leukemic blasts resistance mechanisms that allow them to escape TKI.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Databases, Factual; Drug Resistance, Neoplasm; Gene Expression; Humans; Leukemia, Myeloid, Acute; Mutation; Protein Kinase Inhibitors; Recurrence; Stem Cell Transplantation; Survival Analysis; Transplantation, Homologous; Treatment Outcome; fms-Like Tyrosine Kinase 3
PubMed: 34070902
DOI: 10.3390/ijms22115873