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Oncotarget Sep 2017Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA... (Review)
Review
BACKGROUND
Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality. Furthermore the replication-dependent activity of PARP inhibitor helps to maintain the differential effect between tumoral and healthy tissues. Inhibition of chromatin remodeling, G2/M arrest, vasodilatory effect induced by PARP inhibitor, also participate to their radio-sensitization effect.
MATERIALS AND METHODS
Here, after highlighting mechanisms of PARP inhibitors radiosensitization we methodically searched PubMed, Google Scholar, Cochrane Databases and meeting proceedings for human pre-clinical and clinical studies that evaluated PARP inhibitor radiosensitizing effect. Enhancement ratio, when available, was systematically reported.
RESULTS
Sixty four studies finally met our selection criteria and were included in the analysis. Only three pre-clinical studies didn't find any radiosensitizing effect. Median enhancement ratio vary from 1,3 for prostate tumors to 1,5 for lung cancers. Nine phase I or II trials assessed safety data.
CONCLUSION
PARP inhibitors are promising radiosensitizers, but need more clinical investigation. The next ten years will be determining for judging their real potential.
PubMed: 28978184
DOI: 10.18632/oncotarget.19079 -
Brazilian Oral Research 2023This meta-analysis aimed to investigate the effects of propolis on the severity of coronavirus disease symptoms by reducing periodontal disease. PubMed, EMBASE, SciELO,... (Meta-Analysis)
Meta-Analysis
This meta-analysis aimed to investigate the effects of propolis on the severity of coronavirus disease symptoms by reducing periodontal disease. PubMed, EMBASE, SciELO, Web of Science, and SCOPUS databases were systematically searched. Studies have been conducted analyzing propolis's effects on COVID-19 and periodontitis. The study was conducted according to the PRISMA statement and registered in PROSPERO. Risk of Bias (RoB) assessment and meta-analysis of clinical studies were performed (Review Manager 5, Cochrane). The certainty of the evidence was assessed using GradePro (GDT). Studies have shown propolis flavonoids inhibit viral replication in several DNA and RNA viruses, including coronaviruses. Propolis components have an aminopeptidase inhibitor activity that can inhibit the main proteases of SARS viruses and seem to inhibit protein spikes, which are sites of most mutations in SARS-CoV strains. The meta-analysis showed favorable results with the use of propolis on probing depth (95%CI: 0.92; p < 0.001), clinical attachment level (95%CI: 1.48; p < 0.001), gingival index (95%CI: 0.14; p = 0.03), plaque index (95%CI: 0.11; p = 0.23), and blending on probing (95%CI: 0.39; p < 0.001). The antibacterial activity of propolis could be mediated through its direct action on microorganisms or the stimulation of the immune system, activating natural defenses. Thus, propolis inhibits the replication of SARS-CoV-2 as well as its bacterial activity. Treatment with propolis improves general health and facilitates the activation of the immune system against coronavirus.
Topics: Humans; Propolis; COVID-19; SARS-CoV-2; Periodontal Diseases; Periodontitis
PubMed: 37018812
DOI: 10.1590/1807-3107bor-2023.vol37.0031 -
Frontiers in Genetics 2019Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is endemic in Sub-Saharan Africa, constituting a major health burden. It has the most...
Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is endemic in Sub-Saharan Africa, constituting a major health burden. It has the most divergence in cancer incidence globally, with high prevalence reported in East Asia, Southern Europe, and in East and Southern Africa. Its etiology is multifactorial, with lifestyle, environmental, and genetic risk factors. Very little is known about the role of genetic factors in ESCC development and progression among African populations. The study aimed to systematically assess the evidence on genetic variants associated with ESCC in African populations. We carried out a comprehensive search of all African published studies up to April 2019, using PubMed, Embase, Scopus, and African Index Medicus databases. Quality assessment and data extraction were carried out by two investigators. The strength of the associations was measured by odds ratios and 95% confidence intervals. Twenty-three genetic studies on ESCC in African populations were included in the systematic review. They were carried out on Black and admixed South African populations, as well as on Malawian, Sudanese, and Kenyan populations. Most studies were candidate gene studies and included DNA sequence variants in 58 different genes. Only one study carried out whole-exome sequencing of 59 ESCC patients. Sample sizes varied from 18 to 880 cases and 88 to 939 controls. Altogether, over 100 variants in 37 genes were part of 17 case-control genetic association studies to identify susceptibility loci for ESCC. In these studies, 25 variants in 20 genes were reported to have a statistically significant association. In addition, eight studies investigated changes in cancer tissues and identified somatic alterations in 17 genes and evidence of loss of heterozygosity, copy number variation, and microsatellite instability. Two genes were assessed for both genetic association and somatic mutation. Comprehensive large-scale studies on the genetic basis of ESCC are still lacking in Africa. Sample sizes in existing studies are too small to draw definitive conclusions about ESCC etiology. Only a small number of African populations have been analyzed, and replication and validation studies are missing. The genetic etiology of ESCC in Africa is, therefore, still poorly defined.
PubMed: 31428123
DOI: 10.3389/fgene.2019.00642 -
Translational Psychiatry Dec 2023Prenatal stress and poor maternal mental health are associated with adverse offspring outcomes; however, the biological mechanisms are unknown. Epigenetic modification... (Meta-Analysis)
Meta-Analysis
Prenatal stress and poor maternal mental health are associated with adverse offspring outcomes; however, the biological mechanisms are unknown. Epigenetic modification has linked maternal health with offspring development. Epigenome-wide association studies (EWAS) have examined offspring DNA methylation profiles for association with prenatal maternal mental health to elucidate mechanisms of these complex relationships. The objective of this study is to provide a comprehensive, systematic review of EWASs of infant epigenetic profiles and prenatal maternal anxiety, depression, or depression treatment. We conducted a systematic literature search following PRISMA guidelines for EWAS studies between prenatal maternal mental health and infant epigenetics through May 22, 2023. Of 645 identified articles, 20 fulfilled inclusion criteria. We assessed replication of CpG sites among studies, conducted gene enrichment analysis, and evaluated the articles for quality and risk of bias. We found one repeated CpG site among the maternal depression studies; however, nine pairs of overlapping differentially methylatd regions were reported in at least two maternal depression studies. Gene enrichment analysis found significant pathways for maternal depression but not for any other maternal mental health category. We found evidence that these EWAS present a medium to high risk of bias. Exposure to prenatal maternal depression and anxiety or treatment for such was not consistently associated with epigenetic changes in infants in this systematic review and meta-analysis. Small sample size, potential bias due to exposure misclassification and statistical challenges are critical to address in future efforts to explore epigenetic modification as a potential mechanism by which prenatal exposure to maternal mental health disorders leads to adverse infant outcomes.
Topics: Pregnancy; Infant; Female; Humans; Epigenome; Mental Health; DNA Methylation; Maternal Health; Epigenesis, Genetic
PubMed: 38062042
DOI: 10.1038/s41398-023-02620-1 -
Frontiers in Nutrition 2020Interactions are occurring in the course of liberation, absorption, distribution, metabolism, and excretion of active ingredients, or at the target receptors. They are...
Interactions are occurring in the course of liberation, absorption, distribution, metabolism, and excretion of active ingredients, or at the target receptors. They are causing therapy failures and undesirable events. Forty-seven of fifty-seven human hepatic isoenzymes are specific and relevant in hormone and vitamin metabolism and biosynthesis. Aromatase (syn. CYP19A1) is one of the specific CYP450 isoenzymes so far not elucidated in detail. As aromatase-inhibiting phytochemicals are currently recommended for breast cancer prevention and as add-on accompanying aromatase-inhibitor pharmacotherapy, it was the aim of this literature review to assess whether a common interpretation on genetic and -omics basis could be found. Articles retrieved showed that traditional antioxidation diet is one of the most approved explanations of inhibition of aromatase by phytonutrients of flavonoid derivatives. Flavonoids compete for the oxygen provided by the heme moiety of aromatase in the course of aromatase-catalyzed conversion of steroid precursors to estrogens. Flavonoids are therefore promoted for breast cancer prevention. A further explanation of flavonoids' mechanism of action proposed was related to enzymatic histone deacetylation. By keeping DNA-structure wide through a high acetylation degree, acetylated histones favor transcription and replication. This mechanism corresponds to a procedure of switching genes on. Inhibiting acetylation and therefore switching genes off might be an important regulation of repressing cancer genes. Aromatase expression depends on the genotype and phenotype of a person. Aromatase itself depends on the expression of the heme moiety encoded in the genotype. Biosynthesis of porphyrins in turn depends on the substrates succinate and glycine, as well as on a series of further enzymes, with ALA synthetase as the rate-limiting step. The effect of the heme moiety as prosthetic group of aromatase further depends on the absorption of iron as a function of pH and redox state. To assess the function of aromatase precisely, multiple underlying biochemical pathways need to be evaluated. As a conclusion, the genetic regulation of metabolism is a complex procedure affecting multiple pathways. To understand a metabolic step, multiple underlying individually performing reactions need to be considered if personalized (nutritional) medicine should bring an advantage for a patient. Nutrition sciences need to consider the genome of an individual to truly find answers to nutrition-derived non-communicable diseases. With current GWAS (genome-wide association study) approaches, inherited errors of metabolism are identified and ideally treated effectively. It is much more difficult to get a precise genetic profile for non-communicable diseases stemming from multifactorial causes. Polygenic risks evaluation is feasible but diagnostic tools are not yet available in a desired extent. Neither flavonoid researchers nor providers of genetic testing kits are going into the details needed for a truly personalized nutritional medicine. The next step with profiling the exome and then the whole genome is on the threshold of becoming routine diagnosis and of bringing the desired details.
PubMed: 32328497
DOI: 10.3389/fnut.2020.00037 -
JAMA Oncology Jul 2020The mismatch repair (MMR) pathway plays a crucial role in repairing DNA replication errors in normal and cancer cells. Defects in DNA MMR proteins that determine the... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The mismatch repair (MMR) pathway plays a crucial role in repairing DNA replication errors in normal and cancer cells. Defects in DNA MMR proteins that determine the microsatellite instability-high (MSI-H) condition lead to the accumulation of mutations and the generation of neoantigens, which may stimulate the antitumor immune response. Clinical trials have demonstrated that MSI-H status is associated with long-term benefit in patients treated with immune checkpoint inhibitors (ICIs).
OBJECTIVE
To evaluate the activity of ICIs in terms of overall response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) in patients with MSI-H cancers.
DATA SOURCES
Published articles that evaluated ICIs in the treatment of advanced MSI-H tumors from inception to December 2019 were identified by searching the PubMed, EMBASE, and Cochrane Library databases.
STUDY SELECTION
Prospective or retrospective studies, published in the English language, providing outcome data with ICIs in patients with MSI-H cancer were selected.
DATA EXTRACTION AND SYNTHESIS
Author and year of publication, type of studies, diseases included, median follow up, type of ICI, median OS ,and PFS, ORR, DCR and 1-, 2-, and 3-year OS were retrieved. Analysis was performed in December 2019.
MAIN OUTCOME AND MEASURES
The primary outcome of interest was ORR. Secondary end points were median PFS, median OS, pooled rate of patients alive at 1, 2 ,and 3 years, and pooled rate of patients that attained disease control rate ([DCR] calculated as the sum of stable disease rate and ORR).
RESULTS
Overall, 939 patients (14 studies) were analyzed mainly in pretreated settings. The pooled ORR was 41.5% (95% CI, 34.9%-48.4%). The pooled DCR was 62.8% (95% CI, 54.5%-70.3%). Pooled median PFS was 4.3 months (95% CI, 3-6.8 months). The pooled median OS was 24 months (95% CI, 20.1-28.5 months). The pooled 1- and 2-year OS were 75.6% (95% CI, 61.8%-85.5%) and 56.5% (95% CI, 46%-66.4%), respectively. Because only 1 study provided 3-year OS data, a formal pooled analysis for 3 years was not possible.
CONCLUSIONS AND RELEVANCE
In this meta-analysis of patients with pretreated MSI-H cancer, ICIs were associated with high activity independent of tumor type and drug used. Among molecular biomarkers for selection of treatment, MMR proteins may have a predictive value for the activity of immunotherapy.
Topics: Humans; Immune Checkpoint Inhibitors; Microsatellite Instability; Neoplasms; Treatment Outcome
PubMed: 32407439
DOI: 10.1001/jamaoncol.2020.1046 -
Medicine Dec 2021DNA damage is a fundamental process that plays a considerable role in generating protein diversity. FANCI, loaded on the altered chromatin, plays a vital role in DNA... (Meta-Analysis)
Meta-Analysis
BACKGROUND
DNA damage is a fundamental process that plays a considerable role in generating protein diversity. FANCI, loaded on the altered chromatin, plays a vital role in DNA damage. Abnormal FANCI expression is potentially associated with carcinogenesis.However, the biological role of FANCI in cervical cancer is yet to be determined.
METHODS
We analyzed FANCI expression via multiple gene expression databases. Genes co-expressed with FANCI and its regulators were identified using LinkedOmics. The correlations between FANCI and cancer immune infiltrates were investigated via Tumor Immune Estimation Resource (TIMER).
RESULTS
FANCI was found upregulated with amplification in tumor tissues of multiple cervical cancer cohorts. High FANCI expression was associated with poorer overall survival (OS). Functional network analysis suggested that FANCI regulates spliceosome, DNA replication, and cell cycle signaling via pathways involving several cancer-related kinases and the E2F family. In additional, FANCI expression was positively correlated with infiltrating levels of CD4+ T and CD8+ T cells, and neutrophils. FANCI expression also showed strong correlations with diverse immune marker sets in cervical cancer.
CONCLUSION
These findings suggested that FANCI is correlated with prognosis of and immune infiltration in cervical cancer, laying a foundation for further study of the immune regulatory role of FANCI in cervical cancer.
Topics: Biomarkers, Tumor; CD8-Positive T-Lymphocytes; Fanconi Anemia Complementation Group Proteins; Female; Gene Expression Regulation; Humans; Lymphocytes, Tumor-Infiltrating; Prognosis; Uterine Cervical Neoplasms
PubMed: 34941027
DOI: 10.1097/MD.0000000000027690 -
The Cochrane Database of Systematic... Nov 2019Chronic hepatitis B is associated with high morbidity and mortality. Chronic hepatitis B requires long-term management aiming at reduction of the risks of hepatocellular... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronic hepatitis B is associated with high morbidity and mortality. Chronic hepatitis B requires long-term management aiming at reduction of the risks of hepatocellular inflammatory necrosis, liver fibrosis, decompensated liver cirrhosis, liver failure, and liver cancer, and improving health-related quality of life. The Chinese herbal medicine formula Xiao Chai Hu Tang has been used to decrease discomfort and replication of the virus in people with chronic hepatitis B. However, the benefits and harms of Xiao Chai Hu Tang formula have never been established with rigorous review methodology.
OBJECTIVES
To assess the benefits and harms of Xiao Chai Hu Tang formula versus placebo or no intervention in people with chronic hepatitis B.
SEARCH METHODS
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, and seven other databases to 1 March 2019. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry for ongoing or unpublished trials to 1 March 2019.
SELECTION CRITERIA
We included randomised clinical trials, irrespective of publication status, language, and blinding, comparing Xiao Chai Hu Tang formula versus no intervention or placebo in people with chronic hepatitis B. We included participants of any sex and age, diagnosed with chronic hepatitis B according to guidelines or as defined by the trialists. We allowed co-interventions when the co-interventions were administered equally to all the intervention groups.
DATA COLLECTION AND ANALYSIS
Review authors independently retrieved data from reports and after correspondence with investigators. Our primary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered 'not to be serious'. We presented the meta-analysed results as risk ratios (RR) with 95% confidence intervals (CI). We assessed the risks of bias using risk of bias domains with predefined definitions. We used GRADE methodology to evaluate our certainty in the evidence.
MAIN RESULTS
We included 10 randomised clinical trials with 934 participants, but only five trials with 490 participants provided data for analysis. All the trials compared Xiao Chai Hu Tang formula with no intervention. All trials appeared to have been conducted and published only in China. The included trials assessed heterogeneous forms of Xiao Chai Hu Tang formula, administered for three to eight months. One trial included participants with hepatitis B and comorbid tuberculosis, and one trial included participants with hepatitis B and liver cirrhosis. The remaining trials included participants with hepatitis B only. All the trials were at high risk of bias, and the certainty of evidence for all outcomes that provided data for analyses was very low. We downgraded the evidence by one or two levels because of outcome risk of bias, inconsistency or heterogeneity of results (opposite direction of effect), indirectness of evidence (use of surrogate outcomes instead of clinically relevant outcomes), imprecision of results (the CIs were wide), and publication bias (small sample size of the trials). Additionally, 47 trials lacked the necessary methodological information needed to ensure the inclusion of these trials in our review. None of the included trials aimed to assess clinically relevant outcomes such as all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, or hepatitis B-related morbidity. The effects of Xiao Chai Hu Tang formula on the proportion of participants with adverse events considered 'not to be serious' is uncertain (RR 0.43, 95% CI 0.02 to 11.98; I = 69%; very low-certainty evidence). Only three trials with 222 participants reported the proportion of people with detectable hepatitis B virus DNA (HBV-DNA), but the evidence that Xiao Chai Hu Tang formula reduces the presence of HBV-DNA in the blood (a surrogate outcome) is uncertain (RR 0.62, 95% CI 0.45 to 0.85; I = 0%; very low-certainty evidence). Only two trials with 160 participants reported the proportion of people with detectable hepatitis B virus e-antigen (HBeAg; a surrogate outcome) (RR 0.72, 95% CI 0.50 to 1.02; I = 38%; very low-certainty evidence) and the evidence is uncertain. The evidence is also uncertain for separately reported adverse events considered 'not to be serious'.
FUNDING
two of the 10 included trials received academic funding from government or hospital. None of the remaining eight trials reported information on funding.
AUTHORS' CONCLUSIONS
The clinical effects of Xiao Chai Hu Tang formula for chronic hepatitis B remain unclear. The included trials were small and of low methodological quality. Despite the wide use of Xiao Chai Hu Tang formula, we lack data on all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. The evidence in this systematic review comes from data obtained from a maximum three trials. We graded the certainty of evidence as very low for adverse events considered not to be serious and the surrogate outcomes HBeAg and HBV-DNA. We found a large number of trials which lacked clear description of their design and conduct, and hence, these trials are not included in the present review. As all identified trials were conducted in China, there might be a concern about the applicability of this review outside China. Large-sized, high-quality randomised sham-controlled trials with homogeneous groups of participants and transparent funding are lacking.
Topics: Drugs, Chinese Herbal; Hepatitis B, Chronic; Herbal Medicine; Humans; Phytotherapy; Randomized Controlled Trials as Topic
PubMed: 31697415
DOI: 10.1002/14651858.CD013090.pub2 -
Microbiology and Molecular Biology... Mar 2018The use of lentiviral vectors for therapeutic purposes has shown promising results in clinical trials. The ability to produce a clinical-grade vector at high yields... (Review)
Review
The use of lentiviral vectors for therapeutic purposes has shown promising results in clinical trials. The ability to produce a clinical-grade vector at high yields remains a critical issue. One possible obstacle could be cellular factors known to inhibit human immunodeficiency virus (HIV). To date, five HIV restriction factors have been identified, although it is likely that more factors are involved in the complex HIV-cell interaction. Inhibitory factors that have an adverse effect but do not abolish virus production are much less well described. Therefore, a gap exists in the knowledge of inhibitory factors acting late in the HIV life cycle (from transcription to infection of a new cell), which are relevant to the lentiviral vector production process. The objective was to review the HIV literature to identify cellular factors previously implicated as inhibitors of the late stages of lentivirus production. A search for publications was conducted on MEDLINE via the PubMed interface, using the keyword sequence "HIV restriction factor" or "HIV restriction" or "inhibit HIV" or "repress HIV" or "restrict HIV" or "suppress HIV" or "block HIV," with a publication date up to 31 December 2016. Cited papers from the identified records were investigated, and additional database searches were performed. A total of 260 candidate inhibitory factors were identified. These factors have been identified in the literature as having a negative impact on HIV replication. This study identified hundreds of candidate inhibitory factors for which the impact of modulating their expression in lentiviral vector production could be beneficial.
Topics: Clinical Trials as Topic; DNA Replication; Gene Expression Regulation; Gene Transfer Techniques; Genetic Vectors; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Immunity, Cellular; Lentivirus; Virus Replication
PubMed: 29321222
DOI: 10.1128/MMBR.00051-17 -
AIDS Reviews Oct 2020Antiretroviral therapy (ART) inhibits HIV replication but does not eradicate the latent reservoir. The previous research suggests that earlier ART initiation provides...
Antiretroviral therapy (ART) inhibits HIV replication but does not eradicate the latent reservoir. The previous research suggests that earlier ART initiation provides benefit on limiting reservoir size, but timing and extent of this effect remain unclear. Analytic treatment interruption (ATI) may be used to demonstrate HIV remission, but whether early ART also improves likelihood or duration of even temporary virologic remission is unclear. This review seeks to answer both questions. We performed a systematic review and analysis following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and included 21 interventional or observational studies with sufficient HIV reservoir outcomes. We also aggregated reservoir outcomes and transformed data into approximate measurements of total HIV DNA per million peripheral blood mononuclear cells and analyzed the correlation between timing of ART initiation and reservoir size. People living with HIV who initiate ART in primary infection maintain smaller reservoirs on suppressive ART than those who initiate treatment during chronic infection. The reduction of reservoir is most pronounced when ART is started within 2 weeks of HIV acquisition. Across studies, we found a moderately strong association between longer time to ART initiation and reservoir size, which was strongest when measured after 1 year on ART (Pearson's r = 0.69, p = 0.0003). After ATI, larger pre-ATI reservoir size predicts shorter time to viral rebound. Early ART may also facilitate long-term control of viremia. Although achieving sustained HIV remission will require further interventions, initiating ART very early in infection could limit the extent of the reservoir and also lead to post-ATI control in rare cases.
Topics: Anti-Retroviral Agents; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Viral Load; Virus Latency
PubMed: 33105471
DOI: 10.24875/AIDSRev.20000001