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Biochemical Society Transactions Jun 2021Hypoxia is a feature of most solid tumours and predicts for poor prognosis. In radiobiological hypoxia (<0.1% O2) cells become up to three times more resistant to...
Hypoxia is a feature of most solid tumours and predicts for poor prognosis. In radiobiological hypoxia (<0.1% O2) cells become up to three times more resistant to radiation. The biological response to radiobiological hypoxia is one of few physiologically relevant stresses that activates both the unfolded protein and DNA damage responses (UPR and DDR). Links between these pathways have been identified in studies carried out in normoxia. Based in part on these previous studies and recent work from our laboratory, we hypothesised that the biological response to hypoxia likely includes overlap between the DDR and UPR. While inhibition of the DDR is a recognised strategy for improving radiation response, the possibility of achieving this through targeting the UPR has not been realised. We carried out a systematic review to identify links between the DDR and UPR, in human cell lines exposed to <2% O2. Following PRISMA guidance, literature from January 2010 to October 2020 were retrieved via Ovid MEDLINE and evaluated. A total of 202 studies were included. LAMP3, ULK1, TRIB3, CHOP, NOXA, NORAD, SIAH1/2, DYRK2, HIPK2, CREB, NUPR1, JMJD2B, NRF2, GSK-3B, GADD45a, GADD45b, STAU1, C-SRC, HK2, CAV1, CypB, CLU, IGFBP-3 and SP1 were highlighted as potential links between the hypoxic DDR and UPR. Overall, we identified very few studies which demonstrate a molecular link between the DDR and UPR in hypoxia, however, it is clear that many of the molecules highlighted warrant further investigation under radiobiological hypoxia as these may include novel therapeutic targets to improve radiotherapy response.
Topics: Animals; Apoptosis; Cell Line, Tumor; DNA Damage; Humans; Hypoxia; Neoplasms; Protein Serine-Threonine Kinases; Signal Transduction; Unfolded Protein Response
PubMed: 34003246
DOI: 10.1042/BST20200861 -
Innovation (Cambridge (Mass.)) May 2021COVID-19 has spread globally to over 200 countries with more than 40 million confirmed cases and one million deaths as of November 1, 2020. The SARS-CoV-2 virus, leading... (Review)
Review
COVID-19 has spread globally to over 200 countries with more than 40 million confirmed cases and one million deaths as of November 1, 2020. The SARS-CoV-2 virus, leading to COVID-19, shows extremely high rates of infectivity and replication, and can result in pneumonia, acute respiratory distress, or even mortality. SARS-CoV-2 has been found to continue to rapidly evolve, with several genomic variants emerging in different regions throughout the world. In addition, despite intensive study of the spike protein, its origin, and molecular mechanisms in mediating host invasion are still only partially resolved. Finally, the repertoire of drugs for COVID-19 treatment is still limited, with several candidates still under clinical trial and no effective therapeutic yet reported. Although vaccines based on either DNA/mRNA or protein have been deployed, their efficacy against emerging variants requires ongoing study, with multivalent vaccines supplanting the first-generation vaccines due to their low efficacy against new strains. Here, we provide a systematic review of studies on the epidemiology, immunological pathogenesis, molecular mechanisms, and structural biology, as well as approaches for drug or vaccine development for SARS-CoV-2.
PubMed: 33997827
DOI: 10.1016/j.xinn.2021.100116 -
Frontiers in Immunology 2020Aging is accompanied by alterations in immune response which leads to increased susceptibility to infectious diseases, cancer, autoimmunity, and inflammatory disorders....
BACKGROUND
Aging is accompanied by alterations in immune response which leads to increased susceptibility to infectious diseases, cancer, autoimmunity, and inflammatory disorders. This decline in immune function is termed as immunosenescence; however, the mechanisms are not fully elucidated. Experimental approaches of adaptive immunity, particularly for T cells, have been the main focus of immunosenescence research. This systematic review evaluates and discusses T cell markers implicated in immunosenescence.
OBJECTIVE
To determine the best flow cytometry markers of circulating T cells associated with immunosenescence.
METHODS
We systematically queried PubMed, MEDLINE, EBSCO, and BVS databases for original articles focused on two age groups of healthy humans: 18-44 (young adults) and >60 (older adults) years. In accordance with the Cochrane methodology, we synthesized data through qualitative descriptions and quantitative random effects meta-analysis due to extensive heterogeneity.
RESULTS
A total of 36 studies conducted in the last 20 years were included for the qualitative analysis and four out of these studies were used to perform the meta-analysis. A significant decrease in naïve T cell subset was observed in older adults compared to young adults. Primary markers used to identify senescent cells were loss of CD28 and increased expression of CD57 and KLRG1 in terminally-differentiated memory T cell subset in older adults. Moreover, we observed an increase in proinflammatory cytokines and decrease in telomere length in old adult T cells. It was not possible to perform quantitative synthesis on cell markers, cytokines, and telomere length because of the significant variations between the groups, which is attributed to differences in protocols and unreported measurements, thus generating a high risk of bias.
CONCLUSIONS
Heterogeneity among studies in terms of data report, measurement techniques and high risk of bias were major impediments for performing a robust statistical analysis that could aid the identification of eligible flow cytometry markers of immunosenescence phenotype in T cells.
Topics: Adolescent; Adult; Age Factors; Antigens, CD; Biomarkers; Cytokines; Flow Cytometry; Humans; Immunologic Memory; Immunophenotyping; Immunosenescence; Phenotype; T-Lymphocyte Subsets; Telomere Shortening; Young Adult
PubMed: 33519813
DOI: 10.3389/fimmu.2020.604591 -
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 -
Virology Journal Sep 2020The COVID-19 causing coronavirus is an enveloped RNA virus that utilizes an enzyme RNA dependent RNA polymerase for its replication. Favipiravir (FVP) triphosphate, a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The COVID-19 causing coronavirus is an enveloped RNA virus that utilizes an enzyme RNA dependent RNA polymerase for its replication. Favipiravir (FVP) triphosphate, a purine nucleoside analog, inhibits that enzyme. We have conducted this systematic review and meta-analysis on efficacy and safety of the drug FVP as a treatment for COVID-19.
METHODS
Databases like Pubmed, Pubmed Central, Scopus, Embase, Google Scholar, preprint sites, and clinicaltirals.gov were searched. The studies with the standard of care (SOC) and FVP as a treatment drug were considered as the treatment group and the SOC with other antivirals and supportive care as the control group. Quantitative synthesis was done using RevMan 5.4. Clinical improvement, negative conversion of reverse transcription-polymerase chain reaction (RT-PCR), adverse effects, and oxygen requirements were studied.
RESULTS
We identified a total of 1798 studies after searching the electronic databases. Nine in the qualitative studies and four studies in the quantitative synthesis met the criteria. There was a significant clinical improvement in the FVP group on the 14th day compared to the control group (RR 1.29, 1.08-1.54). Clinical deterioration rates were less likely in the FVP group though statistically not significant (OR 0.59, 95% CI 0.30-1.14) at the endpoint of study (7-15 days). The meta-analysis showed no significant differences between the two groups on viral clearance (day 14: RR 1.06, 95% CI 0.84-1.33), non-invasive ventilation or oxygen requirement (OR 0.76, 95% CI 0.42-1.39), and adverse effects (OR 0.69, 0.13-3.57). There are 31 randomized controlled trials (RCTs) registered in different parts of the world focusing FVP for COVID-19 treatment.
CONCLUSION
There is a significant clinical and radiological improvement following treatment with FVP in comparison to the standard of care with no significant differences on viral clearance, oxygen support requirement and side effect profiles.
Topics: Amides; Antiviral Agents; Betacoronavirus; COVID-19; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Coronavirus Infections; DNA-Directed RNA Polymerases; Databases, Factual; Enzyme Inhibitors; Humans; Pandemics; Pneumonia, Viral; Pyrazines; Randomized Controlled Trials as Topic; SARS-CoV-2; Standard of Care; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 32972430
DOI: 10.1186/s12985-020-01412-z -
Placenta Nov 2020Pre-eclampsia (PE) is the major cause of fetal and maternal mortality and can be classified according to gestational age of onset into early-onset (EOPE, <34 weeks of... (Meta-Analysis)
Meta-Analysis
Pre-eclampsia (PE) is the major cause of fetal and maternal mortality and can be classified according to gestational age of onset into early-onset (EOPE, <34 weeks of gestation) and late- (LOPE, ≥34 weeks of gestation). DNA methylation (DNAm) may help to understand the abnormal placentation in PE. Therefore, we performed a systematic review to assess the role of global DNAm on pathophysiology of PE, focused on fetal and maternal tissues of placenta from pregnant with PE, including EOPE and LOPE. We searched the databases EMBASE, Medline/PubMed, Cochrane Central Register of Controlled Trials, Scopus, Lilacs, Scielo and Google Scholar, and followed the MOOSE guidelines. Moreover, we performed pathway analysis with the overlapping genes from the included studies. Twelve out of 24 included studies in the qualitative analysis considered the classification into EOPE and LOPE. We did not found heterogeneity in the criteria used for diagnosis of PE, and a few studies evaluated whether confounding factors would influence placental DNAm. Fourteen out of 24 included studies showed hypomethylation in placental tissue from pregnant with PE compared to controls. The differences in DNAm are specific to genes or differentially methylated regions, and more evident in EOPE and preterm PE compared to controls, rather than LOPE and term PE. The overlapping genes from included studies revealed pathways relevant to pathophysiology of PE. Our findings highlighted the heterogeneous results of the included studies, mainly focused on North America and China. Replication studies in different populations should use the same placental tissues, techniques to assess DNAm and pipelines for bioinformatic analysis.
Topics: DNA Methylation; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy
PubMed: 32942147
DOI: 10.1016/j.placenta.2020.09.004 -
Advances in Nutrition (Bethesda, Md.) Nov 2020Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered... (Meta-Analysis)
Meta-Analysis
Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered to be 1 of the most recognized diets for disease prevention and healthy aging, partially due to its demonstrated anti-inflammatory and antioxidative properties which may impact on telomere length (TL). The aim of this meta-analysis was to determine the associations between MedDiet adherence and TL maintenance. MEDLINE-PubMed and Cochrane databases were searched up to December 2018 for studies evaluating the association between MedDiet adherence and TL in blood cells. Two reviewers, working independently, screened all titles and abstracts to identify studies that met the inclusion criteria [cross-sectional, case-control, and prospective cohort studies and randomized clinical trials (RCTs) published in English and excluded nonoriginal articles]. Data were pooled by the generic inverse variance method using the random effects model and expressed as standardized mean difference (SMD). Heterogeneity was identified using the Cochran Q test and quantified by the I2 statistic. A total of 8 original cross-sectional studies were included for the quantitative meta-analysis, comprising a total of 13,733 participants from 5 countries. A positive association between adherence to the MedDiet and TL was observed in all meta-analyses, with the exception of those conducted only in men: SMD (95% CI) of 0.130 (0.029; 0.231) for all subjects, 0.078 (0.005; 0.152) for women, and 0.095 (-0.005; 0.195) for men. Only 1 prospective cohort study and 1 RCT were identified, therefore, we could not undertake a meta-analysis for these study designs. The present meta-analysis of cross-sectional studies demonstrates that higher MedDiet adherence is associated with longer TL. At the same time, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.
Topics: Cross-Sectional Studies; Diet, Mediterranean; Humans; Prospective Studies; Telomere; Telomere Shortening
PubMed: 32730558
DOI: 10.1093/advances/nmaa079 -
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 -
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 -
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