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Advances in Nutrition (Bethesda, Md.) Nov 2023Accumulation of deoxyribonucleic acid (DNA) damage diminishes cellular health, increases risk of developmental and degenerative diseases, and accelerates aging.... (Review)
Review
Protective Effects of Micronutrient Supplements, Phytochemicals and Phytochemical-Rich Beverages and Foods Against DNA Damage in Humans: A Systematic Review of Randomized Controlled Trials and Prospective Studies.
Accumulation of deoxyribonucleic acid (DNA) damage diminishes cellular health, increases risk of developmental and degenerative diseases, and accelerates aging. Optimizing nutrient intake can minimize accrual of DNA damage. The objectives of this review are to: 1) assemble and systematically analyze high-level evidence for the effect of supplementation with micronutrients and phytochemicals on baseline levels of DNA damage in humans, and 2) use this knowledge to identify which of these essential micronutrients or nonessential phytochemicals promote DNA integrity in vivo in humans. We conducted systematic literature searches of the PubMed database to identify interventional, prospective, cross-sectional, or in vitro studies that explored the association between nutrients and established biomarkers of DNA damage associated with developmental and degenerative disease risk. Biomarkers included lymphocyte chromosome aberrations, lymphocyte and buccal cell micronuclei, DNA methylation, lymphocyte/leukocyte DNA strand breaks, DNA oxidation, telomere length, telomerase activity, and mitochondrial DNA mutations. Only randomized, controlled interventions and uncontrolled longitudinal intervention studies conducted in humans were selected for evaluation and data extraction. These studies were ranked for the quality of their study design. In all, 96 of the 124 articles identified reported studies that achieved a quality assessment score ≥ 5 (from a maximum score of 7) and were included in the final review. Based on these studies, nutrients associated with protective effects included vitamin A and its precursor β-carotene, vitamins C, E, B1, B12, folate, minerals selenium and zinc, and phytochemicals such as curcumin (with piperine), lycopene, and proanthocyanidins. These findings highlight the importance of nutrients involved in (i) DNA metabolism and repair (folate, vitamin B, and zinc) and (ii) prevention of oxidative stress and inflammation (vitamins A, C, E, lycopene, curcumin, proanthocyanidins, selenium, and zinc). Supplementation with certain micronutrients and their combinations may reduce DNA damage and promote cellular health by improving the maintenance of genome integrity.
Topics: Humans; Prospective Studies; Selenium; Lycopene; Cross-Sectional Studies; Curcumin; Proanthocyanidins; Randomized Controlled Trials as Topic; Vitamins; Vitamin A; Micronutrients; Folic Acid; Zinc; Beverages; Phytochemicals; DNA; DNA Damage; Biomarkers; Dietary Supplements
PubMed: 37573943
DOI: 10.1016/j.advnut.2023.08.004 -
Cancer Treatment Reviews Nov 2023PARP inhibitors (PARPi) are a standard-of-care (SoC) treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Several clinical trials... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
PARP inhibitors (PARPi) are a standard-of-care (SoC) treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Several clinical trials have shown the potential of combining PARPi with other anticancer agents. Therefore, we conducted a systematic review and meta-analysis to comprehensively evaluate the efficacy and safety of PARPi in patients with metastatic prostate cancer.
METHODS
MEDLINE, Cochrane CENTRAL, EMBASE, CINAHL, and Web of Science were searched on March 22nd, 2023, for phase 2 or 3 clinical trials. Efficacy (progression-free survival [PFS], overall survival [OS], PSA decline >50% [PSA50], and objective response rate [ORR]) and safety outcomes were assessed in the included studies.
RESULTS
Seventeen clinical trials (PARPi monotherapy [n = 7], PARPi + androgen-receptor signaling inhibitors [ARSI] [n = 6], and PARPi + immune checkpoint inhibitors [ICI] [n = 4]) were included in the quantitative analyses. PARPi monotherapy improved radiographic PFS and OS over SoC in mCRPC patients with alterations in BRCA1 or BRCA2 genes but not in those with alterations in the ATM gene. Higher rates of PSA50 and ORR were reported in participants treated with PARPi + ARSI than in single-agent PARPi or PARPi + ICI. Although the rate of high-grade adverse events was similar across all groups, treatment discontinuation was higher in patients treated with PARPi-based combinations than PARPi monotherapy.
CONCLUSION
The efficacy of PARPi is not uniform across mCRPC patients with alterations in DNA damage repair genes, and optimal patient selection remains a clinical challenge. No unexpected safety signals for this class of agents emerged from this analysis.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Immune Checkpoint Inhibitors; Patient Selection; Progression-Free Survival
PubMed: 37716332
DOI: 10.1016/j.ctrv.2023.102623 -
Pharmacological Research Oct 2023The addition of PARP inhibitors to chemotherapy has been assessed in > 80 clinical trials across multiple malignancies, on the premise that PARP inhibitors will...
PURPOSE
The addition of PARP inhibitors to chemotherapy has been assessed in > 80 clinical trials across multiple malignancies, on the premise that PARP inhibitors will increase chemotherapy effectiveness regardless of whether cancers have underlying disruption of DNA repair pathways. Consequently, the majority of combination therapy trials have been performed on patients without biomarker selection, despite the use of homologous recombination deficiency to dictate use of PARP inhibitors in the maintenance setting. An unresolved question is whether biomarkers are needed to identify patients who respond to combination PARP inhibitors and chemotherapy.
METHODS
A systematic literature review identified studies using PARP inhibitors in combination with chemotherapy versus chemotherapy alone, where the study included a biomarker of DNA repair function (BRCA1, BRCA2, homologous recombination deficiency test, ATM, ERCC1, SLFN11). Hazard ratios (HR) were pooled in a meta-analysis using generic inverse-variance, and fixed or random effects modelling. Subgroup analyses were conducted on biomarker selection and type of malignancy.
RESULTS
Nine studies comprising 2547 patients met the inclusion criteria. Progression-free survival (PFS) was significantly better in patients with a DNA repair biomarker (HR: 0.57, 95% CI: 0.48-0.68, p < 0.00001), but there was no benefit in patients who lacked a biomarker (HR: 0.94, 95% CI: 0.82-1.08, p = 0.38). Subgroup analysis showed that BRCA status and SLFN11 biomarkers could predict benefit, and biomarker-driven benefit occurred in ovarian, breast and small cell lung cancers. The addition of PARP inhibitors to chemotherapy was associated with increased grade 3/4 side effects, and particularly neutropenia.
CONCLUSIONS
Combination therapy only improves PFS in patients with identifiable DNA repair biomarkers. This indicates that PARP inhibitors do not sensitise patients to chemotherapy treatment, except where their cancer has a homologous recombination defect, or an alternative biomarker of altered DNA repair. While effective in patients with DNA repair biomarkers, there is a risk of high-grade haematological side-effects with the use of combination therapy. Thus, the benefit in PFS from combination therapy must be weighed against potential adverse effects, as individual arms of treatment can also confer benefit.
PubMed: 37717683
DOI: 10.1016/j.phrs.2023.106927 -
Frontiers in Endocrinology 2023In the complex and dynamic processes of replication, transcription, and translation of DNA molecules, a large number of replication errors or damage can occur which lead... (Review)
Review
In the complex and dynamic processes of replication, transcription, and translation of DNA molecules, a large number of replication errors or damage can occur which lead to obstacles in the development process of germ cells and result in a decreased reproductive rate. DNA damage repair has attracted widespread attention due to its important role in the maintenance and regulation of germ cells. This study reports on a systematic review of the role and mechanism of DNA damage repair in germline development. First, the causes, detection methods, and repair methods of DNA damage, and the mechanism of DNA damage repair are summarized. Second, a summary of the causes of abnormal DNA damage repair in germ cells is introduced along with common examples, and the relevant effects of germ cell damage. Third, we introduce the application of drugs related to DNA damage repair in the treatment of reproductive diseases and related surgical treatment of abnormal DNA damage, and summarize various applications of DNA damage repair in germ cells. Finally, a summary and discussion is given of the current deficiencies in DNA damage repair during germ cell development and future research development. The purpose of this paper is to provide researchers engaged in relevant fields with a further systematic understanding of the relevant applications of DNA damage repair in germ cells and to gain inspiration from it to provide new research ideas for related fields.
Topics: DNA Repair; DNA Damage; Reproduction; Germ Cells; Cell Differentiation
PubMed: 37529603
DOI: 10.3389/fendo.2023.1234280 -
La Clinica Terapeutica 2023Cancer, a potentially fatal condition, is one of the leading causes of death worldwide. Among males aged 20 to 35, the most common cancer in healthy individuals is... (Review)
Review
BACKGROUND
Cancer, a potentially fatal condition, is one of the leading causes of death worldwide. Among males aged 20 to 35, the most common cancer in healthy individuals is testicular cancer, accounting for 1% to 2% of all cancers in men.
METHODS
Throughout this review, we have employed a targeted research approach, carefully handpicking the most representative and relevant articles on the subject. Our methodology involved a systematic review of the scientific literature to ensure a comprehensive and accurate overview of the available sources.
RESULTS
The onset and spread of testicular cancer are significantly influenced by genetic changes, including mutations in oncogenes, tu-mor suppressor genes, and DNA repair genes. As a result of identifying these specific genetic mutations in cancers, targeted medications have been developed to disrupt the signaling pathways affected by these genetic changes. To improve the diagnosis and treatment of this disease, it is crucial to understand its natural and clinical histories.
CONCLUSIONS
In order to comprehend cancer better and to discover new biomarkers and therapeutic targets, oncologists are increasingly employing omics methods, such as genomics, transcriptomics, proteomics, and metabolomics. Targeted medications that focus on specific genetic pathways and mutations hold promise for advancing the diagnosis and management of this disease.
Topics: Humans; Male; Testicular Neoplasms; Precision Medicine; Genomics; Proteomics
PubMed: 37994745
DOI: 10.7417/CT.2023.2468 -
Frontiers in Oncology 2023Numerous reviews of the epidemiology and risk factors for breast cancer have been published previously which heighted different directions of breast cancer.
BACKGROUND
Numerous reviews of the epidemiology and risk factors for breast cancer have been published previously which heighted different directions of breast cancer.
AIM
The present review examined the likelihood that incidence, prevalence, and particular risk factors might vary by geographic region and possibly by food and cultural practices as well.
METHODS
A systematic review (2017-2022) was conducted following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, reporting on epidemiological and risk factor reports from different world regions. Medical Subject Heading (MeSH) terms: "Breast neoplasm" "AND" country terms such as "Pakistan/epidemiology", "India/epidemiology", "North America/epidemiology", "South Africa/epidemiology" were used to retrieve 2068 articles from PubMed. After applying inclusion and exclusion terms, 49 papers were selected for systematic review.
RESULTS
Results of selected articles were summarized based on risk factors, world regions and study type. Risk factors were classified into five categories: demographic, genetic and lifestyle risk factors varied among countries. This review article covers a variety of topics, including regions, main findings, and associated risk factors such as genetic factors, and lifestyle. Several studies revealed that lifestyle choices including diet and exercise could affect a person's chance of developing breast cancer. Breast cancer risk has also been linked to genetic variables, including DNA repair gene polymorphisms and mutations in the breast cancer gene (BRCA). It has been found that most of the genetic variability links to the population of Asia while the cause of breast cancer due to lifestyle modifications has been found in American and British people, indicating that demographic, genetic, and, lifestyle risk factors varied among countries.
CONCLUSION
There are many risk factors for breast cancer, which vary in their importance depending on the world region. However, further investigation is required to better comprehend the particular causes of breast cancer in these areas as well as to create efficient prevention and treatment plans that cater to the local population.
PubMed: 37886170
DOI: 10.3389/fonc.2023.1240098 -
The World Journal of Men's Health Apr 2024Varicoceles can be a source of elevated seminal oxidative stress (OS) and sperm DNA fragmentation (SDF). However, it remains unclear whether varicocele repair (VR) could...
Effects of Varicocele Repair on Sperm DNA Fragmentation and Seminal Malondialdehyde Levels in Infertile Men with Clinical Varicocele: A Systematic Review and Meta-Analysis.
PURPOSE
Varicoceles can be a source of elevated seminal oxidative stress (OS) and sperm DNA fragmentation (SDF). However, it remains unclear whether varicocele repair (VR) could reduce these parameters. This systematic review and meta-analysis (SRMA) aims to investigate the impact of VR on SDF and seminal malondialdehyde (MDA).
MATERIALS AND METHODS
A literature search was performed in Scopus, PubMed, Ovid, Embase, and Cochrane databases. This SRMA included randomized controlled trials and observational studies reporting the pre- and postoperative levels of SDF and seminal OS in infertile men with clinical varicocele that underwent VR. Subgroup analyses included techniques of VR and SDF testing. The effect size was expressed as standardized mean difference (SMD).
RESULTS
Out of 1,632 abstracts assessed for eligibility, 29 studies with 1,491 infertile men were included. The analysis showed a significant reduction in SDF after VR, compared to preoperative values (SMD -1.125, 95% confidence interval [CI] -1.410, -0.840; p<0.0001) with high inter-study heterogeneity (I²=90.965%). Reduction in SDF was evident with microsurgical technique and non-microsurgical inguinal approaches (SMD -1.014, 95% CI -1.263, -0.765; p<0.0001, and SMD -1.495, 95% CI -2.116, -0.873; p<0.0001), respectively. Reduction in SDF was significant irrespective of testing was done by sperm chromatin dispersion (SMD -2.197, 95% CI -3.187, -1.207; p<0.0001), sperm chromatin structure assay (SMD -0.857, 95% CI -1.156, -0.559; p<0.0001) or TUNEL (SMD -1.599, 95% CI -2.478, -0.719; p<0.0001). A significant decrease in seminal MDA levels was observed following VR (SMD -2.450, 95% CI -3.903 to -0.997, p=0.001) with high inter-study heterogeneity (I²=93.7%).
CONCLUSIONS
Using pre- and post-intervention data, this SRMA indicates a significant reduction in SDF and seminal MDA levels in infertile men with clinical varicocele treated with VR. These findings may have important implications for the future management of this selected group of infertile patients.
PubMed: 38164034
DOI: 10.5534/wjmh.230235 -
Pharmacological Research Jan 2024Zinc is a crucial trace element in the human body, playing a role in various physiological processes such as oxidative stress, neurotransmission, protein synthesis, and...
Zinc is a crucial trace element in the human body, playing a role in various physiological processes such as oxidative stress, neurotransmission, protein synthesis, and DNA repair. The zinc transporters (ZnTs) family members are responsible for exporting intracellular zinc, while Zrt- and Irt-like proteins (ZIPs) are involved in importing extracellular zinc. These processes are essential for maintaining cellular zinc homeostasis. Imbalances in zinc metabolism have been linked to the development of neurodegenerative diseases. Disruptions in zinc levels can impact the survival and activity of neurons, thereby contributing to the progression of neurodegenerative diseases through mechanisms like cell apoptosis regulation, protein phase separation, ferroptosis, oxidative stress, and neuroinflammation. Therefore, conducting a systematic review of the regulatory network of zinc and investigating the relationship between zinc dysmetabolism and neurodegenerative diseases can enhance our understanding of the pathogenesis of these diseases. Additionally, it may offer new insights and approaches for the treatment of neurodegenerative diseases.
Topics: Humans; Cation Transport Proteins; Disease Progression; Homeostasis; Neurodegenerative Diseases; Zinc
PubMed: 38123108
DOI: 10.1016/j.phrs.2023.107039 -
International Journal of Molecular... Aug 2023PARPi, in combination with ionizing radiation, has demonstrated the ability to enhance cellular radiosensitivity in different tumors. The rationale is that the exposure...
PARPi, in combination with ionizing radiation, has demonstrated the ability to enhance cellular radiosensitivity in different tumors. The rationale is that the exposure to radiation leads to both physical and biochemical damage to DNA, prompting cells to initiate three primary mechanisms for DNA repair. Two double-stranded DNA breaks (DSB) repair pathways: (1) non-homologous end-joining (NHEJ) and (2) homologous recombination (HR); and (3) a single-stranded DNA break (SSB) repair pathway (base excision repair, BER). In this scenario, PARPi can serve as radiosensitizers by leveraging the BER pathway. This mechanism heightens the likelihood of replication forks collapsing, consequently leading to the formation of persistent DSBs. Together, the combination of PARPi and radiotherapy is a potent oncological strategy. This combination has proven its efficacy in different tumors. However, in prostate cancer, there are only preclinical studies to support it and, recently, an ongoing clinical trial. The objective of this paper is to perform a review of the current evidence regarding the use of PARPi and radiotherapy (RT) in PCa and to give future insight on this topic.
Topics: Humans; Male; DNA Repair; Medical Oncology; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms; Radiation Oncology
PubMed: 37629155
DOI: 10.3390/ijms241612978 -
Cancer Treatment Reviews Jun 2024Gastric cancer (GC), known for its unfavorable prognosis, has been classified in four distinct molecular subtypes. These subtypes not only exhibit differences in their... (Review)
Review
BACKGROUND
Gastric cancer (GC), known for its unfavorable prognosis, has been classified in four distinct molecular subtypes. These subtypes not only exhibit differences in their genome and transcriptome but also in the composition of their tumor immune microenvironment. The microsatellite instable (MSI) and Epstein-Barr virus (EBV) positive GC subtypes show clear clinical benefits from immune checkpoint blockade, likely due to a neoantigen-driven and virus-driven antitumor immune response and high expression of immune checkpoint molecule PD-L1. However, even within these subtypes response to checkpoint inhibition is variable, which is potentially related to heterogeneity in the tumor immune microenvironment (TIME) and expression of co-inhibitory molecules. We conducted a systematic review to outline the current knowledge about the immunological features on the TIME of MSI and EBV + GCs.
METHODS
A systematic search was performed in PubMed, EMBASE and Cochrane Library. All articles from the year 1990 and onwards addressing immune features of gastric adenocarcinoma were reviewed and included based on predefined in- and exclusion criteria.
RESULTS
In total 5962 records were screened, of which 139 were included that reported immunological data on molecular GC subtypes. MSI and EBV + GCs were reported to have a more inflamed TIME compared to non-MSI and EBV- GC subtypes. Compared to microsatellite stable (MSS) tumors, MSI tumors were characterized by higher numbers of CD8 + and FoxP3 + T cells, and tumor infiltrating pro- and anti-inflammatory macrophages. HLA-deficiency was most common in MSI tumors compared to other molecular GC subtypes and associated with lower T and B cell infiltrates compared to HLA-proficient tumors. EBV + was associated with a high number of CD8 + T cells, Tregs, NK cells and macrophages. Expression of PD-L1, CTLA-4, Granzyme A and B, Perforin and interferon-gamma was enriched in EBV + tumors. Overall, MSI tumors harbored a more heterogeneous TIME in terms of immune cell composition and immune checkpoints compared to the EBV + tumors.
DISCUSSION AND CONCLUSION
MSI and EBV + GCs are highly Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration.; 2019pro-inflammatory immune cell populations. Although studies on the direct comparison of EBV + and MSI tumors are limited, EBV + tumors show less intra-subgroup heterogeneity compared to MSI tumors. More studies are needed to identify how Intra-subgroup heterogeneity impacts response to immunotherapy efficacy.
Topics: Humans; Stomach Neoplasms; Tumor Microenvironment; Epstein-Barr Virus Infections; DNA Mismatch Repair; Herpesvirus 4, Human; Microsatellite Instability
PubMed: 38669788
DOI: 10.1016/j.ctrv.2024.102737