Deoxyribonucleic Acid Damage Research Articles

PprI: The Key Protein in Response to DNA Damage in Deinococcus.

Deoxyribonucleic acid (DNA) damage response (DDR) pathways are essential for maintaining the integrity of the genome when destabilized by various damaging events, such as ionizing radiation, ultraviolet light, chemical or oxidative stress, and DNA replication errors. The PprI–DdrO system is a newly identified pathway responsible for the DNA damage response in Deinococcus, in which PprI (also called IrrE) acts as a crucial component mediating the extreme resistance of these bacteria. This review describes studies about PprI sequence conservation, regulatory function, structural characteristics, biochemical activity, and hypothetical activation mechanisms as well as potential applications.

Mutational signatures associated with exposure to carcinogenic microplastic compounds bisphenol A and styrene oxide.

Microplastic pollutants in oceans and food chains are concerning to public health. Common plasticizing compounds Bisphenol-A (BPA) and Styrene-7,8-Oxide (SO) are now labeled as carcinogens. We show that BPA and SO cause deoxyribonucleic acid damage and mutagenesis in human cells, and analyze the genome-wide point mutation and genomic rearrangement patterns associated with BPA and SO exposure. A subset of the single- and doublet base substitutions shows mutagenesis near or at guanine, consistent with these compounds’ preferences to form guanosine adducts. Presence of other mutational signatures suggest additional mutagenesis probably due to complex effects of BPA and SO on diverse cellular processes. Analyzing data for 19 cancer cohorts, we find that tumors of digestive and urinary organs show relatively high similarity in mutational profiles, and the burden of such mutations increases with age. Even within the same cancer type, proportions of corresponding mutational patterns vary among the cohorts from different countries, as does the amount of microplastic waste in ocean waters. BPA and SO are relatively mild mutagens, and other environmental agents can also potentially generate similar, complex mutational patterns in cancer genomes. Nonetheless, our findings call for systematic evaluation of public health consequences of microplastic exposure worldwide.

Assessment of DNA Damage in Chick Embryo Brains Exposed to 2G and 3G Cell Phone Radiation using Alkaline Comet Assay Technique

Introduction: The cellular phones/mobile phones have emerged as the fastest growing man-made phenomenon ever discovered in the history. Controversies still exist among the scientific community regarding the ill-effects of Radiofrequency Radiation (RFR) exposure from cell phones on biological tissues. The present study will provide an insight into the basic mechanisms by which RF fields interact with developing brain in an embryo. Aim: To assess the possible Deoxyribonucleic Acid (DNA) damage in developing brain of chick embryo following chronic exposure to Ultra-High Frequency/Radiofrequency Radiation (UHF/RFR) emitted from 2G and 3G cell phone. Materials and Methods: Fertilised hen eggs were divided into three groups. Experimental Group A (exposed to 2G radiation, 24 eggs), Experimental Group B (exposed to 3G radiation, 24 eggs) and Group C sham exposed control group (24 eggs). After the completion of scheduled duration of exposure (72 minutes per day), the chick embryos were sacrificed from 9th-12th day and the brains were dissected out. The chick embryo brains were then subjected to alkaline comet assay technique to assess the DNA damage. The results were statistically compared using one-way Analysis of Variance (ANOVA). Results: In the present study, the exposure of chick embryo brains to 2G and 3G cell phone radiation caused increased mean comet length (p<0.001), mean tail length (p<0.001), mean percentage of DNA in the tail (p<0.001) and mean tail moment (p<0.01) suggestive of increased DNA damage. Conclusion: The present study concludes that the RFR exposure caused significant increase in DNA damage in developing brain of chick embryos with changes more pronounced in 3G exposure group.

Interplay between oxidative stress, SIRT1, reproductive and metabolic functions.

Silent information Regulators (SIRT1) gene stimulates antioxidants’ expression, repairs cells damaged by oxidative stress (OS), and prevents the cells’ dysfunction. In particular, the role of different Sirtuins, particularly SIRT1 in reproduction, has been widely studied over the past decade. Decreased SIRT 1 causes mitochondrial dysfunction by increasing Reactive Oxygen Species (ROS), lipid peroxidation, and DNA damage in both male and female gametes (Sperms and Oocytes), leading to infertility. In the female reproductive system, SIRT1 regulates proliferation and apoptosis in granulosa cells (GCs), and its down-regulation is associated with a reduced ovarian reserve. SIRT1 also modulates the stress response to OS in GCs by targeting a transcription factor vital for ovarian functions and maintenance.ROS-mediated damage to spermatozoa’s motility and morphology is responsible for 30–80% of men’s infertility cases. High levels of ROS can cause damage to deoxyribo nucleic acid (DNA) in the nucleus and mitochondria, lipid peroxidation, apoptosis, inactivation of enzymes, and oxidation of proteins in spermatozoa. SIRT 1 is a cardioprotective molecule that prevents atherosclerosis by modulating various mechanisms such as endothelial injury due to impaired nitric oxide (NO) production, inflammation, OS, and regulation of autophagy. SIRT 1 is abundantly expressed in tubular cells and podocytes. It is also found to be highly expressed in aquaporin 2 positive cells in the distal nephron suggesting its involvement in sodium and water handling. SIRT1 improves insulin resistance by reducing OS and regulating mitochondrial biogenesis and function. It also decreases adiposity and lipogenesis and increases fatty acid oxidation. So, its involvement in the multiple pathways ensures its unique role in reproductive and metabolic derangement mechanisms.

DNA and RNA oxidative damage are associated to mortality in patients with cerebral infarction

ObjectiveSecondary injury due to oxidation may occur during ischemic stroke, possibly leading to oxidative damage to deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Higher blood concentrations of 8-hydroxy-2′-deoxyguanosine (8-OHdG) (through the oxidation of guanosine from DNA) have been found in ischemic stroke patients than in healthy subjects, and in patients with versus without post-ischemic stroke depression. The present study was carried out to explore the possible association between serum DNA and RNA oxidative damage and mortality in patients with cerebral infarction. MethodsA prospective, multicenter observational study was carried out in the Intensive Care Units of 6 Spanish hospitals. We included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as ischemic changes evidenced by computed tomography in more than 50% of the middle cerebral artery territory and a Glasgow Coma Score (GCS)<9. Serum concentrations of the three oxidized guanine species (OGS) (8-hydroxyguanine from DNA or RNA, 8-hydroxyguanosine from RNA, and 8-OHdG from DNA) on the day of MMCAI diagnosis were determined. The study endpoint was 30-day mortality. ResultsWe found higher serum OGS levels (p<0.001) in non-surviving (n=34) than in surviving patients (n=34). Logistic regression analyses showed serum OGS levels to be associated to 30-day mortality controlling for lactic acid, GCS and platelet count (OR=1.568; 95%CI=1.131–2.174; p=0.01). ConclusionsThe novel observation in this study is the association between global serum OGS concentration and mortality in ischemic stroke patients.

Severity and prevalence of sperm DNA damage among infertile males at a tertiary hospital, north central, Nigeria

Context: Seminal fluid analysis (SFA) is the most important investigative tool for evaluation of male infertility. However, it is limited in detecting causes of sperm abnormalities while some individuals with normal SFA are still considered infertile. Evaluating sperm deoxyribonucleic acid (DNA) integrity as an ancillary investigative tool to SFA will enhance the investigation of infertility. Aims: The aim is to assess the prevalence and severity of sperm DNA damage based on semen level of 8-hydroxydeoxyguanosine (8-OHdG) in males with and without abnormal SFA. Settings and Design: This was a descriptive cross-sectional study of 120 males with at least one SFA parameter abnormalities as test controls and 120 normal controls. Subjects and Methods: Seminal 8-OHDG was assayed as a marker of sperm DNA damage using ELISA method. Statistical Analysis Used: Normally distributed data were expressed as mean ± standard deviation otherwise expressed as median and interquartile range. Results: The mean ages of subjects and controls were 35.84 ± 6.0 vs. 36.22 ± 7.56 years. The mean seminal 8-OHDG was significantly higher among subjects than among controls (15.21 ± 3.80 ng/ml vs. 12.45 ± 4.0 ng/ml, P = 0.015). The reference value of seminal 8-OHDG obtained in this study was 4.45–20.45 ng/ml and the prevalence of sperm DNA damage among subjects compared to controls was 10.8% versus 3.3%, P = 0.024. Severe DNA damage corresponding to sperm DNA fragmentation index of >30% was 3.3% in subjects and was not present in any male partner in the control group. Significant sperm DNA damage was also associated with reduced sperm count (P = 0.043), while its association with reduced sperm motility was not statistically significant in this study. Conclusions: The prevalence and severity of sperm DNA damage were more significant among males with, than those without, abnormal SFA parameters.

Inhibitory Effect of Histone Deacetylase Inhibitor on the Proliferation of Leukemia Cells and Its Anti-Tumor Pharmacology

The aim of this study was to explore the inhibitory effect of histone deacetylase inhibitor (HDACI) on the proliferation of leukemia cells. The two kinds of leukemia cells (human promyelocytic leukemia cell (HL-60) and human acute myelogenous leukemia cell (KG-1)) were selected for in vitro research. Besides, Chidamide, a kind of benzamide HDACI, was applied to induce and culture the HL-60 and KG-1 cells, and the anti-tumor cell proliferation activity of Chidamide on HL-60 and KG-1 was detected by the methyl thiazolyl tetrazolium (MTT) assay, which was 5.6 and 6.1 in turn. The cell scratch experiment verified that Chidamide had the metastasis inhibitory effect on HL-60 and KG-1 cells. Flow cytometry was employed to measure the percentage of apoptotic cells, and it was found that the percentage of apoptotic cells was 55.6% ± 1% and 48.6% ± 1% in sequence after HL-60 and KG-1 cells were treated with Chidamide for 36 hours. The number of auto-phagosomes was determined by transmission electron microscopy showing that the number of auto-phagosomes in HL-60 and KG-1 cells was 12 ± 1 and 10 ± 1, respectively after the induction process of Chidamide. The phosphorylated histone H2AX protein (γ-H2AX) recognition antibody immunofluorescence method was adopted to determine the deoxyribonucleic acid (DNA) damage, and the positive rates of HL-60 and KG-1 cells reached 28.41% and 26.35%, respectively after Chidamide treatment. Therefore, Chidamide, as a kind of HDACI, could effectively inhibit the proliferation of leukemia cells, so that the results of this experiment had a good guiding meaning for the clinical diagnosis and treatment of leukemia.

Efficiency Evaluation and Usages of Thunbergia alata, Thunbergia erecta and their Combination

Thunbergiaalata and Thunbergiaerecta have been mostly used for ornamentation but have interesting other uses. However, toxicity and phytochemical studies of these plants are lacking. Therefore, phytochemicals of the two species were investigated by gas chromatography-mass spectrometry, cytotoxicity and genotoxicity were tested via 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide and comet assays in normal human peripheral blood mononuclear cells. Then, the extracts of the two species and their combination were applied to peripheral blood mononuclear cells poisoned with rice whisky and bathroom cleaner as toxic models in everyday life. The results showed that the major phytochemicals were 12.36 % and 24.90 % phytol in ethanol extracts of Thunbergia alata and Thunbergia erecta and 46.29 % and 43.47 % oleamide in hexane extracts of Thunbergia alata and Thunbergia erecta, respectively. Half-maximal inhibitory concentration values, which indicate toxicity in cells, were not detected for either species, but at the deoxyribonucleic acid level, the extracts induced significant deoxyribonucleic acid damage, shown by high Olive Tail Moment values in peripheral blood mononuclear cells (p<0.05). Biological activity of the extracts revealed by higher cell viability percentages and lower Olive Tail Moment values in the treatments (poisoned peripheral blood mononuclear cells treated with plant extracts) than the controls (poisoned peripheral blood mononuclear cells). Taking all the results together, Thunbergia alata and Thunbergia erecta extracts and their combination can be applied for many benefits in humans following properties that have been previously used and their phytochemicals but have limitations of doses.

Impact of smoking on plasma antioxidant defenses and urinary 8-hydroxy-2-deoxyguanosine in ischemic heart diseases

Background: Oxidative stress is associated with various morbid conditions such as atherosclerosis and coronary artery disease. Cigarette smoking is said to be associated with high oxidative stress levels which may predispose to ischemic heart diseases (IHDs). Urinary 8-hydroxy-2-deoxyguanosine (8-OHdG) has emerged as a biomarker for oxidative stress induced deoxyribonucleic acid (DNA) damage. Aim and Objective: The present study aims at evaluating the plasma markers for oxidative stress and urinary 8-OHdG in smokers suffering from IHD. Materials and Methods: For the present study about 327 male subjects, including 127 healthy subjects and 200 consecutively admitted IHD patients were enrolled and were subsequently divided into two subgroups as smokers and non-smokers consisting of 100 non-smokers and 100 smokers, based on the history of smoking. The healthy control group consisted of 64 smokers and 63 non-smokers. All the subjects were evaluated for plasma malondialdehyde levels, total antioxidant status (TAS), and urinary 8-OHdG. Results: There was increased oxidative stress evident by strong negative correlation between 8-OHdG and TAS was observed in the present study. Conclusion: The urinary 8-OHdG may serve as a sensitive indicator of DNA damage in smokers.

Colon Carcinogenesis: The Interplay Between Diet and Gut Microbiota.

Colorectal cancer (CRC) incidence increases yearly, and is three to four times higher in developed countries compared to developing countries. The well-known risk factors have been attributed to low physical activity, overweight, obesity, dietary consumption including excessive consumption of red processed meats, alcohol, and low dietary fiber content. There is growing evidence of the interplay between diet and gut microbiota in CRC carcinogenesis. Although there appears to be a direct causal role for gut microbes in the development of CRC in some animal models, the link between diet, gut microbes, and colonic carcinogenesis has been established largely as an association rather than as a cause-and-effect relationship. This is especially true for human studies. As essential dietary factors influence CRC risk, the role of proteins, carbohydrates, fat, and their end products are considered as part of the interplay between diet and gut microbiota. The underlying molecular mechanisms of colon carcinogenesis mediated by gut microbiota are also discussed. Human biological responses such as inflammation, oxidative stress, deoxyribonucleic acid (DNA) damage can all influence dysbiosis and consequently CRC carcinogenesis. Dysbiosis could add to CRC risk by shifting the effect of dietary components toward promoting a colonic neoplasm together with interacting with gut microbiota. It follows that dietary intervention and gut microbiota modulation may play a vital role in reducing CRC risk.

In Vitro Modulation of Endogenous Antioxidant Enzyme Activities and Oxidative Stress in Autism Lymphoblastoid Cell Line (ALCL) by Stingless Bee Honey Treatment.

Autism has been associated with a low antioxidant defense mechanism, while honey has been known for decades for its antioxidant and healing properties. Determination of stingless bee honey (KH) effects on antioxidant enzyme activities and oxidative damage in Autism Lymphoblastoid Cell Line (ALCL) was performed. ALCL and its normal sibling pair (NALCL) were cultured in RPMI-1640 medium at 37°C and 5% CO2. ALCL was treated with 400 μg/mL KH (24 h), and oxidative stress marker, malondialdehyde (MDA), and antioxidant enzyme activities (catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)) were measured via enzyme-linked immunosorbent assay (ELISA), while deoxyribonucleic acid (DNA) damage was determined via comet assay. Low SOD activity (p < 0.05) and high MDA level (p < 0.05) were observed in ALCL compared to NALCL. Higher grade (Grades 2 and 3) of DNA damage was highly observed (p < 0.05) in ALCL compared to NALCL, whereas lower grade (Grades 0 and 1) DNA damage was highly detected (p < 0.05) in NALCL compared to ALCL. KH treatment caused a significant increase in SOD and GPx activities (p < 0.05) in ALCL compared to untreated ALCL. Correspondingly, KH treatment reduced the Grade 2 DNA damage (p < 0.05) in ALCL compared to untreated ALCL. CAT activity showed no significant difference between all three groups, while the MDA level showed no significant difference between treated and untreated ALCL. In conclusion, KH treatment significantly reduced the oxidative stress in ALCL by increasing the SOD and GPx antioxidant enzyme activities, while reducing the DNA damage.

Erythrocyte GST activity in type 2 diabetes with and without nephropathy

Diabetic nephropathy (DN) is the main cause of chronic kidney disease, and represents the most common and serious complication of diabetes. The occurrence and progression of DN are closely related to oxidative stress. Excessive reactive oxygen species (ROS) induced by hyperglycemia are involved in direct oxidation and damage of deoxyribonucleic acid (DNA), proteins, and lipids. Glutathione S-transferases have central roles in the cellular detoxification of a diverse group of exogenous and endogenous harmful compounds. The present study aims to clarify the possible role of erythrocyte glutathione S-transferase activity in type 2 diabetic patients with and without nephropathy. This study included 60 diabetic patients (20 diabetics with normoalbuminuria, 20 diabetics with microalbuminuria, 20 diabetics with macroalbuminuria) and 20 healthy volunteers as a control group. Glutathione S- transferase (GST), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) activities, and Reduced glutathione (GSH) level were significantly lower in diabetic patients with and without nephropathy as compared to control. Malondialdehyde (MDA) level was significantly higher in diabetic patients with and without nephropathy as compared to control. GST, SOD, GPx, CAT, GSH and MDA were positively correlated with estimated glomerular filtration rate and negatively correlated with albumin creatinine ratio. It was concluded that erythrocyte GST may be used as a biomarker to differentiate between different groups of nephropathy.

Potential Role of Proteasome Accessory Factor-C in Resistance against Second Line Drugs in Mycobacteria.

Objectives Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), can survive inside the host granuloma courtesy the various extrinsic and intrinsic factors involved. Continuous use or misuse of the anti TB drugs over the years has led to the development of resistance in MTB against antibiotics. Drug-resistant TB in particular has been a menace since treating it requires exposing the patient to drugs for a prolonged period of time. Multidrug-resistant (MDR) and extensively drug resistant TB cases have increased over the years mostly due to the exposure of MTB to suboptimal levels of drug. Proteasomes provide MTB its pathogenicity and hence helps it to survive inside the host even in the presence of drugs. Materials and Methods The recombinantly expressed proteasome accessory factor-C (PafC) protein was purified via Ni-NTA affinity chromatography and overexpressed in the nonpathogenic strain of mycobacteria (Mycobacterium smegmatis) for the comparative analysis of minimum inhibitory concentrations of antimycobacterial drugs. The bacteria were subjected to various stress conditions. Secretory nature of PafC was analyzed by probing the purified protein against patient sera. Quantitative mRNA analysis of paf C, lex A, and rec A was performed to check for their level under fluoroquinolone (FQ) presence. The data were validated in clinical samples of pulmonary TB patients. Results pafC , that forms one part of paf operon, is involved in providing MTB its resistance against FQs. Through a series of experiments, we established the fact that PafC is upregulated in mycobacteria upon exposure to FQs and it leads to the increased intracellular survival of mycobacteria under the stresses generated by FQs. The study also refers to the correlation of pafC to deoxyribonucleic acid (DNA) damage repair enzymes lexA and recA at transcriptional level. The results obtained in vitro corroborated when the pulmonary TB patients’ samples were subjected to the same molecular analysis. Statistical Analysis All experiments were conducted at least in triplicate. p -Value of <0.05 was considered to be statistically significant Conclusion PafC plays a significant role in providing resistance to mycobacteria against FQ class of drugs by increasing its intracellular survival through increased drug efflux and getting involved with DNA damage repair machinery.

Machine learning guided prediction of liquid chromatography–mass spectrometry ionization efficiency for genotoxic impurities in pharmaceutical products

The limitation and control of genotoxic impurities (GTIs) has continued to receive attention from pharmaceutical companies and authorities for several decades. Because GTIs have the ability to damage deoxyribonucleic acid (DNA) and the potential to cause cancer, low-level quantitation is required to protect patients. A quick and easy method of determining the liquid chromatography-mass spectrometry (LC/MS) conditions for high-sensitivity analysis of GTIs may prospectively accelerate pharmaceutical development. In this study, a quantitative structure-property relationship (QSPR) model was developed for predicting the ionization efficiency of compounds using liquid-chromatography-mass spectrometry (LC/MS) parameters and molecular descriptors. Before implementing the QSPR prediction model, linear regression analysis was performed to model the relationship between the ionization efficiency and the LC/MS parameters for each compound. Comparison of the predicted peak areas with the experimentally observed peak areas showed good agreement based on the coefficient of determination (R2 > 0.96). The machine learning-based QSPR approach begins with computation of the molecular descriptors expressing the physicochemical properties of a compound, followed by a genetic algorithm-based feature selection. Linear and nonlinear regression were performed, and support vector machine (SVM) was selected as the best machine learning algorithm for the prediction. The SVM algorithm was developed and optimized using 1031 experimental data points for nine compounds, including well-known GTIs. Validation of the model by comparison of the predicted and observed relative ionization efficiencies (RIE) showed a high coefficient of determination (R2 = 0.96) and low root mean squared error value (RMSE = 0.118). Finally, this established prediction model was applied to hydrophilic interaction liquid chromatography coupled with MS for a new compound in new mobile phase compositions and new MS parameter settings. The RMSE of the predicted versus observed RIE was 0.203. This prediction accuracy was sufficient to determine the starting point of the LC/MS method development. The methodology demonstrated in this study can be used to determine the LC/MS conditions for high sensitivity analysis of GTIs.

Primordial follicle survival of goat ovarian tissue after vitrification and transplantation on chorioallanthoic membrane

BackgroundOvarian tissue vitrification is an alternative fertility preservation procedure for young female patients prior to gonadotoxic treatment. Primordial follicle loss might be a potential issue for vitrification and transplantation procedures. This study aimed to evaluate primordial follicle density and deoxyribonucleic acid (DNA) fragmentation in each stage of the preservation procedure of goat ovarian tissue. Follicle density and DNA fragmentation were examined microscopically after staining with hematoxylin eosin and TUNEL assay, respectively. Both parameters were compared between fresh, fresh-transplanted, vitrification, and vitrification-transplanted groups.ResultsA significant decrease was observed in the primordial follicle proportion after vitrification and transplantation compared to the primordial follicle proportion in the fresh group (88.09% vs 52.42%, p < 0.05, 95% CI 11.54, 66.94). There was no significant difference in DNA fragmentations of primordial follicles between each group (p > 0.05).ConclusionsThe vitrification and transplantation process of goat ovarian strips could cause the primordial follicles loss and DNA damage of the follicles. However, primordial follicles loss and DNA damage were not significantly different in each procedure.

Comparing the Role of the p53 Gene and Telomerase Enzyme in 'Accelerated Aging Due to Cancer': A Literature Review.

Aging is defined as progressive physiological alterations in an organism that lead to senescence. In response to stress, when proliferative-competent cells undergo permanent, irreversible growth arrest (like replicative dividing limit, oncogene activation, oxidative stress, or deoxyribonucleic acid (DNA) damage), it is termed as cellular senescence. Biomarkers p53, telomerase, and other inflammatory cytokines have a vital link with senescence, and directed use of these markers might be useful in manipulating cancer and the aging process. We included studies related to topics ' accelerated aging due to cancer', telomerase's relation to Aging and Cancer, p53's relation to Aging and Cancer, Atherosclerosis and Cancer from Search databases like PubMed and Google Scholar. We relied on peer-reviewed articles and included literature from the last 10 years written in the English language. Degenerative diseases in humans are usually linked to atherosclerosis, and atherosclerosis is associated with short leukocyte telomere length. Cancer itself and its treatment are linked with accelerated aging by causing progressive shortening of telomeres during cell replication, resulting in cell death. Gene p53 is known to have a dual effect that works as a tumor suppressor and has pro-aging side effects. In experimental studies, when p53 overcomes multiple regulatory mechanisms controlling its activity, then only the pro-aging side effects of p53 manifested. This might be a potential key for treating cancer without causing the side-effects of aging. In this review, we aim to explain and summarize the interdependent nature of p53, telomeres, and other conventional mechanisms of aging and cancer like inflammation, oxidative stress, uncontrolled proliferation, angiogenesis, micro ribonucleic acids (RNAs), and apoptosis, with a more synergistic approach that can help in developing new therapeutics and play a potential role in shaping modern human lifespan and revolutionize cancer treatment.

Radiotherapy for non-small cell lung cancer in the immunotherapy era: the opportunity and challenge-a narrative review.

Immunotherapy has radically changed the clinical management of patients with cancer in recent years. Immune checkpoint inhibitors (ICIs) reversing the immunosuppressive effects of the tumor microenvironment are one type of immunotherapy, several of which are approved by the US Food and Drug Administration (FDA) as first-line treatments for patients with non-small cell lung cancer (NSCLC). However, response rates to ICIs are around 19–47% among patients with advanced NSCLC. As a result, the development of combined ICI and radiotherapy has begun with the aim of strengthening patients’ antitumor immunity. Radiotherapy with substantial technological improvements not only achieves local tumor control through the induction of deoxyribonucleic acid (DNA) damage in irradiated regions, but also has the potential to mediate immunostimulatory effects that could result in tumor regression beyond irradiated regions. At present, numerous preclinical and clinical research are investigating the efficiency and safety of combining ICI with radiotherapy. The PACIFIC trial showed that combining chemoradiotherapy with ICI could improve clinical outcomes. In this review, we summarize the rationale for combining radiotherapy with immunotherapy. We also discuss the opportunities and challenges of combination therapy, including the timing of radiotherapy, optimal dose and fractionations, radiotherapy target and target volume, acquired resistance, patient selection, and radioimmunotherapy toxicity.

Simulation of Proton-Induced DNA Damage Patterns Using an Improved Clustering Algorithm.

Simulations of deoxyribonucleic acid (DNA) molecular damage use the traversal algorithm that has the disadvantages of being time-consuming, slowly converging, and requiring high-performance computer clusters. This work presents an improved version of the algorithm, "density-based spatial clustering of applications with noise" (DBSCAN), using a KD-tree approach to find neighbors of each point for calculating clustered DNA damage. The resulting algorithm considers the spatial distributions for sites of energy deposition and hydroxyl radical attack, yielding the statistical probability of (single and double) DNA strand breaks. This work achieves high accuracy and high speed at calculating clustered DNA damage that has been induced by proton treatment at the molecular level while running on an i7 quad-core CPU. The simulations focus on the indirect effect generated by hydroxyl radical attack on DNA. The obtained results are consistent with those of other published experiments and simulations. Due to the array of chemical processes triggered by proton treatment, it is possible to predict the effects that different track structures of various energy protons produce on eliciting direct and indirect damage of DNA.

MnSOD Ala16Val polymorphism in cognitive dysfunction in patients with epilepsy: A relationship with oxidative and inflammatory markers

ObjectiveThe objective of the study was to evaluate the neurocognitive profile and its relation with Ala16ValMnSOD polymorphism in epilepsy and if these clinical parameters are linked to oxidative stress and inflammatory markers. MethodsPatients with epilepsy (n = 31) and healthy subjects (n = 42) were recruited. A neuropsychological evaluation was performed in both groups through a battery of cognitive tests. Oxidative stress, inflammatory markers, apoptotic factors, and deoxyribonucleic acid (DNA) damage were measured in blood samples. ResultsStatistical analyses showed the association of MnSOD Ala16Val polymorphism with cognitive impairment, including praxis, perception, attention, language, executive functions, long-term semantic memory, short-term visual memory, and total memory in patients with epilepsy and Valine-Valine (VV) genotype compared with the control group. Compared with the controls and patients with epilepsy, Alanine-Alanine (AA), and Alanine-Valine (AV) genotype, the patients with epilepsy and VV genotype exhibited higher levels of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), activation of caspases 1 and 3 (CASP-1 and -3), and DNA damage. Our findings also showed higher carbonyl protein and thiobarbituric acid reactive substances (TBARS) levels as well as an increased superoxide dismutase (SOD) and acetylcholinesterase (AChE) activities in patients with epilepsy and VV genotype. ConclusionThis study supports the evidence of a distinct neuropsychological profile in patients with epilepsy, especially those with the VV genotype. Furthermore, our results suggest that oxidative and inflammatory pathways may be associated with genetic polymorphism and cognitive dysfunction in patients with epilepsy.

Myrcene Exhibits Antitumor Activity Against Lung Cancer Cells by Inducing Oxidative Stress and Apoptosis Mechanisms

Myrcene, a natural olefinic hydrocarbon, possesses anti-inflammatory, analgesic, antibiotic, and antimutagenic properties, but its anticancer effect has not yet been elucidated. Hence, the present study was framed to investigate the molecular mechanism by which myrcene mediates the anticancer activity of A549 lung adenocarcinoma cells. In vitro, A549 lung cancer cells were cultured either with or without myrcene, and the effects on cellular metabolic activity, levels of reactive oxygen species (ROS), mitochondrial integrity, deoxyribonucleic acid (DNA) damage, and activity of caspases were analyzed. The study demonstrated that compared with control cells, myrcene induces cell death in a dose-dependent manner while inducing ROS levels. Further experiments revealed that the metabolic activity of the A549 lung adenocarcinoma cells was diminished with increased DNA damage and altered cellular integrity. In addition, increased activity of caspase-3 was also evidenced with reduced mitochondrial membrane potential synthesis in the myrcene-treated cells, which demonstrate that lung cancer cells experience signs of toxicity during myrcene treatment through the activation of the apoptosis mechanism via mitochondria-mediated cell death signaling and induction of oxidative stress. The results provide the first report on the evidence of anticancer activity and the possibility of a new drug that could be used for the treatment of lung cancer.