Advances in Genomic Data and Biomarkers: Revolutionizing NSCLC Diagnosis and Treatment.

Non-small cell lung cancer (NSCLC) is a significant public health concern with high mortality rates. Recent advancements in genomic data, bioinformatics tools, and the utilization of biomarkers have improved the possibilities for early diagnosis, effective treatment, and follow-up in NSCLC. Biomarkers play a crucial role in precision medicine by providing measurable indicators of disease characteristics, enabling tailored treatment strategies. The integration of big data and artificial intelligence (AI) further enhances the potential for personalized medicine through advanced biomarker analysis. However, challenges remain in the impact of new biomarkers on mortality and treatment efficacy due to limited evidence. Data analysis, interpretation, and the adoption of precision medicine approaches in clinical practice pose additional challenges and emphasize the integration of biomarkers with advanced technologies such as genomic data analysis and artificial intelligence (AI), which enhance the potential of precision medicine in NSCLC. Despite these obstacles, the integration of biomarkers into precision medicine has shown promising results in NSCLC, improving patient outcomes and enabling targeted therapies. Continued research and advancements in biomarker discovery, utilization, and evidence generation are necessary to overcome these challenges and further enhance the efficacy of precision medicine. Addressing these obstacles will contribute to the continued improvement of patient outcomes in non-small cell lung cancer.

Presence of periodontal pathogenic bacteria in blood of patients with coronary artery disease.

It has been hypothesised that oral bacteria can migrate, through the blood, from the mouth to the arterial plaques, thus exacerbating atherosclerosis. This study compared bacteria present in the peripheral blood of individuals with and without coronary artery disease (CAD). RNA sequences obtained from blood were downloaded from GEO (GSE58150). Eight patients with coronary artery calcification (CAC) scoring > 500 and eight healthy individuals were analysed. After conducting quality control, the sequences were aligned to the hg38 reference genome using Hisat2. Bacterial taxa were analysed by inputting the unmapped sequences into Kraken. Ecological indices were calculated using Vegan. The package DESeq2 was used to compare the counts of bacteria per standard rank between groups. A total of 51 species were found only in patients with CAD and 41 were exclusively present in healthy individuals. The counts of one phylum, one class, three orders, two families and one genus were significantly different between the analysed groups (p < 0.00032, FDR < 10%), including the orders Cardiobacteriales, Corynebacteriales and Fusobacteriales. Twenty-three bacterial species belonging to the subgingival plaque bacterial complexes were also identified in the blood of individuals from both the groups; Fusobacterium nucleatum was significantly less frequent in patients with CAD (p = 0.0012, FDR = 4.8%). Furthermore, the frequency of another 11 bacteria differed significantly among patients with CAD than that among healthy individuals (p < 0.0030, FDR < 10%). These bacteria have not been previously reported in patients with atherosclerosis and periodontitis. The presence of members of the subgingival plaque bacterial complexes in the blood of patients with CAC supports the hypothesis that the periodontopathogens can be disseminated through the blood flow to other body parts where they may enhance inflammatory processes that can lead to the development or exacerbation of atherosclerosis.

Loci associated with genomic damage levels in chronic kidney disease patients and controls.

Chronic kidney disease (CKD) is a multifactorial disorder with an important genetic component, and several studies have demonstrated potential associations with allelic variants. In addition, CKD patients are also characterized by high levels of genomic damage. Nevertheless, no studies have established relationships between DNA damage, or genomic instability present in CKD patients, and gene polymorphisms. To fill in this gap, the potential role of polymorphisms in genes involved in base excision repair (OGG1, rs1052133; MUTYH, rs3219489; XRCC1, rs25487), nucleotide excision repair (ERCC2/XPD, rs1799793, rs171140, rs13181; ERCC4, rs3136166); phase II metabolism (GSTP1, rs749174; GSTO1, rs2164624; GSTO2, rs156697), and antioxidant enzymes (SOD1, rs17880135, rs1041740, rs202446; SOD2, rs4880; CAT, rs1001179; GPX1, rs17080528; GPX3, rs870406: GPX4, rs713041) were inquired. In addition, some genes involved in CKD (AGT, rs5050; GLO1, rs386572987; SHROOM3, rs17319721) were also evaluated. The genomic damage, the genomic instability, and oxidative damage were evaluated by using the micronucleus and the comet assay in 589 donors (415 CKD patients and 174 controls). Our results showed significant associations between genomic damage and genes directly involved in DNA repair pathways (XRCC1, and ERCC2), and with genes encoding for antioxidant enzymes (SOD1 and GPX1). GSTO2, as a gene involved in phase II metabolism, and MUTYH showed also an association with genomic instability. Interestingly, the three genes associated with CKD (AGT, GLO1, and SHROOM3) showed associations with both the high levels of oxidatively damaged DNA and genomic instability. These results support our view that genomic instability can be considered a biomarker of the CKD status.

Genetic Variants Associated with Chronic Kidney Disease in a Spanish Population.

Chronic kidney disease (CKD) patients have many affected physiological pathways. Variations in the genes regulating these pathways might affect the incidence and predisposition to this disease. A total of 722 Spanish adults, including 548 patients and 174 controls, were genotyped to better understand the effects of genetic risk loci on the susceptibility to CKD. We analyzed 38 single nucleotide polymorphisms (SNPs) in candidate genes associated with the inflammatory response (interleukins IL-1A, IL-4, IL-6, IL-10, TNF-α, ICAM-1), fibrogenesis (TGFB1), homocysteine synthesis (MTHFR), DNA repair (OGG1, MUTYH, XRCC1, ERCC2, ERCC4), renin-angiotensin-aldosterone system (CYP11B2, AGT), phase-II metabolism (GSTP1, GSTO1, GSTO2), antioxidant capacity (SOD1, SOD2, CAT, GPX1, GPX3, GPX4), and some other genes previously reported to be associated with CKD (GLO1, SLC7A9, SHROOM3, UMOD, VEGFA, MGP, KL). The results showed associations of GPX1, GSTO1, GSTO2, UMOD, and MGP with CKD. Additionally, associations with CKD related pathologies, such as hypertension (GPX4, CYP11B2, ERCC4), cardiovascular disease, diabetes and cancer predisposition (ERCC2) were also observed. Different genes showed association with biochemical parameters characteristic for CKD, such as creatinine (GPX1, GSTO1, GSTO2, KL, MGP), glomerular filtration rate (GPX1, GSTO1, KL, ICAM-1, MGP), hemoglobin (ERCC2, SHROOM3), resistance index erythropoietin (SOD2, VEGFA, MTHFR, KL), albumin (SOD1, GSTO2, ERCC2, SOD2), phosphorus (IL-4, ERCC4 SOD1, GPX4, GPX1), parathyroid hormone (IL-1A, IL-6, SHROOM3, UMOD, ICAM-1), C-reactive protein (SOD2, TGFB1,GSTP1, XRCC1), and ferritin (SOD2, GSTP1, SLC7A9, GPX4). To our knowledge, this is the second comprehensive study carried out in Spanish patients linking genetic polymorphisms and CKD.

Levels of DNA damage (Micronuclei) in patients suffering from chronic kidney disease. Role of GST polymorphisms.

Chronic kidney disease (CKD) patients are characterized by the presence of high levels of DNA damage, and a poor response to ionizing radiation. In this study, we proposed that variants in GST genes could explain this fact. One-hundred twenty seven CKD patients and one-hundred forty five controls constituted the studied groups. Micronuclei (MN) frequency was determined in peripheral blood lymphocytes at both basal level, and after challenging the cells with 0.5 Gy of ionizing radiation. The following polymorphisms: GSTP1 (rs749174), GSTO1 (rs2164624), and GSTO2 (rs156697) were evaluated in the two groups. Results indicate that gene variants were distributed differentially between CKD patients and controls. Although GSTO1 and GSTO2 variants were associated with lower levels of MN, this was observed in both CKD patients and controls. When net MN values were determined after irradiation, GSTO1 and GSTO2 variants were also associated with lower MN-frequencies. On the contrary, individuals with the GSTP1 variant showed higher values of induced MN. In conclusion, we have demonstrate that the selected GST polymorphism play a role in the incidence of CKD, and affects the levels of MN. Interestingly, the modulating effects observed on both, the basal and induced levels of DNA damage, are characteristic of the overall population, not only of the CKD patients.

Influence of Carnicor, Venofer, and Sevelamer on the levels of genotoxic damage in end-stage renal disease patients.

End-stage renal disease (ESRD) patients present high levels of phosphorus and calcium products in serum, which contribute to the development of vascular calcification and cardiovascular disease, and to low iron stores and carnitine deficiency. For these reasons, ESRD patients are generally supplemented with different medicines. Some of the most common treatments include the use of Carnicor, Venofer, and Sevelamer drugs. Carnicor is used as a source of L-carnitine, acting as antioxidant and neuroprotector. Venofer is used to reduce the deficit of iron. Sevelamer is used to treat hyperphosphatemia. To determine the potential harmful genotoxic effects of these drugs, a group of 214 patients included in a hemodialysis program with different intakes of Carnicor, Venofer, and Sevelamer were evaluated. The levels of basal and oxidative DNA damage, as well as chromosomal damage, were measured in all individuals using the comet and the micronucleus assays, respectively. Our results indicate that Carnicor administration was associated with low but significant increases in the frequency of basal DNA damage and micronuclei. Environ. Mol. Mutagen. 59:302-311, 2018. © 2018 Wiley Periodicals, Inc.

DNA damage in kidney transplant patients. Role of organ origin.

Chronic kidney disease (CKD) patients are characterized by elevated levels of genomic damage. This damage increases when kidney function decreases being maximum in hemodialysis patients. As kidney transplantation improves renal function, and it is related with better survival, the aim of our study was to evaluate potential changes in DNA damage levels after kidney transplantation, and comparing living donor recipients with cadaveric donor recipients. The alkaline comet assay was used to determine DNA breaks and oxidative damaged DNA; and the micronucleus assay was used to determine chromosomal breakage and/or aneuploidy. Fifty CKD patients were followed up after 6 and 12 months of their kidney transplantation. All patients increased their genomic damage levels after 6 and 12 months of renal transplantation, compared with those observed before transplantation, despite of the improvement of their metabolic functions. Donor advanced age correlated positively with higher DNA damage. Genomic damage was lower in living donor transplants with respect to cadaveric donor transplants. Our conclusion is that DNA damage increased in kidney transplantation patients, whereas their renal function improved. Higher levels of DNA damage were found in cadaveric donor transplants when compared to living donor transplants. Environ. Mol. Mutagen. 58:712-718, 2017. © 2017 Wiley Periodicals, Inc.

Vitamin E-coated dialysis membranes reduce the levels of oxidative genetic damage in hemodialysis patients.

End-stage renal disease patients present oxidative stress status that increases when they are submitted to hemodialysis (HD). This increase in oxidative stress can affect their genetic material, among other targets. The objective of this study was to evaluate the effect of using polysulfone membranes coated with vitamin E, during the HD sessions, on the levels of genetic damage of HD patients. Forty-six patients were followed for 6 months, of whom 29 changed from conventional HD to the use of membranes coated with vitamin E. The level of genetic damage was measured using the micronucleus and the comet assays, both before and after the follow-up period. Serum vitamin E concentration was also checked. The obtained results showed that 24% of our patients presented vitamin E deficiency, and this was normalized in those patients treated with vitamin E-coated membranes. Patients with vitamin E deficiency showed higher levels of oxidative DNA damage. After the use of vitamin E-coated membranes we detected a significant decrease in the levels of oxidative damage. Additionally, hemoglobin values increased significantly with the use of vitamin E-coated membranes. In conclusion, the use of vitamin E-coated membranes supposes a decrease on the levels of oxidative DNA damage, and improves the uremic anemia status. Furthermore, the use of this type of membrane was also effective in correcting vitamin E deficiency.

Levels of DNA damage in peripheral blood lymphocytes of patients undergoing standard hemodialysis vs on-line hemodiafiltration: A comet assay investigation.

Chronic kidney disease (CKD) patients exhibit high levels of genetic damage. Part of this genetic damage is supposed to be caused by the hemodialysis (HD) therapy. Different and more efficient HD procedures could reduce the genetic damage and improve health status of CKD patients. In the present study, we analyzed if changing to online hemodiafiltration (OL-HDF) has a beneficial effect on the levels of genetic damage. The levels of genetic damage (DNA breaks and oxidatively damaged DNA) were analyzed in peripheral blood lymphocytes by using the comet assay. Forty-nine patients submitted to HD, 34 of them changing to OL-HDF and 15 patients continuing in low-flux HD, were included in the study. Plasma antioxidant capacity was also determined. Second sampling period was established after 6 months on the new or traditional HD protocol. A slight decrease in the levels of DNA damage was observed in patients who switched to OL-HDF (P=0.048) in relation to the reference group. This reduction is indicative that OL-HDF shows greater efficiency than low-flux HD in the reduction of basal levels of genetic damage.

Unfermented grape juice reduce genomic damage on patients undergoing hemodialysis.

Chronic kidney disease (CKD) patients in dialysis (HD) are considered to be submitted to a continuous oxidative stress. This stress can cause damage on DNA and, consequently, contribute to the high levels of DNA damage observed in these patients. Due to the well-known role of polyphenols as antioxidant agents we proposed its use to reduce the levels of genotoxicity present in HD-CKD patients. The objective of this study was to evaluate the antigenotoxic effects of unfermented grape juice (UGJ) on HD-CKD patients. The levels of DNA damage were analyzed using different biomarkers, such as breaks and oxidized DNA bases by the comet assay, chromosome damage by the micronucleus test. In addition, TEAC (Trolox equivalent antioxidant capacity) was also evaluated. Thirty-nine patients were followed for six months, of whom 25 were supplemented by UGJ and 14 were not supplemented. The obtained results showed a significant decrease in the underlying levels of oxidative DNA damage, in the supplemented group. Regarding the clinical parameters, LDL and cholesterol, were significantly reduced in the patients studied after the supplementation period, although cholesterol was also decreased in the non-supplemented patients. In conclusion, in our studied group the supplementation with UGJ reduced the levels of oxidative DNA damage of HD-CKD patients.

Genetic damage in patients moving from hemodialysis to online hemodiafiltration.

End-stage renal failure patients exhibit a high incidence of genetic damage and genomic instability. Part of this genetic damage is assumed to be caused by the hemodialysis (HD) procedure. To reduce these effects, different alternative HD procedures have been proposed, such as the use of high efficiency convective therapies to improve the reactive oxygen species/antioxidant ratio. To determine the efficiency of online hemodiafiltration (HDF) technique on the levels of DNA damage, we have measured the frequency of micronucleus in peripheral blood lymphocytes of 33 individuals moving from low-flux HD to post-dilution online HDF. In addition to basal levels of genetic damage, potential changes in radiosensitivity were measured as indicators of genomic instability. Plasma antioxidant capacity was also determined. Second samples were obtained after 6 months on the HDF protocol. Results indicate that moving to online HDF therapy produce a significant reduction of the basal levels of genetic damage, but does not affect the genomic instability status. In addition, a greater increase in plasma antioxidant capacity was observed. In spite of the lack of correlation between these parameters, our results confirm the usefulness of the online HDF technique as a way to reduce DNA damage in HD patients.

Genomic damage as a biomarker of chronic kidney disease status.

Patients suffering from chronic kidney disease (CKD) exhibit a high incidence of cancer and cardiovascular diseases, as well as high levels of genomic damage. To confirm the association of CKD with genomic damage we have carried out the largest study to date addressing this issue, using a total of 602 subjects (187 controls, 206 pre-dialysis CKD patients and 209 CKD patients in hemodialysis). DNA oxidative damage was measured in all individuals using the comet assay. Our results indicate that CKD patients have significantly higher levels of DNA damage than controls, but no significant differences were observed between pre-hemodialysis (pre-HD) and hemodialysis (HD) patients. When oxidative damage was measured, no differences were observed between patients and controls, although HD patients showed significantly higher levels of oxidative damage than pre-HD patients. In addition, a positive relationship was demonstrated between genomic damage and all-cause mortality. Our study confirms that genomic damage can be predictive of prognosis in CKD patients, with high levels of DNA damage indicating a poor prognosis in HD patients.

Radiosensitivity in patients suffering from chronic kidney disease.

PURPOSE: Patients suffering from chronic kidney disease (CKD) exhibit a high incidence of cancer, as well as high levels of genetic damage. We hypothesized that these patients show genomic instability detected as an increased chromosomal radiosensitivity in front of the genetic damage induced by ionizing radiation. MATERIAL AND METHODS: The background levels of genetic damage and the net genetic damage after in vitro irradiation with 0.5 Gy were analyzed using the micronucleus (MN) assay in peripheral blood lymphocytes. A total number of 552 individuals (179 controls and 373 CKD patients) were included in the study. RESULTS: The net radiation-induced genetic damage was significantly higher in CKD patients than in controls; but no differences between those patients submitted to hemodialysis and those in pre-dialytic stages were detected. A positive correlation was observed between basal and net micronucleus frequencies in CKD patients what would indicate an underlying genetic background modulating DNA damage levels. CONCLUSIONS: Our results indicate that CKD patients present genomic instability, measured as an increased chromosomal radiosensitivity in front of ionizing radiation.

Time in hemodialysis modulates the levels of genetic damage in hemodialysis patients.

It is assumed that hemodialysis treatment can diminish the levels of genetic damage in circulating lymphocytes by cleaning the blood of uremic toxins that cause oxidative stress. However, the hemodialysis process by itself may also induce genomic damage by producing reactive oxygen species (ROS). We conducted a follow-up study in a group of 70 hemodialysis patients followed for a mean time of 15 months. We investigated the effect of exposure time in hemodialysis on the levels of genetic damage in peripheral blood lymphocytes using the micronucleus assay. In addition, genetic damage after in vitro irradiation with 0.5 Gy was also analyzed to evaluate changes in radiosensitivity. Our results showed that, at the end of the study, there was a decrease in both the basal levels of genetic damage (9.9 ± 1.0 vs. 7.6 ± 0.7) and radiosensitivity values (38.5 ± 3.0 vs. 27.6 ± 2.4). We conclude that hemodialysis procedures may act as an ameliorating factor reducing the genetic damage present in chronic kidney disease patients.