This study aims to describe the prevalence of depression and anxiety among a population sample of people at high risk for type 2 diabetes in Kerala, India, and examine the relationship between depressive symptoms, anxiety, and incident Type 2 Diabetes Mellitus (T2DM) over a two-year period. We used data from the Kerala Diabetes Prevention Program, a cluster-randomized controlled trial for diabetes prevention among 1007 high-risk individuals. The prevalence of depression and anxiety were estimated using the 9-item Patient Health Questionnaire and the Generalized Anxiety Disorder 7-item scale, respectively. We calculated proportions for depression and anxiety and performed generalized estimating equations (GEE) to examine the relationship between baseline mental health status and incident T2DM. The prevalence of depression and anxiety at baseline were 7.5% and 5.5%, respectively. Compared with those reporting none/low symptoms, the odds ratio for incident diabetes was 1.07 (95% CI 0.54–2.12) for participants with moderate to severe depression and 0.73 (95% CI 0.23–2.28) for participants with moderate to severe anxiety, after adjusting for potential confounders. Our findings suggest that the prevalence of depression and anxiety were higher than those previously reported in the general population in India. However, among this sample of community-based adults at high risk of developing T2DM, the presence of moderate to severe depression and/or anxiety symptoms was not significantly associated with the risk of developing T2DM.Trial registration: Australia and New Zealand Clinical Trials Registry ACTRN12611000262909. Registered 10 March 2011. Addressing common mental disorders (CMDs), such as depression and anxiety, has become a global health priority; CMDs account for around a third of non-fatal disease burden worldwide and around 10 percent of overall disease burden  such as There is now a significant body of research examining the relationship between diabetes and CMDs. In particular, there is robust evidence indicative of a bidirectional relationship between diabetes and depression in population-based samples or among people with T2DM , 4. HoweWhile there are far fewer studies examining the relationship between anxiety and T2DM, of which the existing evidence is inconsistent, there is also some evidence that anxiety has been shown to be a predictor for incident T2DM. A meta-analysis found that 10 of 14 studies reported significant associations between baseline anxiety and incident diabetes . Among tCurrent projections estimate that by 2030 developing countries will see a 69% increase in the number of people with diabetes, compared to a 20% increase in developed countries, with India having the largest absolute number of adults with diabetes in the world . DiabeteTo date, however, the majority of research has centered on documenting the burden of mental disorders among people with diabetes and testing depression and diabetes treatment models. A recent systematic review found a significant relationship between diabetes and depression among Indian populations with diabetes, with a pooled prevalence of depression about 38% . AnxietyIn this study, we aimed to 1) describe the prevalence of depression and anxiety among a population sample of people at high risk for type 2 diabetes in Kerala and 2) examine the relationship between depressive symptoms, anxiety, and incident T2DM over a two-year follow-up period; adjusting for sociodemographic, behavioral, and clinical factors associated with these chronic conditions , 6. SociThe study was approved by the Institutional Ethics Committee of the Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, and by the Human Research Ethics Committees of Monash University, Australia and the University of Melbourne, Australia. The study was also approved by the Health Ministry Screening Committee of the Government of India, meeting all national level requirements to conduct this research. Written informed consent was obtained from all study participants.This study included participants from a cluster-randomised controlled trial, the Kerala Diabetes Prevention Program (K-DPP). A detailed description of the K-DPP study design and methods  has beenData on IDRS, socio-demographic characteristics, and anthropometrics were collected during home visits. All other measures were obtained at community-based clinics at baseline, one and two years , a valid and reliable depression severity measure , was admThe seven-item Generalized Anxiety Disorder Scale (GAD-7) was administered at baseline to assess the presence and severity of generalized anxiety disorder among participants. The GAD-7 was developed and validated within a primary care setting , and hasA psychometric validation of the translated PHQ-9 and GAD-7 instruments supports the use of both scales to measure anxiety and depressive symptom severity among individuals in India .Data on age, sex, years of education, marital status, and family history of diabetes were collected by interviewer-administered standardized questionnaires. Age and years of education were reported as continuous values, while sex  and family history of diabetes (yes or no) were dichotomized response options. Marital status was a categorical variable with five response options  that were combined to create two response options: married or unmarried.Alcohol use was assessed with the item: “Did you consume an alcoholic drink ) in the last 30 days?” (yes/ no) . Tobacco2). BMI was categorized as underweight (<18.5 kg/m2), normal (18.5–22.9 kg/m2), overweight (≥23 but <25 kg/m2), and obese (≥25 kg/m2) [Body mass index (BMI) was calculated using clinical measures of height, collected using a Seca stadiometer, and weight, using a TANITA body composition analyzer, with the formula: weight (kg) / height (m5 kg/m2) . Central5 kg/m2) , measure5 kg/m2) . Blood p5 kg/m2) . Blood s5 kg/m2) .In accordance with the American Diabetes Association criteria, we categorized participants as having incident T2DM over two years if they had a FPG of ≥ 7.0 mmol/l and/or 2-hr PG of ≥11.1 mmol/l and/or clinically diagnosed by a physician and taking glucose lowering medications .xtgee command in Stata. GEE only requires correct specification of the distribution of the dependent variable so that the variance can be efficiently calculated as a function of the mean and the regression coefficients can be properly interpreted. Since our dependent variable  was binary, we specified binomial family with ‘logit’ link function to connect the covariates and marginal means, as recommended by McCullagh and colleagues [Data are summarized using frequency and percentage for categorical variables, and by mean  for continuous variables. Since we are interested in estimating population-average effects , we used Generalized Estimating Equations (GEE)  to modellleagues . An exchlleagues , 47. Furlleagues , 48. Stalleagues . Resultslleagues –51.Covariates (or confounders) were chosen from the literature and based on their possible associations with incident diabetes –51. The Model 1: adjusted for study arm, sex, age, years in school, marital status, and family history of diabetes.Model 2: adjusted for study arm, sex, age, years in school, marital status, and family history of diabetes, alcohol use, tobacco use, leisure time physical activity, and fruit and vegetable consumption.Model 3: adjusted for study arm, sex, age, years in school, marital status, and family history of diabetes, alcohol use, tobacco use, leisure time physical activity, fruit and vegetable consumption, central obesity, hypertension, and LDL cholesterol.The goodness-of-fit of each model was assessed using Pan’s Quasilikelihood under the Independence model Criterion (QIC), with the model having the lowest QIC value deemed to have the best fit .To examine the possibility of participation bias, we compared individuals who had ≥1 follow-up visits (n = 958) and those that did not attend any follow-up visit (n = 49) using descriptive statistics. No hypothesis testing technique was used for this purpose, as there is a high likelihood for a type II error, given the small number of participants with no follow-up visits.Missing data occurred in 8.7% of the diabetes incidence data, in 3.6% of the PHQ-9 data, 0.4% of the GAD-7 data, and 0.5% of the central obesity data. All other variables included in the GEE models were 100% complete. To assess the robustness of our main results  to missing data, we performed 10 multiple imputations (MI) using chained equations . GEE modThe study was approved by the Institutional Ethics Committee of the Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, and by the Human Research Ethics Committees of Monash University, Australia and the University of Melbourne, Australia. The study was also approved by the Health Ministry Screening Committee of the Government of India, meeting all national level requirements to conduct this research.Of the 1,007 individuals enrolled in the K-DPP, 919 (91.2%) had complete incident T2DM data over two years. A detailed description of baseline characteristics of the K-PP participants has been previously reported .At baseline, 7.5% and 5.5% of participants scored > = 10 on the PHQ-9 and GAD-7, respectively. Of those who completed both mental health questionnaires, 2.7% had > = 10 on both the PHQ-9 and GAD-7.Model 3 had the best fit for both depression and anxiety as it had the lowest QIC values. Compared with those reporting none/low symptoms, the odds ratio for incident diabetes was 1.07 (95% CI 0.54–2.12) for participants with moderate to severe depression and 0.73 (95% CI 0.23–2.28) for participants with moderate to severe anxiety after adjusting for potential confounders. The results of these complete case analyses were similar to those from the multiple imputations MI analyses see .This study aimed to understand the relationship between CMDs and the development of T2DM among individuals who were at risk of developing diabetes in India. The prevalence of depression in our study population was more than double that previously reported in Kerala, and the prevalence of anxiety was 9-fold higher in this study, compared with the general population of Kerala. While studies among people with diabetes report depression prevalence rates as high as 49% , the preIndividuals who developed diabetes compared to those who did not, had significantly different clinical risk factor profiles, including higher central obesity, BMI, hypertension, and LDL cholesterol. However, there was no significant differences in mental health status at baseline between those who did and did not develop diabetes over the ensuing 24 months. This lack of association was confirmed by the GEE analyses, which showed that mental health at baseline was not related to diabetes incidence two years later. Although the evidence is mixed, this finding does not support a number of other previous studies, albeit those primarily undertaken in high-income countries , 6.Given that diabetes has a prodromal period of three to six years , 58, it The strength of this study is its use of a large, randomized, community-based sample, which offers an examination of the relationship between CMDs and diabetes in a representative sample of people at risk for developing diabetes. Although data were obtained from a cluster randomized control trial, clustering was controlled for in all analyses and study participants were treated as a cohort while controlling for intervention effects in the GEE models. The short study timeline of two years limited the number of incident diabetes cases. A 7-year follow-up of the K-DPP trial is currently underway and the results obtained from those future studies will be able to build on the analysis conducted in this paper. Additionally, while the PHQ-9 and GAD-7 questionnaires are screening tools based on diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, additional clinical examinations are necessary to provide formal diagnosis. Finally, while the follow-up rate was high (95.8%), participants with one or more follow-up visits were different in some characteristics from those lost to follow-up. However, it is less likely that our results would be altered had these lost to follow-up individuals participated in the trial, as our main results were robust to those from the MI results based on complete datasets.This study documented higher prevalences of depression and anxiety than previously reported for the general population samples in Kerala, India, as well as those reported in WHO global mental health estimates. Despite this, these findings indicate that the presence of moderate to severe depression and anxiety symptoms was not associated with an increase in the risk of developing T2DM over a two-year period among high-risk individuals in this study. Longer follow-up needs to be undertaken in order to determine whether this relationship exists in this population, and the potential causal relationship is warranted for additional validation under the Mendelian Randomization framework –64.S1 Dataset(DTA)Click here for additional data file.S2 Dataset(DO)Click here for additional data file.S3 Dataset(DTA)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Background: Plasma albumin (ALB) reflects protein nutritional status in rats, but it is not clear whether it is associated with dietary protein insufficiency in pregnant women and/or their risk of low birth weight delivery. This study aimed to investigate whether maternal serum ALB redox state reflects maternal protein nutritional status and/or is associated with infant birth weights. Methods: The relationship between the serum reduced ALB ratio and infant birth weight was examined in an observational study of 229 Japanese pregnant women. A rat model simulating fetal growth restriction, induced by protein-energy restriction, was used to elucidate the relationship between maternal nutritional status, maternal serum ALB redox state, and birth weight of the offspring. Results: In the human study, serum reduced ALB ratio in the third trimester was significantly and positively correlated with infant birth weight. In the rat study, serum reduced ALB ratio and birth weight in the litter decreased as the degree of protein-energy restriction intensified, and a significant and positive correlation was observed between them in late pregnancy. Conclusions: Maternal serum reduced ALB ratio in the third trimester is positively associated with infant birth weight in Japanese pregnant women, which would be mediated by maternal protein nutritional status. LBW delutrition ,4,5,6,7,utrition ,8. LBW dutrition , and fetutrition . This lautrition , which hutrition ,12,13, outrition ,15,16,17utrition , which iutrition . Specifiutrition .Albumin (ALB) is the most abundant circulating protein . ALB canWe hypothesized serum maternal ALB redox state during pregnancy would be correlated with infant birth weight, which could be mediated by maternal nutritional status. The aim of this study was to investigate whether maternal serum ALB redox state is associated with maternal nutritional status and/or infant birth weights. We conducted an observational study on Japanese pregnant women to examine the association between serum ALB redox state and infant birth weight. We also executed an animal experiment that simulated FGR, by maintaining pregnant rats on an AIN-93G diet  ad libitThis study was conducted in accordance with the principles of the Declaration of Helsinki and with the approval of the Institutional Review Board of Hokkaido University Hospital (Protocol No. 017-0281). Pregnant women that were scheduled to give birth between October 2018 and April 2019 were recruited at Obihiro Kosei General Hospital, Hakodate Central General Hospital, and JCHO Hokkaido Hospital, all of which are located in Hokkaido prefecture, Japan. Women were eligible if they (1) were aged 18 or older at recruitment, (2) intended to receive medical examinations during pregnancy and to give birth at any of the above three hospitals, and (3) were well informed of, in full understanding of, and in agreement with their participation in the study. Exclusion criteria were the women (1) had their first medical examination at 14 weeks of gestation or later and (2) were judged as inappropriate to participate in this study by the physicians. A total of 379 women participated in this study, and written informed consent was obtained from all of them. The participants visited the hospitals for medical examinations during the first (<14 weeks of gestation), the second (between 24 weeks and 27 weeks + 6 days of gestation), and the third trimester (around 36 weeks of gestation) of the gestational period. During the visits, demographic information was collected; blood was drawn from the antecubital vein and the serum fraction was obtained after centrifugation and stored at −80 °C. Demographic information was also collected at delivery.This study was a part of a larger study; it was conceived and the approval was obtained again after the remaining part was completed. All the analyses were thus conducted retrospectively. Among the 379 participants, 270 completed all three medical examinations during pregnancy, and gave birth. For the analyses of this study, 4 subjects were excluded as they had multiple pregnancies, 8 subjects were excluded as they had missing data on blood biochemistry, and 29 subjects were excluded as they were diagnosed with diabetes mellitus or gestational diabetes mellitus (DM/GDM); DM is a risk factor for large for gestational age rather than premature delivery , and DM/n = 6), being fed the AIN-93G diet ad libitum, or given the same diet reduced by 20%, or 40% of the average amount of ad libitum feeding. These groups were designated as the control (CTRL), 20% energy restriction (20% ER), and 40% energy restriction (40% ER) groups, respectively, and were maintained on this dietary regimen from PD10 until delivery (PD22). On PD9, PD16, and PD19, body weights of the dams were measured, and blood was collected from the lateral tail vein on the same days. The blood samples were then centrifuged, and the serum fraction was obtained after centrifugation and stored at −80 °C. On the delivery day (PD22), body weights of all of the pups were measured. The sum of birth weights in each dam was designated as “litter weight”, and the litter weight was then divided by the litter size (number of pups) to obtain the “birth weight in the litter”. All of the dams and pups were finally euthanized by deep anesthesia with sevoflurane .The design of this animal experiment was proposed by the authors, and then approved by the Animal Research Committee of Morinaga Milk Industry Co., Ltd. (Protocol No. 18-026). The experiment was performed between September 13th and October 4th, 2018, in accordance with the committee’s guidelines. Eighteen pregnant Wistar rats (dams) on pregnancy day1 (PD1) were commercially obtained . The dams were acclimated to the facility condition for 8 days ,24,25, dSerum ALB redox state was expressed by the ratio of reduced to total ALB, designated as serum reduced ALB ratio; it was determined by applying serum samples to HPLC as described previously ,29. As sp < 0.05. As for the animal experiment, a wild type animal model was selected in this experiment and statistical analyses were conducted based on the assumption that the dietary groups had normal distributions and homogeneity of variance. As for multiple linear regression analyses vs. infant birth weight, the serum reduced ALB ratio in the third trimester, pre-pregnancy body weight, pre-pregnancy BMI, gestation period, and body weight at delivery, as reported in the Results section, were selected as independent variables as they were found to be significantly correlated with infant birth weight in single linear regression analyses (p < 0.05).Data were analyzed by one-way ANOVA followed by a Tukey–Kramer HSD test, simple linear regression analyses, and multiple linear regression analyses using JMP software . Significance was demonstrated at Characteristics of the participants are summarized in Serum reduced ALB ratios differed significantly between the trimesters; the ratio in the second trimester was the highest and that of the third trimester was the lowest A. Serum p = 0.138), presumably because of the small sample size.Simple linear regression analyses were conducted to examine the relationships of maternal serum parameters vs. infant birth weight . Serum rMultiple linear regression analyses were then conducted for combinations of the above five parameters vs. infant birth weight . Serum rThe average energy and protein intakes of the dams were 196.2 kJ/d and 2.2 g/d in the CTRL group, 143.1 kJ/d and 1.6 g/d in the 20% ER group, and 107.7 kJ/d and 1.2 g/d in the 40% ER group, respectively. Body weights of the 40% ER group were significantly lower compared with the CTRL group on PD16 and PD19, whereas weight gains were different between all the three groups on PD16 and PD19 in the same directionality as the energy/protein intakes . When thSerum reduced ALB ratios of the 20% ER and 40% ER groups were significantly lower compared with the CTRL group on both PD16 and 19 A. In conSimple linear regression analyses were conducted to examine the relationship of the serum reduced ALB ratio or ALB concentration vs. birth weight in the litter; the analyses were conducted for all the animals in the three dietary groups together . Serum rWhen serum samples on PD19 were incubated at 4 °C for 5 weeks, the means ± SDs of reduced ALB ratios were down to 36.3 ± 6.7% in the CTRL group, 33.1 ± 5.4% in the 20% ER group, and 28.5 ± 3.9% in the 40% ER group, respectively, and significant differences in the serum reduced ALB ratio seen between the groups before the incubation was dissolved after the incubation. Still, the significant and positive correlation between the serum reduced ALB ratio and birth weight in the litter was persistent after the incubation .Protein-energy undernutrition is considered potentially prevalent in Japanese pregnant women ,20, and In the human observational study, LBW delivery comprised 3.9% of all the participants, which is lower than previously reported for Japanese pregnant women (9.4%) . Among tThe relationship between serum ALB redox state and birth weight of the offspring was also examined in an FGR model in rats. In order to simulate FGR, pregnant animals are normally placed on low-protein diets ,12,13, oThe largest limitation of this study was that, when considering the fact that serum reduced ALB ratio is normally >70% , albuminIn conclusion, maternal serum reduced ALB ratio in the third trimester is associated with infant birth weight in Japanese pregnant women, which is also substantiated by a rat model simulating FGR by protein-energy restriction, as we hypothesized. According to the rat model and with reference to previous literature ,24,25, p


BPA is still the subject of extensive research due to its widespread use, despite its significant toxicity resulting not only from its negative impact on the endocrine system but also from disrupting the organism’s oxidative homeostasis. At the molecular level, bisphenol A (BPA) causes an increased production of ROS and hence a change in the redox balance, mitochondrial dysfunction, and modulation of cell signaling pathways. Importantly, these changes accumulate in animals and humans, and BPA toxicity may be aggravated by poor diet, metabolic disorders, and coexisting diseases. Accordingly, approaches using antioxidants to counteract the negative effects of BPA are being considered. The preliminary results that are described in this paper are promising, however, it should be emphasized that further studies are required to determine the optimal dosage and treatment regimen to counteract BPA toxicity. It also seems necessary to have a more holistic approach showing, on the one hand, the influence of BPA on the overall human metabolism and, on the other hand, the influence of antioxidants in doses that are acceptable with the diet on BPA toxicity. This is due in part to the fact that in many cases, the positive effect of antioxidants in in vitro studies is not confirmed by clinical studies. For this reason, further research into the molecular mechanisms of BPA activity is also recommended. From a public health point of view, bisphenol A (BPA) is an important topic because it is commonly found in the human living environment. Global growth in BPA production (9618.7 kt by 2020) indicates that it is still popular with consumers [3, with a melting point of 158 °C and a boiling point of 360 °C. It is poorly soluble in water (120–300 ppm at 21.5 °C), while well soluble in organic solvents such as diethyl ether, acetone, benzene, ethanol, as well as in strong bases and acetic acid [Bisphenol A is a white solid with a density of 1.2 g/cmtic acid ,5.BPA is used in many areas of industry, primarily to produce plastics such as polyacrylates, polyesters, polycarbonates, epoxy, and phenolic resins . PolycarMytilus galloprovincialis [Perna viridis [Due to such different uses of bisphenol, its presence is often detected in wastewater, especially from factories that are engaged in industrial production ,19,20. Iincialis  and the  viridis  or marin viridis ,33,34,3550 of this compound was established at 3250 mg/kg body weight [When studying BPA toxicity in rats after its oral administration, an LDy weight . The refBPA penetrates the skin because very high levels of BPA in plasma and urine have been found in cashiers in contact with the thermal paper of cash receipts. It can also cross the placental barrier and has been detected in the mother’s and foetal serum and placenta . It has BPA has teratogenic, mutagenic, and carcinogenic effects, and can also interfere with the process of chromosome separation during meiosis. It can have a carcinogenic effect and increase susceptibility to cancer . ExtensiThe metabolism of BPA has been extensively studied using both in vivo and in vitro systems. This compound is present in human serum, urine, amniotic fluid, and breast milk in populations of industrialized countries around the world . Orally-BPA can be coupled with sulfuric acid via the phenol sulfotransferase SULT1A1 and ST1A3 ,56. Howe2●−), hydrogen peroxide (H2O2), peroxyl radical (ROO●), and hydroxyl radical (●OH). In turn, nitrogen free radicals include nitric oxide (NO●) and peroxynitrite anion (ONOO●) [2O2), and hydroperoxides, respectively, into harmless molecules . Non-enzymatic antioxidants such as vitamins A, E, C, flavonoids, carotenoids, glutathione, and melatonin, interrupt and terminate the free radical chain reactions. It is worth emphasizing that antioxidants can safely interact with the free radicals that are generated by exposure to BPA and interrupt the chain oxidation reaction before important molecules such as DNA, RNA and proteins are damaged [Every cell in the human body maintains a state of homeostasis between oxidizing agents , reactive nitrogen species (RNS)), and antioxidants. Members of the reactive oxygen species that are present in human body include singlet oxygen, superoxide anion (O (ONOO●) . Up to 1 (ONOO●) . Oxidati (ONOO●) ,64. It o (ONOO●) . Antioxi damaged .In animal models, BPA severely damages the function of many vital organs and cells, such as liver, kidney, pancreas, and testes, what is accompanied by an increased production of ROS. In addition, BPA disturbs the dynamic balance of enzyme antioxidants, reducing the levels of SOD, GSH, and CAT in the blood and pancreas .2●−) to hydrogen peroxide and molecular oxygen, making the potentially harmful peroxide anion less dangerous [Superoxide dismutase  is a metalloenzyme that is the first line of defense against harmful ROS. It catalyzes the dismutation of two molecules of the superoxide anion , which is found in almost all aerobic organisms . In animCAT prevents the oxidative action of destroying 17β-estradiol and diethylstilbestrol. Banerjee et al.  evaluateKabuto et al. found that five-day exposure of male mice to 25 and 50 mg BPA/kg/d significantly decreased the activity of CAT in the liver. However, the authors did not investigate whether the altered CAT activity was responsible for the functional changes in the liver cells .Glutathione (GSH) is a water-soluble tripeptide consisting of glutamine, cysteine, and glycine. GSH plays a role in the detoxification of various electrophilic compounds and peroxides by participating in enzymatic reactions that are catalyzed by glutathione S-transferases (GST) and glutathione peroxidases (GPx) . GST is The intraperitoneal administration of BPA (50 mg/kg/d) for five days to adult male mice increased the level of GSH + GSSG in the brain, kidneys, liver, and testes, while in the testes there was a decrease in GSH activity. The results that were obtained suggest that the injection of BPA induced an overproduction of hydrogen peroxide in mice. Hydrogen peroxide is easily converted into a hydroxyl radical. The decrease in GSH and the increase in GSSG may be caused by the hydroxyl radical. BPA can show its toxicity by increasing the level of hydrogen peroxide .Pregnancy exposure to BPA (50 mg/kg body weight/day) significantly reduces the expression of GSH S-transferases in sperm from adult F1 male mice. Reduced levels of GSH S-transferase are associated with a loss of fertility in male offspring. In other studies, a decreased expression of GSH S-transferases and an increased expression of GSH peroxidase were observed in mature mouse sperm after in vitro exposure to 1 μM BPA for six hours. The altered antioxidant activity in sperm was also associated with an abnormal acrosomal response and impaired the detoxification process of the mitochondria, subsequently affecting the ability of the sperm to fertilize the oocyte in the in vitro fertilization test .When BPA was administered to rats in an amount of 130 mg/kg bw that was dissolved in olive oil, decreased activity of catalase (CAT), glutathione S-transferase (GST), glutathione peroxidase (GPx), and superoxide dismutase (SOD) was observed. Additionally, the biochemical changes were accompanied by histopathological changes indicating the destruction of the normal structure of the liver. Histological studies have shown that exposure to BPA causes sinus dilatation, inflammatory cell infiltration, congestion, and necrosis of the liver parenchyma .4 [Genistein is an isoflavone chromen-4-one), the main source of which is legumes, especially soybeans. It is also present in broad beans, chickpeas, vegetables, fruits, and nuts . It is w4 . It also4 , HT-29, 4 ,83), pan4 , human b4 , SK-BR-34  and ZR-74 ), esopha4 , and pro4 , geniste4 . Geniste4 .In the studies of Jadhav et al.  an attemp < 0.05), and this effect was more pronounced with the combination of BPA and genistein (p < 0.01). The results suggest a synergistic effect of genistein and BPA on E1 metabolism, which is associated with an increased risk of breast cancer development [In turn, studies of the influence of genistein and BPA on the metabolism of estrone (E1) in rat liver microsomes showed that both substances inhibited 2-hydroxylation and 16α-hydroxylation of E1, but to a different extent, thus reducing the 2-OH-E1/16α ratio, what is biomarker of breast cancer risk. Although the 2-OH-E1/16α-OH-E1 ratio was lower in the BPA-treated group than under control conditions, the difference was not statistically significant. The 2-OH-E1/16α-OH-E1 ratio was significantly reduced in the genistein group . On the other hand, genistein at a dose of 20, 40 mg/kg bw/day enhanced the activity of antioxidant enzymes CAT, GPx, and SOD; improved the functioning of the Nrf2-Keap1 pathway; and inhibited an excessive accumulation of lipid peroxidation products (MDA). Additionally, exposure to BPA and genistein alters the expression of the estrogen receptor alpha (ERα) in the ovary. The use of a specific ERα agonist/antagonist confirmed that BPA and genistein have opposite regulatory effects on the Nrf2-Keap1 pathway by targeting Erα .In turn, the influence of BPA and genistein on the secretion of cytokines and chemokines was investigated using PMA-differentiated-U937 (a widely used cell line for primary human macrophages). BPA suppressed the cytokine/chemokine secretion at 1 mM while increased their secretion at 10 mM. Genistein reversed the macrophage inhibitory effects of BPA at high doses and produced synergistic effects with BPA at low concentrations .In a further study, pregnant Sprague-Dawley rats were dosed with BPA at 25 or 250 mg/kg/day by gavage from day 10 to 21 of gestation with or without genistein at 250 mg/kg/food (~5.5 mg/kg/day). The exposure to BPA induced early prostate changes, while genistein attenuated some of the deleterious effects of this xenoestrogen on the level of epithelial cell proliferation, androgen receptor expression, and prostate architecture in male offspring. At PND 180, a significant increase in the incidence of multifocal prostatitis/reactive hyperplasia and atypical hyperplasia was observed in male offspring from mothers receiving BPA 25 mg/kg/day. On the other hand, genistein alleviated some of the adverse effects of BPA pregnancy exposure in early and late prostate development in F1 offspring .ERβ expression was also found in B and T lymphocytes. Antiproliferative activity of BPA (50 µg/kg BW/d) and genistein (1 mg/kg BW/d) on the growth of mouse (EG7) and human lymphoma (Granta-519) was found in vivo in a mouse model. Researchers even suggest the use of dietary supplements with phytoestrogens in the prevention of lymphoid tumors .Curcuma longa and other Curcuma species. Curcuma longa has been used traditionally in Asian countries as a medicinal herb. Curcumin has antioxidant properties as it increases the activity of SOD and CAT. It can also inhibit ROS-producing enzymes such as lipoxygenase/cyclooxygenase and xanthine hydrogenase/oxidase [2+ to Fe3+ in the Fenton reaction [Curcumin -1,6-heptadiene-3,5-dione) is also called diferuloylmethane. Curcumin is the main natural polyphenol that is found in the rhizomes of /oxidase . Moreovereaction . Curcumireaction ,103,104.In a study by Apaydin et al.  in rats In turn, in the studies that were conducted by Uzunhisarcikli et al., rats were administered the same dose of curcumin and BPA as in the above study. The treatment with curcumin significantly alleviated the oxidative stress that was induced by BPA, mainly through the preservation of endogenous liver antioxidants such as GPx, GST, CAT, and SOD. In addition, curcumin itself neutralizes ROS and activates the transcription factor Nrf2, which is responsible for the regulation of the expression of genes that encode most of the phase II detoxification enzymes and antioxidant enzymes . MoreoveLycopene is mainly found in tomatoes and is an example of a carotenoid with a linear structure containing eleven conjugated and two unconjugated double bonds . The strAccording to Rao et al. , the daiIn the lungs, BPA caused a chronic inflammatory response in the form of increased macrophages, lymphocytic infiltration, congestion, and interstitial haemorrhage and fibrosis. Increased levels of pro-inflammatory interleukins IL-1β and IL-6 have been found, in addition to decreased levels of anti-inflammatory IL-10. Additionally, BPA causes a significant increase in Bax and caspase-3 expression and a decrease in Bcl-2 expression. Lycopene mitigated all the toxic effects of BPA and brought all the oxidant/antioxidant markers back to near-normal levels. It caused an increase in GSH level and SOD activity. Significantly increased expression of Bcl-2 and decreased expression of Bax and caspase-3 were observed in the group of rats that received lycopene and BPA compared to the BPA group. The anti-apoptotic properties of lycopene can be explained by the inhibition of the caspase-3 pathway and Bax expression . This acIn a study with female Wistar rats, lycopene 10 mg/kg body weight and BPA 10 mg/kg body weight were administered daily by gavage for 30 days. In rats that were administered BPA alone, high levels of serum liver enzymes were found with low levels of total proteins (TP) and albumin. BPA also induced hepatic oxidative stress. The administration of lycopene reduced the cytotoxic effect of BPA on hepatic tissue by improving the biomarkers of liver function and the oxidative-antioxidant state, as well as DNA damage around the control values. The beneficial antioxidant effect of lycopene was confirmed by the increased antioxidant activity of SOD, GPx, and CYP along with decreased levels of malonyldialdehyde (MDA) in rats that were co-administered with BPA and lycopene. Lycopene protects against the oxidation of proteins, lipids, and DNA by scavenging singlet oxygen and superoxide radicals, thus limiting the production of MDA as an end-product of lipid peroxidation .In another study, pregnant mice were administered BPA orally at 500 mg/kg/day from day 8 of gestation to day 14. The second group was administered lycopene at a dose of 20 mg/kg/day from days 1 to 7, followed by BPA at a dose of 500 mg/kg/day from 8 to 14 day. BPA lowered testosterone, luteinizing hormone, and follicle-stimulating hormone, while lycopene treatment increased them significantly. BPA raised estradiol, while lycopene lowered estradiol in the offspring. BPA caused testicular damage, as indicated by fewer Leydig cells and ovarian damage, less body granularity in adult offspring, while lycopene reduced the damage. The mother’s exposure to BPA increased Bax and decreased Bcl-2 in testicular and ovarian tissue in the offspring of mice. Lycopene decreased Bax in the testes and ovaries, and increased Bcl-2 in the ovarian tissue in the offspring of mice. Lycopene, therefore, has a protective effect on the reproductive toxicity that is caused by exposure to BPA .H-1-benzopyran-4-one) and is naturally found in many fruits, vegetables, and medicinal herbs. This compound is insoluble in cold water and slightly soluble in hot water [Luteolin is 3′,4′,5,7-tetrahydroxyflavone -5,7-dihydroxy-4ot water . It is oot water . Luteoliot water . It has ot water .Drosophila melanogaster, BPA was shown to induce antioxidant-oxidative imbalance and a behavioral deficit. Luteolin that was administered at a dose of 50, 100, 150, and 300 mg/kg increased D. melanogaster survival by 58, 68, 68, and 73%, respectively. Luteolin increased the activity of GST, CAT, and acetylcholinesterase (AChE). However, while luteolin improved the catalase activity, it did not prevent the BPA-induced increase in H2O2 levels. In addition, thiol-containing compounds act as reducing agents to maintain cellular redox homeostasis. The fact that luteolin increased the total thiol levels and prevented BPA-induced thiol depletion indicates its contribution to maintaining the redox balance despite the presence of toxic BPA metabolites [In studies that were carried out on abolites .The nephroprotective effect of luteolin on BPA-induced toxicity was investigated in rats that were dosed orally at 100 and 200 mg/kg. Luteolin reduced BPA-induced kidney abnormalities, blood urea nitrogen, serum creatinine, and serum uric acid. Additionally, it was observed that luteolin decreased the production of such inflammatory mediators as TNF-α, IL-1β, and IL-6 and enhanced the expression of Nrf2 and heme oxygenase 1 (HO-1). Luteolin activates the Nrf2/ARE/HO-1 defense pathway, which plays an important role in the therapeutic treatment of BPA-induced renal toxicity .Melatonin (N-acetyl-5-methoxytryptamine) is an important endogenous hormone that is secreted mainly by the pineal gland that regulates the circadian rhythm and is involved in the maintenance of redox homeostasis. Due to its small size and lipophilicity, this compound easily crosses biological membranes and reaches all cell compartments. Melatonin directly enhances the activity of NK cells, stimulates the secretion of IL-2 and IL-6, and protects hematopoietic progenitor cells against radiotherapy and chemotherapy . MelatonThe effect of melatonin on the regulation of the transcription factor OCT4 (Octamer Binding 4) by the alpha estrogen receptor (ERα) in breast cancer stem cells (BCSC) was investigated. The cells were treated with 10 nM estrogen (E2) or 10 µM BPA and 1 mM melatonin. E2 or BPA induced increases in the number and size of mammoths that were reduced by treatment with melatonin. In addition, the binding of ERα to OCT4 was decreased, accompanied by a reduction in OCT4 and ERα expression .Subsequent studies were performed in Sprague-Dawley rats that were administered BPA at a dose of 200 mg/kg body weight per day for ten consecutive days. BPA caused a decrease in the SOD activity, which eased pretreatment with melatonin, which was administered at a dose of 10 mg/kg body weight/day .In turn, in a study on MCF-7 and T47D breast cancer cell lines, melatonin (1 nM) significantly reduced cell proliferation that was raised by BPA (100 nM). It also lowered the activity of phosphorylated extracellular regulated kinase (ERK) and serine/threonine specific protein kinase (AKT). The concurrent administration of BPA and melatonin also increased the levels of melatonin receptor 1 (MT1). Melatonin can also significantly block the increased expression of steroid receptor coactivators  and the activity of the BPA-induced estrogen response element ,132.The beneficial effects of melatonin in alleviating BPA-induced oxidative stress were also found in a subsequent study when Sprague Dawley rats were administered subcutaneously with BPA  and melatonin (4 mg/kg BW) for 16 days. Exposure to BPA caused oxidative stress and further increased the expression of PUMA, p53, and Drp-1, causing apoptosis in rat brain tissue. Melatonin significantly attenuated the toxic effects that were induced by BPA by scavenging the ROS, increasing the activity of antioxidant enzymes , Px), and attenuated brain apoptosis by normalizing p53, PUMA, and Drp-1 expression both at the transcriptional and translational levels. Additionally, histological studies showed normalization of the cellular architecture by melatonin .In the studies of Olukole et al. , it has Ginkgo biloba extract, melatonin, and their combination against BPA-induced liver and kidney toxicity in male rats was also investigated. Elevated plasma levels of TNF-α and ALT and AST activity in combination with increased urea and creatinine levels with a concomitant reduction in total plasma protein may reflect the deleterious effect of BPA. Protective effects against BPA-induced hepato- and nephrotoxicity were observed when the BPA-treated rats were concurrently administered G. biloba extract, melatonin, or a combination thereof. Both the G. biloba extract and melatonin increased the level of GSH and the activity of SOD, GST, and CAT [The effect of  and CAT ,135.O-glycoside between the naringenin flavanone and the rhamnose disaccharide. This glycoside is found mainly in citrus fruits, especially grapefruits. It has a distinct bitter taste and is moderately soluble in water [Naringin is a flavan-7-in water . The gutin water . It has in water . Naringiin water . It normin water . In a stin water . Additioin water . It alsoin water . It alsoin water . Naringiin water . TGF-β iin water .L-arginine methyl ester hydrochloride), it has been shown that naringin supplementation (80 mg/kg) can reduce the toxicity of BPA (50 mg/kg). Naringin was observed to prevent the reduction in nitric oxide (NO) levels. NO is one of the critical mediators of inflammation in humans as well as in murine cancer models. NO is produced by induced nitric oxide synthase/nitric oxide synthase 2 (iNOS/NOS2) in vascular endothelial cells and on the one hand dilates blood vessels and on the other hand participates in the immune response to cancer and infection [In studies by Akintude et al.  in albinnfection . NO actiNaringin inhibits the expression of TNF-α and IL-1β, the expression of which is increased by BPA ,148. TheNaringin may be protective against BPA-induced cardiotoxicity in Wistar rats that were administered 50 mg/kg of BPA and 40, 80, and 160 mg/kg of naringin for 30 days. In rats that were administered BPA alone in a dose of 160 mg/kg, a significant increase in the levels of aspartate aminotransferase, lactate dehydrogenase, creatine kinase-MB, triglycerides, lipid peroxidation, and a significant decrease in glutathione, superoxide dismutase, catalase, and glutathione peroxidase were observed. Naringin at a dose of 80 and 160 mg/kg was protective against BPA-induced cardiotoxicity due to its antioxidant activity and inhibition of lipid peroxidation .It was also investigated whether naringin  that was administered simultaneously with BPA (50 mg/kg/day) could modify the influence of BPA on cognitive functions and inhibit possible oxidative stress in the brain tissue of rats. Naringin administration led to BPA restoring the depleted GSH and GPx activity, suggesting the ability of naringin to enhance oxidative defense by restoring the levels of these antioxidants. At the cellular level, naringin alleviates the toxic effects of reactive oxygen species by directly stimulating the transcription of genes encoding several antioxidant enzymes such as CAT, SOD, and GPx. This may explain the fact that administration of naringin to BPA-treated rats caused a significant increase in CAT and SOD activity. The administration of naringin also attenuated AChE activity after BPA administration. BPA is known to reduce the activity of acetylcholine transferase, which causes cognitive dysfunction and oxidative stress. Naringin also lowered the concentration of malondialdehyde and nitrite, which were increased by BPA .Another study by the same group of researchers showed that BPA significantly increased the levels of triglycerides, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), lipid peroxidation, and aspartate aminotransferase (AST), and significantly decreased the activity of CAT, GPx, SOD, and glutathione. In addition, BPA caused periportal inflammation and microbubal steatosis in rat tissue. The administration of 80 and 160 mg/kg of naringin reduced the BPA-induced hepatotoxicity and changed the level of lipid and liver enzyme peroxidation in rat blood serum .Quercetin is 3,5,7,3′,4′-pentahydroxyflavone that is commonly found in many vegetables and fruits . The antQuercetin has an anti-estrogenic effect and increases the testosterone levels in male rats . It alsoThe effect of BPA on human hemoglobin is unclear, but the affinity between BPA and hemoglobin and erythrocytes is indicated. BPA has been observed to cause an increase in lipid peroxidation (LPO) in human erythrocytes and a decrease in SOD, CAT, and GPx activity. In a study by Sangai et al. , quercetTaurine (2-aminoethanesulfonic acid) is a non-protein sulfur-containing amino acid, which is essential in the nutrition of children  and a conditionally essential amino acid for adults. In humans, significant amounts of taurine are found in skeletal muscle, the heart, and the placenta. It plays an important role in human physiology, being the main antioxidant, anti-inflammatory, and anti-apoptotic factor in the body. It is a physiological stabilizer of cell membranes and a key element of the nerve and muscle conduction network. Taurine protects neurons from ROS or metal toxicity by maintaining the integrity of plasma membranes and organelles  of the cell. Taurine participates in the conjugation of bile acids to form bile salts in the liver, which facilitate the intestinal absorption of dietary lipids (including fat-soluble vitamins) .In studies by Uzunhisarcikli et al., rats were administered taurine (100 mg/kg bw) with BPA (130 mg/kg). A protective effect of taurine against BPA-induced oxidative stress was observed, which can be attributed to its ability to scavenge ROS and induce antioxidant enzyme activity by activating the Nrf2 signaling pathway, similar to curcumin .All over the world, BPA is still widely used in the production of plastics which are intermediates in the sourcing of everyday objects. The negative effects of this chemical compound have been extensively researched in recent years, resulting in many review articles. The conducted research shows that exposure to BPA induces the occurrence of organ pathology, which may ultimately contribute to the development of neoplasms. Undoubtedly, BPA disrupts the endocrine system. In addition, it can also negatively affect the organism’s oxidative homeostasis, as it not only causes increased ROS production and thus disrupts the redox balance, but also causes mitochondrial dysfunction and the modulation of cell signaling pathways. However, the influence of BPA on the process of carcinogenesis is still unclear and requires better understanding, especially in particular types of cancer. It is also necessary to conduct in vivo analyses on people that are professionally exposed to BPA in terms of cancer induction, as well as epigenetic research in this area. Further work is also required to determine the long-term impact of BPA-induced micro-RNA modifications on the neoplastic process. Also, research on the molecular mechanism of BPA’s action on the human body requires a more holistic approach, e.g., using the latest metabolomics tools. It is worth emphasizing that BPA toxicity may be exacerbated by a poor diet, metabolic disorders, and coexisting diseases. So far, no cheap alternative to BPA has been found, and the so far known BPA substitutes such as bisphenol F and bisphenol S are not safe alternatives at all. For this reason, ways to reduce the toxicity of BPA are intensively sought. One of the promising solutions seems to be the use of antioxidants with proven anti-cancer activity, such as genistein, curcumin, quercetin, naringin, and melatonin, which were discussed in this paper. The aforementioned polyphenols have also shown promising anti-cancer activity by targeting oncogenic and tumor suppressor micro-RNAs . It shou


A total of 32 different types of single or core-shell NPs in different sizes and concentrations have been used in the studies.In recent years, high atomic number nanoparticles (NPs) have emerged as promising radio-enhancer agents for cancer radiation therapy due to their unique properties. Multi-disciplinary studies have demonstrated the potential of NPs-based radio-sensitizers to improve cancer therapy and tumor control at cellular and molecular levels. However, studies have shown that the dose enhancement effect of the NPs depends on the beam energy, NPs type, NPs size, NPs concentration, cell lines, and NPs delivery system. It has been believed that radiation dose enhancement of NPs is due to the three main mechanisms, but the results of some simulation studies failed to comply well with the experimental findings. Thus, this study aimed to quantitatively evaluate the physical, chemical, and biological factors of the NPs. An organized search of PubMed/Medline, Embase, ProQuest, Scopus, Cochrane and Google Scholar was performed. In total, 77 articles were thoroughly reviewed and analyzed. The studies investigated 44 different cell lines through 70  As a result, attempts are being made to improve the efficiency of RT mainly by: (I) enhancing the radiation dose inside the cancer cells; (II) sensitizing the tumors that are radio-resistant; (III) applying targeted RT.10 Radio-sensitizers are materials that increase sensitivity of the tumor tissue to radiation.11In general, the sensitivity of the highly or functionally active tumor cells is somewhat higher than that of nearby or adjacent normal tissue. Thus, the dose of radiation required to destroy cancerous tissue is far lower than that of normal tissue.13 quantum dots,15 super paramagnetic iron oxides,16 and non-metal-based NPs.17 With development of nanotechnology, NPs especially noble metal NPs, have also been developed as a hopeful approach to improve RT technique efficacy due to their unique physical and chemical properties. Radio-sensitizers have provided novel and great tools for imaging,19 diagnosing,20 and treating cancer.24 To date, several different NPs such as gold, iron, bismuth, titanium and carbon have been applied as probable tumor-selective radio-sensitizers.27 Radio-sensitizers are chemical or pharmacologic agents which enhance the response of cells to radiation. Ideal sensitizers should have these characteristics: Selectively sensitize, chemically stable and slowly metabolized, effective throughout cell cycle and effective at low daily doses of radiation. The relative efficacy of a particular cell radio-sensitizer is most often described with the sensitizer enhancement ratio (SER) or dose enhancement factor (DEF). The SER and DEF are the dose ratio of radiation alone versus in the presence of the cell sensitizer to produce the same biologic effect. If they were greater than one, then the addition of the agents is functioning as a radio- sensitizer. If they were less than one, then the drug is a radio-protector.In order to enhance radiation dose to the tumor, multiple approaches have been proposed such as metal based nanoparticles (NPs),The mechanism of photon interactions with high-Z NPs is strongly related to radiation beam energy. However the probability of photoelectric interaction is dominant during low energy radiation, Campton scattering and pair production mainly accrue in mega voltage (MV) energies. Briefly, the basis of cellular damage with high atomic number NPs is based on generation of secondary electrons, free radicals, and reactive oxygen species (ROS).Having explored electronic resources, it seems that no systematic review study has been done in this field. This study presents a historical report and provides a comprehensively review and analysis of the published studies. The first aim of the current study is the quantitative evaluation of the physical, chemical, and biological parameters of NPs affecting radiation enhancement. The second goal is assessing the NPs materials with a particular focus on the in-vitro outcomes as well as the principal mechanisms of response in non-metal and metal-based NPs radio sensitization. Also, we investigated the effect of the NPs type, NPs size, NPs concentration, cell line type, and radiation beam energy on the radiation dose enhancement during RT modality.28The literature review was done and reported according to the standards set out in Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) checklist.Articles were included in the current review based on the following inclusion criteria: (i) the original, quantitative papers, review papers, thesis, conference papers, meetings and ongoing papers in English language; (ii) the study involved only experimental procedures, not simulation ; (iii) studies which investigated the effect of NPs as a radio sensitizer substance in RT; (iv) photon RT not particle . On the other hand, articles that used NPs for drug delivery, drug formulation, shielding material or as imaging agents were excluded.29 was used for quality assessment of included studies. Two investigators separately rated the methodological quality of included studies.The Consolidated Standards of Reporting Trials (CONSORT) checklistA literature search was performed to find published studies that involved NPs as a radio sensitizer for cancer treatments. An organized search of PubMed/Medline, Embase, ProQuest, Scopus, Cochrane and Google Scholar was performed based on Mesh key words and suitable synonyms. Two researchers (RM and FS) independently and separately performed literature search. Our search strategy in each database was established by the following terms: ((enhancement [Title/Abstract]) AND (((“Radiotherapy”[Mesh]) OR Radiotherapy [Title/Abstract]) OR Radiation [Title/Abstract])) AND  OR “Nanoparticles”[Mesh]). Database search had no limitation in time, and our last update on search was in March 2019. To have a comprehensive search and to find probable appropriate articles, manual search was also conducted on the reference list of articles. The search was limited to articles published in English.The results of systematic literature search from the data bases were collected in Endnote X7. After removing duplicates, the articles were selected independently by two subject specialists in three stages. At first, the titles of all articles were reviewed and articles that were not consistent with the study objectives were excluded from the study. In the next step, the abstract and the full text of the articles were considered, and the full texts of relevant articles that involved inclusion criteria identified and included. For each eligible study, one reviewer extracted the data and then the results were checked by second reviewer. Any in consistencies were resolved through discussion and by consulting a third reviewer. After the final selection of studies, the required information was extracted and summarized using the extraction table. The extracted data of each study included the following content: publication year, cell line type, NPs type, NPs size, NPs concentration, photon energy, DEF or SER and mechanisms of cell damage. The total articles presented as a flow chart for the selection of the included studies .Totally, 1670 relevant articles were identified through the literature search; of these 77 studies met the inclusions criteria which examined the effectiveness of NPs during RT and thence considered as relevant and included in the systematic review. In these studies, DEF of different NPs had been investigated in a wide range of radiation beam energy values from 88 keV to 18 MV. Specifically, 52 studies used radiation beams with less than 300 keV, 43 studies with radiation energy over 1 MV, and only six studies used Cs-137 radioactive source with 662 keV photons energy.Various types of NPs also were used, of which the most common types were gold  in 56 studies, gadolinium  in seven studies, core-shell NPs, in six studies, bismuth  in 4 studies, platinum , silver , and iron , with each used in three studies, titanium  in two studies; other NP types included hafnium , silicon , zinc , neodymium , lanthanide , cerium , tantalum , which each used in one study .106  depending on the NPs type, NPs concentration, NPs size, cell line, radiation energy, and delivery condition. Table S1107 Further, with increasing experimental and simulation studies in the field, it was found that the DEF values obtained in experimentally biological (in-vitro and in-vivo) studies were considerably greater than those found by the simulation (mass attenuation coefficients) studies in both kilo-voltage and mega-voltage radiation energy. These findings reported other mechanisms through which NPs sensitize cells to radiation. Indeed, based on the results of previous studies, it can be concluded that the mechanism of NPs radiation dose enhancement in biological systems is classified into three sections: 1) physical phase, 2) chemical phase, and 3) biological phase.109 Thus, the disagreement between DEF values of experimental and simulation studies can be explained by the lack of chemical and biological phases on cellular damage in simulation studies.The integration of nanotechnology with biotechnology allows us to deliver high atomic number metal NPs to the target cells as radio-sensitizers due to their elevated absorbance properties in comparison to surrounding soft tissue.110 The probability of each three different mechanism depends on the photon energy and the atomic number of the radio sensitizer. Further, original studies suggest the key NPs chemical characteristics including size, shape, crystal structure, surface area, surface energy, surface characteristics, and inner structure generally influence the toxic manifestations of these materials.112The physical phase of radio-sensitizers is based on the photoelectric effect, coherent and incoherent scattering, and pair production. Each photon can interact with the matter and be completely absorbed or be scattered and thus deposit part or all of its energy according to three possible mechanisms.113 (2) cell cycle disruption, and (3) DNA repair inhibition.114The biological effects of NPs are a major cause for cell death. They reflected in cells as increased ROS and oxidative products, as well as elimination of cellular antioxidants. Thus, according to studies to date, three important biological pathways for radio sensitization have been introduced: (1) oxidative stress,116 Also, the smaller the NP size, the longer they remain in the blood circulation. Smaller NPs are filtrated through kidneys quickly, while larger ones avoid clearing.NPs surface chemistry is a key parameter which affects bio-distribution and cellular uptake of NPs. NPs are single elements with a diameter of 1 to 100 nm. The smaller the NP diameter, the larger the surface area/volume ratio. The larger surface area causes more atoms to form around the surface of NPs, making NPs highly reactive and conferring them new and unique physicochemical properties. Thus, an important difference between NPs and micro-particles is their surface area. NPs are capable of interacting radiation due to their larger surface area thereby enhancing the physical, chemical, and biological effects.118 In the study by Gurr et al, they disclosed a strong relationship between the size and toxicity of TiO2 NPs. TiO2 NPs with diameter < 50 nm caused increased micronuclei number in human bronchial epithelial cells, while TiO2 micro particles with diameter > 200 nm were nearly harmless at the same concentration.119There are studies proving that NPs of any compound are more cytotoxic than MPs of the same compound.120 Also, the majority of studies have found that size is an influential radiation sensitivity parameter. Large-sized Au NPs have the most efficient DEF. Wang et al50 examined the in-vitro Au NPs radiosensitization effect in the breast cancer cell line (MDA-MB-231). DEFs of 1.49 and 1.86 were observed with 16 nm and 49 nm Au NPs, respectively. Brun et al56 prepared a comprehensive study for size effect of Au NPs for radiosensitization. They found that DEFs of 1, 1.75, 1.76, 2.65, and 2.95 were obtained associated with 8 nm, 20 nm, 37 nm, 74 nm and 92 nm of Au sample size, respectively. Similarly, Bobyk et al32 showed that use of 1.9 nm and 15 nm caused DEF 1.92 and 1.40, respectively. Also, a systematic study of the size-dependent radiosensitization of Au NPs against HeLa cell line found that 4.8 nm, 12.1 nm, 27.3 nm, and 46.6 nm Au NPs revealed DEFs of 1.41, 1.65, 1.58, and 1.42 obtained at the same concentration and radiation energy, respectively. Since only NPs with size 1-100 nm are able to enter cells, optimal size design can enhance the cell internalization and consequently results.As cellular uptake of the NPs depends on surface chemistry, Chompoosor et al determined the effect of Au NPs surface functionality on ROS generation and DNA damage. They approved that the cytotoxicity and genotoxicity of Au NPs depend on their surface chemistry (hydrophobicity). Increasing the hydrophobicity of the particles improved their cytotoxicity.33 examined the radiation enhancement of Au NPs in several cell lines with two different concentrations at 160 kVp photon irradiation. The following DEFs have been reported for various cell lines using 0.05 and 0.5 mM concentrations of Au NPs: DEFs of 0.86 and 0.87 (L 132), 1.04 and 0.96 (Astro), 1.16 and 1.97 (AGO), 1.30 and 1.91 (T98G), 1.67 and 1.11 (MDA 231), 1.41 and 1.09 (MCF7), 1.07 and 1.02 (PC3), and 0.98 and 0.81 (DU145), respectively. In another study, Rahman et al47 examined the effect of different concentrations of Au NPs on enhancing the radiation effects. They revealed that DEFs significantly increased using a high concentration of NPs. DEFs of 2.4 and 2.0 were noted while using 1mM and 0.5 mM at 80 kVp, respectively. Also, DEFs of 2.2 and 1.4 were obtained using 1mM and 0.5 mM at 150 kVp, respectively.Based on literature review, the effect of NPs’ concentrations on dose enhancement is far greater than NPs’ size. Elevation of the NPs’ concentration reduces the cell growth rate. This decrease seems reasonable as the concentration rise of NPs increases the number of NP atoms. Thus, more physical, chemical, and biological interactions occur between cells, photons, and atoms. Higher NP concentrations seem to carry a higher risk of toxicity. Thus, the balance between dose enhancement effect and toxicity should be set. Butterworth et al2 and Pb NPs toxicity in human lung epithelial (A549) cells. They found that TiO2 was not toxic to A549 cells. However, cell viability diminished due to Pb-induced toxicity, production of ROSs, and reduction in antioxidant levels. Interestingly, in co-exposure group (TiO2  NPs + Pb), TiO2 significantly reduced Pb toxicity in A549 cells. Cellular uptake confirmed that TiO2 NPs increased the bioaccumulation of Pb in cells.121Ahamed et al explored the effects of TiO122 As for Pt, the Pt NPs were shown to enter the cells through diffusion, leading to an increase in DNA damage and apoptosis.123 Asharani et al compared the toxicity between 3–10 nm Pt, 5–35 nm Ag, and 15–35 nm Au NPs covered with PVA, and concluded that Ag NPs were the most toxic, followed by Pt NPs, while Au NPs presented no indication of toxicity.124Several studies confirmed that Ag NPs mostly cause significant cytotoxicity.The choice of optimal beam energy in using a dose-enhancing agent is an important consideration. Several reports have shown the efficiency of NPs’ radio-sensitization at low energy beam (kV). Meanwhile, such radio enhancement is shown at MV X-rays. Initial RT was carried out with kV energy range. With advances in RT and the potential damage of low-energy radiation to the skin, today, most RT units use clinical linear accelerators for producing MV X-rays.125 The interaction of photons with materials at low energies is based on the photoelectric phenomenon. The photoelectric effect exhibits a cross-section with Z3/E3 depending on the photon energy and material atomic number, and is enhanced due to increased absorption by electron shells  as shown in 2, so the relative effect of NPs for Au NPs to soft tissue is approximately 127 (792/72).In order to find the best radiation energy used in RT to produce the most effective dose enhancement effect in a tumor, we need to have a closer look to the interactions between radiation and matter. Theoretical principles of X-ray interactions with NPs have already been described.4 per MeV) are produced at the tumor site, which has a very low energy (< 50 eV) and low linear energy transfer (LET).126 Thus, their energy is left to their immediate surroundings and damaging target cells. It is well known that secondary electrons induce significant single- and double-stranded breaks in DNA due to the rapid collapse of molecular resonance located in the DNAs basic components  and of proteins (e.g. amino acids).129As a result of all these mechanisms, secondary electrons .The mass attenuation coefficients of applied NPs and soft tissue are shown in 41 observed that DEFs of 1.41, 1.29 and 1.16 were acquired in MDA-MB-231 cells by 1.9 nm Au NPs in combination with 160 kVp, 6 MV, and 15 MV X-rays, respectively. To sum up, in almost all studies, the dose enhancement of photons with MV energies is lower than kV energies, but still far greater than the MC simulation, which is due to the biological effect of NPs.It is expected that the radio-sensitization of NPs is insignificant at MV energies due to the negligible contribution of photoelectric absorption of photons. Chithrani et al assessed the dependence of radio-sensitization at the clinically relevant radiation energy. They reported a decrease in radio-sensitization  with increasing energies. Similarly, Jain et alThe cytotoxicity of NPs varies in different cell types. NPs could enhance the sensitivity of some cells to irradiation but not all cells, as glucose-coated Au NPs did not radio sensitize human diploid fibroblast cells but did enhance human prostate carcinoma cells. As another proof, despite cellular uptake in human prostate cancer cells and lung epithelial cells, radiosensitization was observed in neither of them. Au NPs’ cellular uptake levels and cell cycle phases might justify it. Metallic materials block cells at the G2/M phase, the most radiosensitive phase of the cell cycle, and therefore augment cell radio-sensitivity.131 Similarly, Jain et al40 evaluated the cytotoxicity of 1.9 nm Au NPs in normal L132, prostate cancer DU145, and breast cancer MDA-MB-231 cells in combination with 6 megavoltage X-ray. DEFs of 1.08, 1.13 and 1.29 were achieved in L132, Du 145 and MDA-MB-231 cells, respectively. Due to the same NP and radiation energy, this cannot be contributed to levels of radiosensitization based on physical action. So it obviously showed that different cell lines had a various biological response to Au NPs. Au NP chemo-sensitization was observed in MDA-MB-231 cells treated with bleomycin which approved different biological respond. Similar results were shown in McMahon et al study.132 This suggests that some cell lines show little or no radio-sensitization despite taking up similar numbers of NPs.Albanese and Chan investigated the effect of Au NPs aggregation with different sizes on cellular uptake and toxicity in three different cell lines. Their contrasting results suggested that cell type may play a significant role. It was found that, while there was no difference in the toxic response of single and aggregated NPs, the uptake patterns had a clear difference between single and aggregated NPs. There was a 25% reduction in the uptake of aggregated NPs with HeLa and A549 cells compared to single NPs. However, there was an increase of 200% in cell uptake of MDA-MB 435 for the largest synthesized aggregates.134 ROS can damage cancer cells in several ways, such as DNA damage, interfering with signaling functions, and modulating gene transcription.135 The most commonly produced ROS in biological systems include anion superoxide (O2), hydrogen peroxide , and hydroxyl reactive radicals (-OH). The extent of damage caused by ROS depends not only on the type and amount of ROS, but also on the time and duration of exposure to ROS and the external factors of the cell, such as temperature, oxygen pressure, and the surrounding environment including ions and proteins.136 In physiological conditions, the concentration of H2O2 is low and about 5-50 nM. If the H2O2 concentration reaches 1-3 μM, apoptosis (planned cell death) induction happens. For concentrations above 3 μM, it becomes toxic to the cell and leads to its necrosis (un-programmed cell death pathway).138 Antunes and Cadenas verified that by increasing certain ROSs , the cell’s viability declines.139 Shukla et al assessed genotoxicity of TiO2 NPs on human epidermal cells (A431) as an in vitro model.140 They observed a statistically significant relationship between ROS generation and DNA damage and micronucleus formation on exposure to TiO2 NPs group. Their results are in agreement with Kang et al. who reported that TiO2 NPs induced ROS generation in human lymphocytes.141 Also, they have been described cell–specific DNA DSB formation, cytokinesis arrest, and apoptosis in the absence of radiation with 30 nm Au NPs.Although the main mechanism whereby NPs induce cell damage effects is still unknown, it has been suggested by different biological studies that they can produce ROS, and therefore can affect the concentration of intracellular calcium, activate transcription factors, and induce cytokine production.2-Si NPs penetrated the mitochondrial membrane and significantly raised intracellular ROS levels in MCF-7 cells under radiation.103Nonmetal NPs (silicon and carbon-based NPs) can also induce radiosensitization effects based on an oxidative stress mechanism. Si NPs significantly improved ROS production in glioma C6 and MCF-7 cells under X-ray irradiation. Positively charged NH142 Geng et al39 showed that Au NPs enhanced the production of intracellular ROS when irradiated with 90 kVp or 6 MV X-rays in SKOV-3 human ovarian cancer cells. Wason et al investigated whether and to what extent cerium oxide NPs might affect radiation-induced ROS production in pancreatic cancer cells and normal pancreatic cells.143 Surprisingly, the results disclosed a 200% increase in radiation-induced ROS generation in L3.6pl cells with cerium oxide NPs compared to cells exposed to radiation alone. These results indicate that increasing ROS production by NPs may be one of the mechanisms that facilitates NPs radio sensitivity. The enhanced radio-sensitivity of cancer cell by NP is shown in ROS generation has also been proposed as a possible mechanism by ionizing radiation.in vitro studies did not fully match with the in vivo experiments. This may be due to disparity between predicted levels of radiosensitization based on physical and biological actions. Also, reviewing the studies, showed that the radiosensitization of a particular cell line depends on many factors, and even different cell lines show different responses to the NPs. So to boost efficiency, specific NPs must be used for each cell line. Moreover, interesting is the existence of various mechanisms of cell damage by NPs. Simultaneous use of several types of NPs or the use of Nano-complexes to increase the efficiency of treatment as a radio-sensitizer can be very promising in the future.Definitely, NPs supported RT open up new perspectives in the fight against cancer. However, there are some problems and limitations that prevent it from translated into the clinic. It was found that the promising preclinical results of The studies conducted on the potential of using NPs in RT have confirmed the role of these various NPs in enhancing the radiation dose in loaded tissues. NPs have proved to cause radio-sensitization at kilo-voltage and megavoltage photon energies. RT dose enhancement with NPs appears to be a promising approach for improved cancer treatment. Different NPs sensitize cancer cells to RT through multiple mechanisms, including oxidative stress, DNA damage, cell-cycle arrest and apoptosis. For successful RT, it seems to use, (1) NPs with high atomic number (Z) to enhance RT efficacy via their photoelectric and Compton effects, (2) targeting cancer cells with specific targeting molecules extends the circulation time of the NPs to increase their accumulation in cancer cells and (3) the combination of two different types of radio-sensitizers or the combination of radio-sensitizers can result in significantly synergistic tumoricidal effects. Finally, using NPs can be an asset not just to radio-sensitize cells but also to provide contrast as they can be imaged, which can lead to better drug tracking and detection of the exact location of the tumor for RT. Despite their unique merits, it is difficult to move toward clinical programs without understanding the mediating mechanisms of biological effects in cells.Not applicable.The author declares that there is no conflict of interest.This study was supported by Research Center for Evidence Based Medicine (RCEBM), Tabriz University of Medical Sciences, Tabriz, Iran.The authors would like to thank Director of Research Development and Coordination Center (RDCC), Dr. Ghojazadeh, for his assistance withresearch methodology.Supplementary file 1 contains Table S1Click here for additional data file.


Following the publication of this paper, the authors have realized that they overlooked indicating that Zhikun Chen and Qin Che contributed equally to this work. Therefore, the affiliations for this paper should have been written as follows:1*, QIN CHE2* and CHUNXUE XIE3ZHIKUN CHEN1Emergency, 2Infectious Diseases and 3General Practice, Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. ChinaDepartments of *Contributed equallyThe authors confirm that there are no further errors in the study, and all the authors agree to this correction. The authors regret their oversight, and apologize for any inconvenience caused.


Pieces of evidence strongly indicate that providing high-quality family planning services is accompanied by an increase in contraceptive uptake and a decrease in contraception discontinuation. Contraceptive, especially Implanon discontinuation is a global issue that could be linked to a summary outcome indicator of poor family planning service quality. Although Implanon is becoming more popular among Ethiopian contraceptive users, little is known regarding the survival and predictors of discontinuation. The study aimed at exploring the survival and predictors of Implanon discontinuation among women enrolled in family planning units of Public hospitals in southern Ethiopia, 2021.A hospital-based retrospective cohort study was conducted among Implanon users who enrolled in family planning units of Public Hospitals. Five years of medical records, from January 1, 2016, to December 30, 2020, were reviewed. A total of 502 women were selected by using a random sampling technique. A standardized abstraction tool was used to collect data from medical records and registration books. The data were entered into Epidata Version 3.1 and then exported to STATA 14 for analysis. The median was calculated in the case of survival time. Across covariates, the Kaplan Meier survival curve was used to estimate time to Implanon discontinuation. To identify statistically significant predictors of Implanon discontinuation, a multivariable Cox proportional hazard model was fitted.The incidence rate of Implanon discontinuation was 1.87 per 100 person-months of observation. The overall estimated survival probability at the end of 24 and 36 months was 67.4%  and 25.9%  months respectively. Residence , parity , pre-insertion counselling , experiencing heavy vaginal bleeding , post-insertion follow up  were identified as a significant predictors of Implanon discontinuation.The risk Implanon of discontinuation was high, especially at 24 and 36 months. In family planning service delivery points, health care providers should pay special attention to clients who live in rural areas and do not have children. In addition, health care providers should provide pre-insertion counseling and post-insertion follow-up that focus on potential side effects. Finally, family planning units need to engage in early side effect management and reassurance to mitigate discontinuation.The online version contains supplementary material available at 10.1186/s13690-022-00859-6. In 2015, 64% of married or in-union women of reproductive age group over the world used at least one method of contraception. Contraception use, on the other hand, was substantially lower in the least developed countries (40%), especially in Africa 33%) [3% [3]. CEvidence strongly indicates that providing high-quality family planning services is accompanied by an increase in contraceptive uptake and a decrease in contraception discontinuation . ContracImplanon is a second-generation single-rod implantable Long-acting Reversible Contraceptive (LARC) that is implanted subdermally and provides effective contraception for up to 3 years with a clinical failure rate of less than 1% . It contAlthough Implanon is generally well tolerated, recent studies have revealed that some women will discontinue using it for a variety of reasons . ImplanoThe probability of Implanon discontinuation varies greatly around the world, ranging from 3 to 69% . AccordiThe Ethiopian Federal Ministry of Health (FMOH) initiated an Implanon scale-up program through the Integrated Family Health Program (IFHP) in 2009, intending to increase community access to and use of Implanon by allowing health extension workers to provide Implanon insertion services , 29. ImpTo reduce the prevalence of unmet contraception needs, researchers need to investigate the rate to which and the reasons why contraceptive users become non-users . Rather Guraghe zone is one of 13 zones of the Southern Nation Nationality and People Region (SNNPR), with a population of 1,835,110 people, 19.84% of whom are women of reproductive age (15–49 years old). Wolkite, the zone’s capital, is located 158 km south of Addis Ababa, the capital city of Ethiopia, and 337 km south of Hawassa . Regarding health facilities, there were 74 health centers, 6 hospitals, and 444 health posts (unpublished data) . Women who did not get pre-insertion counseling had a 2.4 times higher chance of discontinuing their Implanon than those who did . In terms of side effects, women who experienced significant and/or persistent vaginal bleeding were 3.9 times more likely to discontinue the Implanon than their counterparts . Women without post-insertion follow-up had a 3.15 times higher risk of discontinuance than those with recorded follow-up schedules . When comparing women who previously used Implanon as a contraceptive technique to those who used a condom as a contraceptive method, those who previously used Implants had a 53% lower likelihood of discontinuation   women were discontinued and 297 were censored. This finding resulted in a cumulative incidence of removal of 22.4(95%CI = 19.56–25.8) per 100 person-years of observation which is higher than studies conducted in the Democratic Republic of Congo, Nigeria, and Thailand with an overall incidence rate of 11.52, 19 and 2.3 and per 100 person-years of observation respectively , 36, 37.In the current study the discontinuation rate was 12.1% in 12 months, which was higher than studies conducted in Democratic Republic of Congo (8.4%) , NigeriaParity was found to be a strong predictor of discontinuation. The risk of discontinuance was two times higher among women who had no child (nulliparous) compared to those who had 5 or more children. This finding is supported by studies conducted in Bangladesh , the DemThe Hazard of discontinuation among women with no pre-insertion counseling was 2.4 times higher as compared to those women who got counseling. This finding was consistent with studies conducted in Ethiopia , 32, 41,Women without documented post-insertion follow-up had a 3.15 times higher risk of discontinuing Implanon than women with documented follow-up schedules. This conclusion was supported by studies conducted in northern Ethiopia (Amhara and Tigri regions) , 31 and Those who had previously used Implants had a 53% lower likelihood of discontinuing Implanon than those who had previously used a condom as a contraceptive method. A study conducted in Egypt agreed with this finding . This coThe presence of prolonged/heavy vaginal bleeding has also been shown to have a significant effect on the incidence of discontinuation. This was in line with studies conducted in northern Ethiopia , 32, SouTo our knowledge, this study may be the first of its kind at the national level in assessing the incidence and predictors of discontinuation among Implanon users by using a fairly strong study design. As a result, these findings may have relevant programmatic input for policymakers, healthcare providers, and other stakeholders participating in FP programming as an input to intervene in discontinuation by understanding the possible predictors. Because records with missing information or charts that were lost for certain patients were excluded, selection bias may have occurred. On the other hand, because the data is gathered through record review, the incompleteness of information and the reliability of the recorded data, such as excessive vaginal bleeding, remains a major concern.The risk Implanon of discontinuation was high, especially at 24 and 36 months. Residence, parity, pre-insertion counseling, Post-insertion follow-up, heavy and prolonged vaginal bleeding, and previous uptake of Implanon were identified as significant predictors of Implanon discontinuation. In family planning service delivery points, health care providers should pay special attention to clients who live in rural areas and do not have children. In addition, health care providers should provide pre-insertion counseling and post-insertion follow-up that focus on potential side effects. In addition, family planning departments must engage in early side effect treatment and reassurance to mitigate discontinuation.Additional file 1.Additional file 2.


In this study, we established a nomogram for the prognostic prediction of patients with early-onset cervical cancer (EOCC) for both overall survival (OS) and cancer-specific survival (CSS). The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 10,079 patients diagnosed with EOCC between 2004 and 2015; these cases were then randomly divided into training and validation sets. The independent prognostic factors were identified in a retrospective study of 7,055 patients from the training set. A prognostic nomogram was developed using R software according to the results of multivariable Cox regression analysis. Furthermore, the model was externally validated using the data from the remaining 3,024 patients diagnosed at different times and enrolled in the SEER database. For the training set, the C-indexes for OS and CSS prediction were determined to be 0.831  and 0.855 (95 % CI: 0.839–0.871), respectively. Receiver operating characteristic (ROC) analysis has revealed that the nomograms were a superior predictor compared with TNM stage and SEER stage. The areas under the curve (AUC) of the nomogram for OS and CSS prediction in the ROC analysis were 0.855 (95 % CI: 0.847–0.864) and 0.782 (95 % CI: 0.760–0.804), respectively. In addition, calibration curves indicated a perfect agreement between the nomogram-predicted and the actual 1-, 3-, and 5-year OS and CSS rates in the validation cohort. Thus, in this study, we established and validated a prognostic nomogram that provides an accurate prediction for 3-, 5-, and 10-year OS and CSS of EOCC patients. This will be useful for clinicians in guiding counseling and clinical trial design for cervical cancer patients. Cervical cancer remains the fourth most common female malignancy in the world ,2, rankiAt present, the tumor lymph node metastasis (TNM) staging system proposed by the American Joint Commission on Cancer (AJCC) has been widely used to predict the prognosis of various cancers. This system considers tumor invasion (T), regional lymph node (N), and distant metastasis (M) as predictors . HoweverIn recent years, nomograms based on the regression coefficient of each variable integrate multiple prognostic factors and may better predict survival rate . It has From 2004 to 2015, we adopted SEER * stat software  in order to identify 10,079 eligible patients who were diagnosed with EOCC from the SEER database of the National Cancer Institute, which includes clinicopathological and individualized prognosis data. The exclusion criteria were as follows: (I) patients over 45 years old; (II) patients with multiple primary tumors; (III) unknown survival time; (IV) non-histological studies; (V) unknown AJCC stage; (VI) unknown TNM stage; and (VII) patients with no surgery. The screening scheme for the subjects is provided in Clinical variables extracted from the SEER database included age at diagnosis, race, marital status, histological type of origin, primary tumor site, histologic type, tumor academic stage, NM stage, SEER stage, tumor size (cm), chemotherapy, and radiotherapy. The EOCC patients were then divided into three groups based on age  was used for creating nomograms. A consistency index (C-index) and calibration curve were used to evaluate the performance and accuracy of the nomogram. The C-index value ranged from 0.50 to 1.00 and was positively correlated with the prediction performance of the model. This shows that the model is accompanied with a perfect discrimination ability when the value is 1.00. When the calibration curve is applied to a fully calibrated model, the prediction will fall on the 45° diagonal in the figure.Kaplan–Meier curve and logrank tests were used to examine the OS and CSS of the EOCC patients. The objective was to identify the predictive clinical factors for OS and CSS in patients with EOCC by univariate and multivariate regression analyses. The Cox proportional hazard results were used as the basis of nomogram construction and validation. R software version 3.5.1  and curves were used to evaluate the predictive performance of nanograms, TNM stage and SEER stage. Statistical analyses were conducted using Statistical Package for the Social Sciences software . When p < 0.05, the results were statistically significant.In addition, receiver operating characteristic (ROC) curves were used to evaluate the predictive performance of nomograms, TNM stage, and SEER stage. Statistical analyses were conducted using the Statistical Package for the Social Sciences software . P-values < 0.05 were considered statistically significant.In total, 10,079 eligible patients, who were diagnosed as having EOCC from 2004 to 2015, were identified in the SEER database; these cases were then randomly divided into a training set  and a validation set . For all patients, there were 5,123 (50.8 %) patients <37 years old and 2,487 (24.7 %) patients >40 years old. For the race group, 8,138 (75.8 %) patients were white, whereas 939 (9.3 %) patients were black. Further, 5,067 (50.3 %) were identified to be married and 4,475 (44.2 %) unmarried. With respect to TMN stage, the majority of patients were classified as N0 , M0 , and T1  according to laboratory examinations and postoperative pathological results. Squamous cell carcinoma was the most prevalent pathology, accounting for 60.6 % (6106) of the tumors. In the SEER stage group, 8,029 (79.7 %) patients were found to have localized disease. There were 6,191 (61.4 %) patients with a tumor size (cm) ≤ 4. The treatment protocol for the patients included chemotherapy  and radiotherapy . Baseline demographic and clinical characteristics of the patients are shown in Univariate and multivariate Cox regression analyses were performed to identify the independent prognostic factors for OS and CSS. For the univariate analysis, these included age, race, marital status, histological type, grade, AJCC stage, T stage, M stage, N stage, SEER stage, tumor size (cm), chemotherapy, and radiotherapy as prognostic factors for OS and CSS. Meanwhile, for multivariate Cox analysis, four variables  were excluded from the independent prognostic factors for OS . The mulThe prognostic nomograms were based on the multivariate Cox regression results. The prognostic nomogram for 3-, 5-, and 10- year OS and CSS Figs.  and 2B cEach subtype of the variables that made up the nomogram corresponds to a point on the “Points” scale. We then calculated the total score of a specific EOCC patient by adding the scores of each subtype corresponding to each variable. Then, a straight line was drawn from the position of these total scores on the “Total points” scale, thus providing each patient with 3-, 5-, and 10-year OS and CSS probabilities.The time-dependent ROC curves for OS and CSS were used to evaluate the prediction performance of the nomogram in different sets. An AUC value of 0.5 indicates that the nomogram has no predictive effect, whereas an AUC value of 1 indicates that the nomogram can completely distinguish patients with different survival rates. The higher the value between 0.5 and 1, the stronger the resolution of the nomogram. The area under the curve (AUC) values of the nomogram for OS  and CSS Next, the C-index was then used to verify the nomogram. Significant differences were noted in OS and CSS among the nomogram, TNM stage, and SEER stage . In the Cervical cancer remains to be the fourth most common malignant tumor among women threatens the lives of most women across the globe . In pracA nomogram is a graphical representation of a multivariable prognostic model that integrates multiple prognostic factors and can be used to accurately evaluate individual probabilities of survival at certain times. This present study focused on prognosis prediction for EOCC patients based on the construction of a nomogram. First, univariate and multivariate Cox regression analysis were performed to assess independent prognostic factors for OS and CSS. The results of the multivariate analysis also indicated that race, histological type, grade, AJCC stage, T stage, SEER stage, tumor size (cm), chemotherapy, and radiotherapy were independent prognostic factors of CSS for EOCC patients. We established prognostic nomograms for 3-, 5-, and 10-year OS and CSS for EOCC patients.The ROC curve, DCA curve, and C-index were used to verify the clinical practicability and predictive performance of the nomogram, which revealed its superiority compared with TNM stage and SEER stage. At the same time, the prediction accuracy for OS and CSS at 3-, 5-, and 10- years was evaluated using a calibration curve, which was in good agreement with the actual observational results. In practice, the area under the curve (AUC) values of the nomogram for OS , S2A andAs a prognostic tool to graphically display clinical results, a nomogram can accurately predict the overall survival (OS) and cancer-specific survival (CSS) rates of patients, which is attributed to the multiple clinical variables included in its calculation. Recently, nomograms consisting of various clinical variables have been used to predict the prognosis of different CC patients -15. WangIn this present study, clinical variables including race, histological type, grade, AJCC stage, T stage, SEER stage, tumor size (cm), chemotherapy, and radiotherapy were independent risk factors affecting the prognosis of EOCC patients. Other studies reported that age and race are risk factors for the prognosis of various cancers ,13,14. GThe grade, tumor size, and histological type of the tumor also significantly influence patient prognosis ,17. In tOur study had some limitations. First, the SEER database did not contain detailed information regarding chemotherapy, such as the use of targeted drugs, which are important in the prognosis of CC. Because of lacking information on living environment, lifestyle, adjuvant therapy, and commodities, it was not possible to consider all prognostic factors comprehensively, which was also an intrinsic limitation of SEER research. Secondly, we did not conduct an external validation to further assess this nomogram.Our study is the first to construct a precise nomogram for predicting the 3-, 5-, and 10-year OS and CSS for EOCC patients, which exhibited a better predictive performance compared with TNM and SEER stages. This model may assist clinicians in designing personalized treatments for EOCC patients.