Polymorphisms in Estrogen Receptor-Α and -Β Genes and Their Correlations with Risk Factors in Iranian Breast Cancer Patients

Receptor-mediated estrogen activation participates in the development and progression of breast cancer. Evidence suggests that alterations in estrogen signaling pathways, including estrogen receptor-α (ER-α) and estrogen receptor-β (ER-β) occur during breast cancer development. Estrogen receptor genes (ERs) polymorphism has been found to be associated with breast cancer and clinical features of the disease in Caucasians. In order to investigate whether polymorphisms in the ER-α and ER-β are associated with breast cancer risk in a case-control study was conducted with 150 Iranian patients newly diagnosed invasive Breast Ductal Carcinoma, and 147 healthy women. PCR single-strand conformation polymorphism method and direct sequencing screened the selected encoding regions exon 4 ER genes for mutation or variant sites were performed. Three silent single nucleotide polymorphisms (SNPs) were found in the ER- α gene (exon 1, exon 4, exon 8 respectively), as reported previously in other studies, but at significantly different frequencies and one SNP was found in ER- β gene (exon 7). The statistical significance was achieved in the most of demographic characteristics. Age at menarche of less than or equal to twelve years old in codon 594 of ER- α gene and among the eight different races the race of Fars in all four polymorphic sites of ER-α and ER-β genes were revealed statistically significant differences between case and control groups (p=< 0.05). Furthermore, blood group B of all four ABO blood groups, was shown statistically significant differences between case and control groups (p=< 0.05) for all four polymorphic sites of codons 10, 325, 594 of ER-α and 392 in ER-β . The frequency of allele 1 in codon 594 exon 8 was significantly higher in breast cancer patients (48.0%) than in control individuals (1.4%; P = 0.001). The codon 392 polymorphisms were presented only in cases group, in genotypes of heterozygote with statistically significant frequency of 8.7% and in the genotypes of homozygote with statistically significant frequency of 1.3%. Furthermore, in 1he exon 4 we found a novel mutation at codon 323 in Iranian women, and the statistical significance was achieved for the presence and absence of LN metastases at this codon (P = 0.017). Combination of the three SNP markers in ER-α may increase the incidence of age at menarche of less than or equal twelve years old, which itself could increase accuracy in predicting developing breast cancer later in their lifetime. Moreover, SNP in codon 392 of ER-β gene is more effective than those SNPs in three polymorphic sites of ER-α gene, in developing familial breast cancer and LN metastases phenotype. This was the first systematic association study in ER-α and ER-β genes polymorphisms and demographic characteristics for breast cancer risk in Iran. In conclusion, our data suggest that ER- α and ER-β genes polymorphisms are correlated with various aspects of breast cancer risk in Iranian women. Moreover, the greater the frequency of allele 1 in codon 10, codon 325 and codon 392 the lesser the likelihood of LN metastasis in the Iranian breast cancer patients. We also noted that greater the frequency of allele 1 in codon 10 in the form of 01, the more likely in patients with familial breast cancer. Our findings suggest that, SNP in codon 392 of estrogen receptor- β gene is much effective than those SNPs in codons 10, 325, 594, of estrogen receptor-α gene, in developing familial breast cancer. Therefore, ER-α and ER-β genotypes, as determined during pre-surgical evaluation, might represent a surrogate marker for predicting breast cancer in Iran

Estrogen receptor-α gene, codon 594 (G3242A) polymorphism among Iranian women with breast cancer: a case control study

A case-control study was conducted to establish a database of ESR1 polymorphisms in Iranian population in order to compare Western and Iranian (Middle East) distributions and to evaluate ESR1 polymorphism as an indicator of clinical outcome. The ESR1 gene was scanned in Iranian patients newly diagnosed invasive breast tumors, (150 patients) and in healthy individuals (147 healthy control individuals). PCR single-strand conformation polymorphism technology and direct sequencing was performed. The silent single nucleotide polymorphism (SNPs) was found, as reported previously in other studies, but at significantly different frequencies. The frequency of genotype 01 in codon 594 (ACG-ACA), (G3242A), exon 8 was significantly higher in breast cancer patients (48.0%) than in control individuals (1.4%; p = 0.001). The allele 1 in codon 594 was significantly more common in breast cancer patients with age at menarche </=12 (40.8%) than in those which their menstruation began at older than 12 years old (23.9%; p = 0.002). The allele 1 in codon 594 exhibited, the greater the frequency, the lesser the likelihood of LN metastasis. Present results demonstrated that this particular SNP marker may increase accuracy in predicting LN. Therefore, this SNP marker further increased predictive accuracy in Iranian population. These data suggest that ESR1 polymorphisms are correlated with various aspects of breast cancer in Iranian ESR1 genotype, as determined during pre-surgical evaluation, might represent a surrogate marker to increase predicting breast cancer in Iranian population

Comparison of methods for determination of glomerular filtration rate: low and high-dose Tc-99m-DTPA renography, predicted creatinine clearance method, and plasma sample method

The gamma camera uptake method with Tc-99m-DTPA (diethylenetriaminepentaacetic acid) is a simple method for determination of glomerular filtration rate (GFR), and is less time-consuming than other methods, but its diagnostic accuracy is debated. Gate’s method (low-dose; LD), the high-dose method (HD), the predicted-clearance method, and the plasmaclearance method with Tc-99m-DTPA are compared in this study. We also performed GFR measurement and diuretic renography simultaneously. Tc-99m DTPA renography was performed in 36 patients aged 18–72 years with a wide range of renal function (serum creatinine 1.37 ± 0.49mg/dl).GFR was determined by four methods: the gamma camera uptake method with low-dose Tc-99m DTPA (Gates, LD); the gamma camera uptake method with high-dose Tc-99m DTPA (HD); the predicted creatinine clearance method (Cockcroft– Gualt, CG); and the plasma sample clearance (PSC) method using a mono-exponential curve. The PSC method was chosen as reference. The regression equations for the CG, Gates (low-dose), and HD methods against the PSC method were 28.68 + 0.80X (r = 0.72; P value\0.0001, RMSE = 21.65 ml/min/ 1.73 m2), 6.19 + 0.79X (r = 0.90; P value\0.0001, RMSE = 10.64 ml/min/1.73 m2), and 6.53 + 0.88X (r = 0.93; P value\0.0001, RMSE = 9.35 ml/min/ 1.73 m2), respectively. In comparison with determination of GFR by the PSC method, the CGmethod tended to overestimate GFR while, perversely, the LD and HD methods tended to underestimate GFR. The three methods were in agreement with the PSC method but the high-dose GFR method resulted in less error in estimation of GFR. Furthermore, GFR measurement and diuretic renography could be performed at the same time when the high-dose method was used. Because of the low cost and negligible radiation burden, this method might be preferred for routine practice in nuclear medicine

Risk factors for breast cancer in Iranian women: a case-control study

The objective of the present study was to investigate risk factors for breast cancer in Iranian women. A case-control study was conducted from April 2004 to May 2007 in Tehran, Iran. Demographical data and risk factor related information were collected using a short structured questionnaire. In all, 150 women with breast cancer and 147 control women were interviewed. In multivariate analysis, only body mass index or BMI age at menarche, age at marriage, race, ABO and Rh blood groups and family history of breast cancer were associated with significantly increased risk for breast cancer (P<0.05). The findings of the present study suggest that family history and marital status may have an impact on the incidence of breast cancer in Iranian women

Estrogen receptor-α gene codon 10 (T392C) polymorphism in Iranian women with breast cancer: a case study

A case study was conducted to establish a database of polymorphisms in Iranian population in order to compare Western and Iranian (Middle East) distributions and to evaluate ESR1 polymorphism as an indicator of clinical outcome. The ESR1 gene was scanned in Iranian patients newly diagnosed invasive breast tumors, (150 patients) and in healthy individuals (147 healthy control individuals). PCR single-strand conformation polymorphism methodology and direct sequencing were performed. The silent single nucleotide polymorphism (SNPs) was performed, as reported previously in other studies, but at significantly different frequencies, with further increasing predictive accuracy in Iranian population. Data suggest that ESR1 polymorphisms are correlated with various aspects of breast cancer in Iranian ESR1 genotype, as determined during pre-surgical evaluation, might represent a surrogate marker for predicting breast cancer

Prevalence of enterotoxin-encoding genes among diverse Shigella strains isolated from patients with diarrhea, southwest Iran

Shigella spp. are a major cause of bacillary dysentery, particularly among children in developing countries such as Iran. This study aimed to investigate the presence of two important Shigella enterotoxins (ShET-1 and ShET-2), encoded by the set and sen genes, respectively, by polymerase chain reaction (PCR) assay among Shigella species isolated from children affected by shigellosis in Ahvaz, southwest of Iran. In this cross-sectional study, from June 2016 to April 2017, altogether 117 Shigella isolates were collected from fecal specimens of children aged <15 years with diarrhea in Ahvaz, southwest Iran. All isolates were identified by standard microbiological and molecular methods. The presence of enterotoxin genes was determined by PCR. The most prevalent isolate was Shigella flexneri (47.9%), followed by Shigella sonnei (41%) and Shigella boydii (11.1%), respectively. Shigella dysenteriae was not detected in patients’ samples. The frequencies of set1A, set1B, and sen genes were 5.1% (6/117), 15.4% (18/117), and 76.9% (90/117), respectively. This study provides initial background on the prevalence and distribution of the Shigella enterotoxin genes in Shigella isolates in southwest of Iran. In addition, this study revealed a high prevalence of sen enterotoxin gene in Shigella species

Estrogen Receptor-Beta Gene Polymorphism in women with Breast Cancer at the Imam Khomeini Hospital Complex, Iran

ER-alpha and ER-beta genes have been proven to play a significant role in breast cancer. Epidemiologic studies have revealed that age-incidence patterns of breast cancer in Middle East differ from those in the Western countries. Two selected coding regions in the ER-β gene (exons 3 and 7) were scanned in Iranian women with breast cancer (150) and in healthy individuals (147). PCR single-strand conformation polymorphism was performed. A site of silent single nucleotide polymorphism was found only on exon 7. The SNP was found only in breast cancer patients (5.7%) (χ2 = 17.122, P = 0.01). Codon 392 (C1176G) of allele 1 was found to have direct association with the occurrence of lymph node metastasis. Our data suggest that ER-β polymorphism in exon 7 codon 392 (C1176G) is correlated with various aspects of breast cancer and lymph node metastasis in our group of patients

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Genetic Polymorphisms in The Estrogen Receptor - α Gene Codon 325(CCC}CCG) and Risk of Breast Cancer Among Iranian Women: A Case Control Study

Background:The Iranian breast cancer patients are relatively younger than their Western counterparts.Evidence suggests that alterations in estrogen signaling pathways,Including estrogen receptor-α ER- α ), occur during breast cancer development in Caucasians.Epidemiologic studies have revealed that age-incidence patterns of breast cancer in Asians differ from those in Caucasians.Genomic data for ER- α in either population is therefore of value in the clinical setting for the Iranian breast cancer.Methods:A case-control study was conducted to establish a database of ERpolymorphisms in Iranian women population in order to compare Western and Asian   with Iranian (Asian-Caucasians) distributions and to evaluate ER- polymorphism as an indicator of clinical outcome.DNA samples were prepared from Iranian women with breast cancer referred to Imam Khomeini Hospital Complex clinical breast cancer group (150 patients)and in healthy individuals (147 healthy control individuals ).PCR single-strand conformation polymorphism technology was performed.Results:Asite of silent single nucleotide polymorphism (SNP) was found,as reported   previously in Western and Eastern studies, but at significantly different frequencies.The frequency of allele 1 in codon 325 (CCC}CCG)was significantly higher in the breast cancer patients (39.6%) than control individuals (28.9%; P = 0.007).The allele 1 had also significant association with the occurrence of lymph node metastasis.Conclusion:Data suggested that ER- α polymorphisms in exon 4 codon 325 was correlated with various aspects of breast cancer in Iran.ER- α genotype,as determined during presurgical evaluation, might represent a surrogate marker for predicting the breast cancer lymph node metastasis