Personalized clinical managements through exploring circulating neural cells and electroencephalography.

BACKGROUND: Since an initial diagnosis of Alzheimer disease (AD) in 1907, early detection, was unavailable through 116 years. Up-regulation of V-Ets erythroblastosis virus E26 oncogene homolog 2 (Ets2) is capable to enhance neuronal susceptibility and degeneration. Protein expression (PE) of Ets2 has functional impact on AD and Down's syndrome, with diverse intensity. PE of Ets2 has an influential pathogenic impact on AD. Clinical aspects of neurological disorders directly interact with psychological maladies. However, deterioration requires an early management including programmed based protection. AIM: To include cell biology in neuro-genetics; personalized, prognostics, predictive, preventive, predisposing (5xP) platform, accompanied by stratifying brain channels behavior pre- and post-intervention by light music in the AD-patients. METHODS: Include exploration of PE assay and electroencephalography of brain channels. The processes are applied according to: (1) Triangle style, by application of cellular network; and (2) PE assay of Ets2 in the peripheral blood of the patients with AD, by Manual single cell based analysis, and Flow-cytometry. (1) Applying the Genetic counselling and pedigree analysis; (2) considering the psychological status of the referral cases; (3) considering the macro-and/or micro-environmental factors; (4) performing the required Genetics' analysis; and (5) applying the required complementary test(s). RESULTS: PE of Ets2 has pathogenic role in AD. PE unmasked the nature of heterogeneity/diversity/course of evolution by exploring Ets2, D1853N polymorphism in Ataxia Telangiectasia mutated gene (ATM), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and course of evolution at the single cell level of the brain. Ets2 revealed different cellular behavior in the blood and suggested the strategy as 'Gene Product-Based Therapy' and the personalized managements for the patients. PE reflected weak expression of ATM, mosaic pattern of Ets2; remarkable expression of VEGF and EGF by highlighting an early detective platform, considering circulating neural cells (CNCs) and the required molecular investigation, for the target individual(s) predisposed to AD or other neural disease including brain neoplasia. Brain channels-cooperation with diverse/interactive-ratios lead to strategic balancing for improving the life-quality in AD. CONCLUSION: We highlighted application of the single CNCs and correlated Ratio based between Brain channels by providing the 5xP personalized clinical management model for an early detection and therapy of the patients with AD and their targeted/predisposed relatives. Novel-evolutionary/hypothetic/heterogenic-results in brain-channels offer personalizd/constructive markers with unlimited cooperation in health and disease.

Evolutionary model of brain tumor circulating cells: Cellular galaxy.

BACKGROUND: Although circulating tumor cells (CTCs) have been the focus of consideration for a decade, a categorized cell-based diagnostic strategy is unavailable. The personalized management and complementary/analytical-strategy of data require an alphabetic guide. Therefore, we aimed to determine the behavior of CTCs in tumor and blood in order to provide the hypothetical-based agenda in the brain neoplasms. Exploring the protein expression (PE) using a single cell-based method would clarify the heterogeneity and diversity in tumor and blood, which are key events in the evolution in brain tumors. In fact, heterogeneity, diversity, and evolution are required for cancer initiation and progression. AIM: To explore CTCs in brain tumors and blood cells and to assay intensity of PE through personalized insight. METHODS: The focal population included 14 patients with meningioma, and four patients with metastatic brain tumors (T). PE was assayed by immunofluorescence in tumors cells and CTCs in 18 patients with brain tumors. Ratio test was applied between the T cells and CTCs in tumor tissue and in vascular system. T/CTC ratio-based classification of PE in macrophage chemoattractant chemokine ligand 2 (CCL2), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), CD133, cyclin E, neurofilament marker, cytokeratin 19, and leukocyte common antigen (CD45) were investigated. RESULTS: Total analyzed cells ranged between 10794-92283 for tumor cells and between 117-2870 for CTCs. Characteristics of histopathologic and status of an ataxia-telangiectasia mutated polymorphism (D1853N) in 18 patients affected with brain tumors were also provided. The course of evolution and metastatic event relied on the elevated protein expression in CTCs, which could be considered as a prognostic value. Diverse protein expression of the migrated cells into the blood stream and the tumor was indicative of the occurrence of evolution. Besides, the harmonic co-expression between CCL2/EGF and CCL2/VEGF could facilitate the tumor progression including the metastatic event. Expression of these proteins in the migrated vasculature and into the buccal tissue offered a non-invasive follow-up detection in neoplastic disorders. PE-exploration of neurofilament marker/CD133/VEGF of the CTCs in meningioma and cytokeratin 19/CD45/ cyclin E in the patients with metastatic brain tumor would clarify the tumor biology of the brain neoplastic disorders. CONCLUSION: The alphabetical base of the evolutionary mechanisms relies on dual-, triple-, and multi-models with diverse intensity of expression. In fact, cross-talk between initiative and the complementary channels defines the evolutionary insight in cancer. A diverse-model of protein expression, including low, medium, and high intensity, is the key requirement for the completed model. The cluster of cells with diverse expression and remarkable co-expression between CCL2/EGF/VEGF and NM/CD133/VEGF in CTCs may be indicative of probable invasiveness of the tumor. Furthermore, the mode of cytokeratin-19+/CD45- can be traced in the metastatic patients.

Diversity in tumor territory of meningioma: Protein expression in vascular endothelial growth factor and epidermal growth factor.

Background: Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are involved in tumor development and progression. But, the classified-based data of protein expression (PE) in meningiomas is unavailable. Therefore, we aimed to explore the PE of VEGF and EGF in meningiomas by considering evolutionary strategy and the regional tumor-based assay. Methods: PE was assayed using immunofluorescence (IF) within the peripheral, central, and basal sections of four meningioma tumors, and a lung metastatic brain tumor as a positive control. Results: Diverse characteristics and harmonic cross-talk in the individual sections and between different tumor sections were traced. The mode of PE was puzzling and personalized issue. Co-expression had a key impact on tumor evolution and diverse PE profiles led to draw the heterogenic classification, as the personalized/complementary insight in the functional behavior of VEGF and EGF. D1853N polymorphism of ATM gene was mosaics in two patients with meningiomas. Conclusion: The classified heterogeneity, harmonic co-expression, and diverse functional information in different regions of tumors may lead to predict the aggressiveness mode of tumors as a translational insight to the clinical managements including therapy in brain tumors.

Serum Level of Total Lipids and Telomere Length in the Male Population: A Cross-Sectional Study.

Telomeres contain TTAGGG (T; Thymine, A; Adenine and G; Guanine) repetitive sequences and are placed at the end of human chromosomes. Telomere dysfunction is implicated in some age-related and chronic diseases, but its association with total serum lipids and obesity is unknown. Our objective was to determine influenced of total serum lipids on leukocyte telomere lengths (TLs). Participants were selected by cluster sampling from 22 districts of Tehran. The questionnaires were completed by 500 subjects and after the initial assessment in terms of lifestyle, nutrition, home, and job, 300 healthy people, aged 25-40 years were finally selected. TLs and serum level of total lipids were measured by quantitative real-time PCR and the Phillips method, respectively. The average telomere length (T/S) and total lipids were 1.05 ± 0.3 mg/dl and 643.3 ± 70.8 mg/dl, respectively. We found that a one unit difference in the following parameters were associated with kilo base pair differences in TL: Age -0.0002 (95% CI [-0.0022, -0.0018]), BMI -0.0019 (95% CI [-0.0003, -0.0034]), TC 0.0001 (95% CI [-0.0006, -0.0007]), TG -0.0010 (95% CI [-0.0015, -0.0004]), PL 0.0001 (95% CI [-0.0005, -0.0007]), and TSL -0.0003 (95% CI [-0.0008, 0.0001]). Spearman correlation analysis revealed an inverse relationship between TC (R = -0.53; 95% CI [-0.61, -0.44]), TG (R = -0.50; 95% CI [-0.58, -0.41]), PL (R = -0.46; 95% CI [-0.54-0.36]), and TSL (R = -0.63; 95% CI [-0.69, -0.56]) with T/S. Our research suggests that the inverse relationship was found between TL and weight, BMI, age, and TSL which were associated with obesity. High serum lipids concentration may be associated with systemic inflammation and atherosclerosis and may lead to oxidative stress, resulting in telomere shortening.

Environmental and behavioral determinants affecting the association of airway macrophages carbon load with distance to major roads and traffic density.

Biomarkers are promising indicators to evaluate human exposure to air pollutants and to predict the health outcomes. Area of Airway macrophages that is occupied by Black Carbon could be used as a biomarker of personal long term exposure to traffic related air pollution. Association of airway macrophages carbon load with weighted average distance and environmental and subject-specific behavior are considered in this study. Sputum samples were taken from 160 healthy adult women and airway macrophages carbon load (AMCL) were determined in 93 subjects, which represent a success rate of 62% in sputum induction. Nearest distance of the subjects to major roads and average weighted distance were calculated for each subject. A questionnaire was field according to general and behavioral characteristics of the participants. There was not any significant difference (P-value >0.05) between induced and non-induced subjects. Subjects with indoor kitchen without separation wall, passive smokers and those with longer presence time in high traffic streets showed higher carbon area. Weighted average distance had a better association (ß = -0.186, 95%CI: -0.139, -0.230, P-value = 0.00) with AMCL than nearest distance to major roads (ß = -0.155, 95%CI: -0.109, -0.201, P-value = 0.19). Association of Weighted average distance with AMCL was interrupted in subjects with a garage connected to house environment, those with IK kitchen, those with a hood above the stove and passive smokers. The findings indicated that more generation and distribution of indoor air pollutants can completely enhance the internal exposure and indoor pollution has the same importance as outdoor pollution.

ATM in breast and brain tumors: a comprehensive review.

The ATM gene is mutated in the syndrome, ataxia-telangiectasia (AT), which is characterized by predisposition to cancer. Patients with AT have an elevated risk of breast and brain tumors Carrying mutations in ATM, patients with AT have an elevated risk of breast and brain tumors. An increased frequency of ATM mutations has also been reported in patients with breast and brain tumors; however, the magnitude of this risk remains uncertain. With the exception of a few common mutations, the spectrum of ATM alterations is heterogeneous in diverse populations, and appears to be remarkably dependent on the ethnicity of patients. This review aims to provide an easily accessible summary of common variants in different populations which could be useful in ATM screening programs. In addition, we have summarized previous research on ATM, including its molecular functions. We attempt to demonstrate the significance of ATM in exploration of breast and brain tumors and its potential as a therapeutic target.

Detection of CCND1 , C-MYC , and FGFR1 amplification using modified SYBR Green qPCR and FISH in breast cancer

Background/aim: The aims of this study were to detect CCND1 , C-MYC , and FGFR1 amplification using qPCR, confirmation with FISH, and to further assess their clinicopathological relevance. Materials and methods: Thirty-five breast tumor samples were analyzed for amplification of the selected genes using modified SYBR Green qPCR. The accuracy of the qPCR was assessed by FISH as a gold-standard method. Results: CCND1 , C-MYC , and FGFR1 amplifications were observed in 34.28%, 28.57%, and 17.14% of the 35 samples, respectively. qPCR results were significantly confirmed by FISH and qPCR and FISH showed excellent correlation (P = 0.000). CCND1 amplification with tumor stage (P = 0.044), positive metastatic status (P = 0.042), positive family history (P = 0.042), and C-MYC status (P = 0.005); C-MYC amplification with tumor size (P = 0.021), tumor grade (P = 0.018), tumor stage (P = 0.032), and FGFR1 status (P < 0.000); and FGFR1 amplification with tumor size (P = 0.041) and positive ER status (P = 0.042) were statistically associated. Conclusion: Our findings revealed that the applied qPCR approach could precisely quantify the relative gene copy number. More studies with a larger sample size are suggested to confirm the clinicopathological value of CCND1 , C-MYC , and FGFR1 amplification.

Five- hit hypothesis in ATM gene: An individualized model in a breast cancer patient.

The aim of this study was to trace D1853N in a proband affected with primary BC to explore the molecular, cellular and structural aspects of ATM. Exon 37 and splicing regions were PCR-sequenced. Allelic location of the alterations was determined by molecular cloning. Possible impact of alterations was investigated through the bioinformatics and protein expression assays. Five genetic variants including IVS 36-91 AA>TT, IVS 36-8 T>C, D1853N, IVS 37+47 A>G, IVS 37+60 Del T were found in the target regions of ATM and all the alterations were occurred heterezygously. IVS 36-8 T>C and D1853N were observed in blood and tumor tissue, whilst splicing variants were only occurred in tumor tissue. Missense D1853N alteration seems to be effective on 2D and 3D structure of ATM protein and the probability of splicing found to be decreased by intronic variants. Protein expression of ATM also confirmed the occurrence and functional impact of alterations. Results reflect a five-hit hypothesis in a proband with BC that influence ATM, as a guard of genomic stability, at molecular, cellular, and structural levels.

Exploration of Involved Key Genes and Signaling Diversity in Brain Tumors.

Brain tumors are becoming a major cause of death. The classification of brain tumors has gone through restructuring with regard to some criteria such as the presence or absence of a specific genetic alteration in the 2016 central nervous system World Health Organization update. Two categories of genes with a leading role in tumorigenesis and cancer induction include tumor suppressor genes and oncogenes; tumor suppressor genes are inactivated through a variety of mechanisms that result in their loss of function. As for the oncogenes, overexpression and amplification are the most common mechanisms of alteration. Important cell cycle genes such as p53, ATM, cyclin D2, and Rb have shown altered expression patterns in different brain tumors such as meningioma and astrocytoma. Some genes in signaling pathways have a role in brain tumorigenesis. These pathways include hedgehog, EGFR, Notch, hippo, MAPK, PI3K/Akt, and WNT signaling. It has been shown that telomere length in some brain tumor samples is shortened compared to that in normal cells. As the shortening of telomere length triggers chromosome instability early in brain tumors, it could lead to initiation of cancer. On the other hand, telomerase activity was positive in some brain tumors. It is suggestive that telomere length and telomerase activity are important diagnostic markers in brain tumors. This review focuses on brain tumors with regard to the status of oncogenes, tumor suppressors, cell cycle genes, and genes in signaling pathways as well as the role of telomere length and telomerase in brain tumors.

Foods, Dietary Patterns and Occupational Class and Leukocyte Telomere Length in the Male Population.

Telomeres contain TTAGGG repetitive sequences and are located at the end of human chromosomes. Telomere dysfunction is associated with some age-related and chronic diseases, but its relationship with foods, dietary patterns, and occupational class in the young male population is not yet known. In this cross-sectional study, 300 healthy men, residents of Tehran, aged 25-40 years were enrolled from January to December 2016. We employed a cross-sectional study of 300 healthy people, residents of Tehran, aged 25-40 years. A food frequency questionnaire was used to obtain food intakes of all participants and converted into actual food intake (g/day). The principal components analysis was used to determine dietary patterns and other demographic characteristics. Leukocyte telomere length (TL) was measured by quantitative real-time polymerase chain reaction (PCR) to measure number of telomere repeat copy number (T) to the relative number of 36B4 copies (S) (T/S ratio). T/S in office-workers, waste recyclers, and other workers were 1.22 ± 0.4, 1.08 ± 0.3, and 1.094 ± 0.34, respectively. The results of multivariate linear regression adjusted for age, body mass index (BMI), and smoking were showed that whole grains (ß = 0.02; p = .05), refined grains, fruits and vegetables, fish and dairy products were associated with an increase in log-T/S, but consumption of nuts and seeds (ß = -0.00072; p = .06), meats (ß = -0.00043; p = .9), produced meats (ß = -0.00238; p = .03), oils and solid fats (ß = -0.00146; p = .03) had a negative relationship with log-T/S in all studied occupational classes. A positive relationship was reported between the healthy (ß = 0.017; p = .2) and traditional dietary pattern (ß = 0.012; p = .4) with log-T/S, but western pattern identified negative relationship (ß = -0.004; p = .7). Adherence to a healthy (with consumption whole grains, refined grains, dairy, and cereals) and then traditional pattern with increased consumption of fruits, vegetables and whole grains, fish and dairy products are necessary to prevent TL destruction in all studied occupational classes.

Hypermethylation pattern of ESR and PgR genes and lacking estrogen and progesterone receptors in human breast cancer tumors: ER/PR subtypes.

BACKGROUND: The option of endocrine therapy in breast cancer remains conventionally promising. OBJECTIVE: We aimed to investigate how accurately the pattern of hypermethylation at estrogen receptor (ESR) and progesterone receptor (PgR) genes may associate with relative expression and protein status of ER, PR and the combinative phenotype of ER/PR. METHODS: In this consecutive case-series, we enrolled 139 primary diagnosed breast cancer. Methylation specific PCR was used to assess the methylation status (individual test). Tumor mRNA expression levels were evaluated using real-time RT-PCR. Immunohistochemistry data was used to present hormonal receptor status of a tumor (as test reference). RESULTS: Methylation at ESR1 was comparably frequent in ER-breast tumors (83.0%, P< 0.001; sensitivity = 83.0%, specificity = 65.2% and diagnostic odds ratio, DOR = 12.0) and strongly correlated with ER-/PR- conditions (Cramer's V= 0.44, P< 0.001). Methylated PgRb promoter frequently was observed in tumors recognised as ER- or negative ER/PR (77.1%, P< 0.01). Assessment of DNA methylation of ESR1 harbouring methylation at PgRb was a case significantly suggested to be able to detect the lack of ER/PR expressions (55.6%, P< 0.01; sensitivity = 80.6%, specificity = 68.7% and DOR = 8.7). However, methylated PgRb was quite acceptable determinant to contribute with methylated ESR1 to rank tumors as ER-/PR- (64.4%, P< 0.01; sensitivity = 78.0%, specificity = 62.5% and DOR = 6.0). CONCLUSIONS: Despite the methylation status of ESR1 showed preponderant contribution to tumoral phenotypes of ER- and ER-/PR-, the hypermethylation of PgRb seem another epigenetic signalling variable actively associate with methylated ESR1 to show lack of ER+/PR+ tumors in breast cancer.

Prognostic significance of MYCN gene amplification and protein expression in primary brain tumors: Astrocytoma and meningioma.

BACKGROUND: Astrocytoma and meningioma are the most common primary brain tumors. MYCN as a member of MYC proto-oncogenes has recently appeared as an attractive therapeutic target. Functions of MYCN are critical for growth of nervous system and neural differentiation. OBJECTIVE: We examined MYCN amplification and protein expression in astrocytoma and meningioma cases. METHODS: In this study, we used real-time PCR, FISH assay and flowcytometry to analyze DNA amplification and protein expression of MYCN. RESULTS: Among 30 samples of brain tumor, 14 cases (46.6%) revealed MYCN amplification. High-protein expression of MYCN was also observed in 43.3% of patients. There was a significant correlation between MYCN gene amplification and protein expression (r= 0.523; p= 0.003), interestingly five case showed discrepancy between the gene amplification and protein expression. Although MYCN amplification fails to show correlation with poor prognosis (p= 0.305), protein high-expression of MYCN significantly reduce disease-free survival (p= 0.019). CONCLUSIONS: Our results challenge the concept of the neural specificity of MYCN by demonstrating contribution of MYCN in meningioma. Moreover, this study highlights the importance of research at both level of DNA and protein, to determine the biological functions and medical impacts of MYCN.

Is Leukocyte Telomere Length Related with Lung Cancer Risk?: A Meta-Analysis.

BACKGROUND: Epidemiological studies have probed the correlation between telomere length and the risk of lung cancer, but their findings are inconsistent in this regard. The present meta-analysis study has been carried out to demonstrate the association between relative telomere length in peripheral blood leukocytes and the risk of lung cancer using an established Q-PCR technique. METHODS: A systematic search was carried out using PubMed, EMBASE, and ISI before 2015. A total of 2925 cases of lung cancer and 2931 controls from 9 studies were employed to probe the relationship between lung cancer and telomere length .ORs were used at 95% CI. Random-effects models were used to investigate this relationship based on the heterogeneity test. Heterogeneity among studies was analyzed employing subgroup analysis based on type studies and the year of publication. RESULTS: Random-effects meta-analysis revealed that patients with lung cancer were expected to have shorter telomere length than the control (1.13, 95% CI: 0.82-1.81, P=0.46). The summary of the pooled ORs of telomere length in adenocarcinoma lung cancer patients was 1 (95%CI=0.68-1.47, I2=93%) compared to patients with squamous cell lung cancer, which was 1.78 (95% CI=1.25-2.53, I2=3.9%). The meta-regression revealed that the effect of telomere length shortening, decreased and increased with the year of publication and the age of risks to lung cancer, was clearly related to short telomeres lengths. CONCLUSION: Lung cancer risks clearly related with short telomeres lengths. In patients with breathing problems, lung cancer risk can be predicted by telomere length adjustment with age, sex, and smoking.

Association of folate and other one-carbon related nutrients with hypermethylation status and expression of RARB, BRCA1, and RASSF1A genes in breast cancer patients.

UNLABELLED: Dietary methyl group donors could influence the hypermethylation status of certain putative genes. The present study explored the possible associations of dietary intake of one-carbon metabolism-related nutrients with promoter hypermethylation status and expression of retinoic acid receptor-beta (RARB), breast cancer-1 (BRCA1), and Ras association domain family-1, isoform A (RASSF1A) genes in Iranian women with breast cancer (BC). The hypermethylation status was investigated in 146 dissected BC tissue samples using methylation-specific PCR. The expression level was evaluated by real-time RT-PCR. Dietary nutrients were estimated using a validated 136-item food frequency questionnaire. Expression levels of the genes were associated with the unmethylated status of related promoters (p < 0.05). The crude dietary folate and adjusted cobalamin intakes were inversely associated with methylated RARB and BRCA1. Low intake of residual folate and cobalamin was correlated with the methylated status of RARB for subjects at <48 years of age, and folate alone was linked to BRCA1 at >48 years of age. High dietary intake of riboflavin and pyridoxine was the only determinant of the methylated promoter of RARB at odds ratios (ORs) of 4.15 (95 % confidence interval (CI) 1.28-13.50) and 2.53 (95 % CI 1.14-3.83) in multivariate models, respectively. One-carbon nutrients most often correlated inversely with the methylation-influenced expression of RARB. Although high folate intake increased the chance of unmethylation-dependent overexpression of BRCA1 3-fold, cobalamin and methionine were inversely linked to methylation-mediated expression. Nutritional epigenomics less actively influenced RASSF1A. These findings provide new insights into and a basic understanding of the selective contributions of individual B vitamins on hypermethylation and methylation-related expression of RARB and BRCA1 in BC. KEY MESSAGE: Hypermethylation at promoters of RARB, BRCA1, and RASSF1A is associated with reduced transcript levels of the respective gene in primary breast cancer tissue samples. Dietary folate and cobalamin intake is inversely associated with methylated RARB and BRCA1. High dietary intake of riboflavin and pyridoxine is associated with increased methylation in the RARB promoter. There is evidence for the age-dependent effects of nutrient intake on promoter methylation status. Bioavailability to the pool of nutrients might determine selectivity.

Personalized evolutionary hypothesis in genomics and auxiliary lymph node through diverse subtelomeric signal profile.

Few available data on the genomic-somatic evolution in breast cancer create limitation to provide the appropriate clinical managements. As an example, human subtelomeres (ST) are diverse-prone and variable targets. STs, as hot spots, have positive and negative impacts on the status of health and malady. We showed higher subtelomere signal copy number (SCN) of specific chromosomes in genomics than in auxiliary lymph node (ALN). Dissimilarity of signal intensity (SI) is found for all chromosomes. Significantly higher SI in genomics than in ALN cells were specified as chromosomes 5, 6, 9-12, 16-19 for weak; 1, 5-9, 19, X for medium; and 2, 5, 9, 10, 16, 18 for strong SI. For lacking, and presence of one and two SCNs; p/q ratio reflected differences for all chromosomes; but, 2, 3, 5, 7, 8, 10, 16, 18, 20, and X chromosomes were involved for three SCN. Chromosomes 1, 4, 9, 12, 17-19 lacked three SCN in ALN and lymphocytes. Weak SI ratio was higher in p- than in q-arm in majority of chromosomes. Manner of evolution and diversity in p- and q-arms is expressive of a novel definition as two diverse domains with a personalized insight. These data have been accompanied by periodic charts as ST array profiles which provide specific and individualized pattern in breast neoplasm. Such profiling at genomics level could be considered as a prediction through the patients' life. Moreover, subtelomere territory by interacting with protein expression of Ki67, cyclin D1, and cyclin E; and molecular targets including telomere length at genomics and somatic level provides package of information to bridge cancer cell biology to the cancer clinic as "puzzling paradigm."

A meta-analysis on concordance between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) to detect HER2 gene overexpression in breast cancer.

BACKGROUND: We performed this meta-analysis study to evaluate the concordance and discordance between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in detecting HER2 alteration in human breast cancer. METHODS: As a meta-analysis, the present study evaluated the available data from previous studies on the HER2 gene detected by IHC and FISH. To indicate the meta-analysis results, a forest plot was used. RESULTS: We identified 172 citations, for which our inclusion criteria were met by 18 articles, representing 6629 cases. The overall concordance and discordance rate between IHC staining with score 0/1+ and FISH for detection failure of HER2 expression was 96 and 4 %, respectively. The present study showed that the overall proportion of FISH positive and negative rate for IHC score 2+ for detection of HER2 expression was 36 and 64 %, respectively; and 91 and 9 % for 3+ IHC scores. CONCLUSION: The results of this study show that IHC score 0/1+ and 3+ cannot be completely considered as negative and positive breast cancer test, respectively. Therefore, we suggest a valid and complementary test, the same as FISH, to explore HER2 expression.

Plasma total homocysteine level in association with folate, pyridoxine, and cobalamin status among Iranian primary breast cancer patients.

Recently the elevated plasma total homocysteine (tHcy) concentration has been concerned as the secondary feature of tumoral proliferation and enhances the likelihood of thrombogenesis in cancer patients. The objective of this study was to determine the associations between folate, cobalamin, and pyridoxine with fasting plasma tHcy concentration in breast cancer (BC) patients. The intake levels of nutrients were assessed using a validated food frequency questionnaire in 141 newly diagnosed BC patients. The plasma tHcy and pyridoxal-5-phosphate were measured using high performance liquid chromatography with fluorescence detector. Plasma tHcy levels were observed to be significantly higher among BC participants with Stage III where the plasma concentrations of folate was also comparatively less (P < 0.05) than other stages. Dietary pyridoxine was even being consumed less at this stage (P < 0.05). The plasma, dietary, and residual variables of folate were inversely correlated with plasma tHcy concentration (P < 0.05). Dietary cobalamin was also associated negatively with tHcy (P < 0.05). The odds ratio of comparing the highest tertile of plasma cobalamin (>394 pmol/l) and folate (>11.4 ng/ml) vs. the lowest categories were associated with reduced odds of high tHcy occurrence with 0.20 (95% confidence interval: 0.04-0.98) and 0.14 (95% confidence interval: 0.03-0.64), respectively. In conclusion, nutrition-related methyl-group insufficiency could lead to imbalance in tHcy metabolism, as a possible cancer marker.

Effects of Eicosapentaenoic Acid Supplementation on Lipid and Lipoprotein Profile in Hypertriglyceridemic Subjects with Different Proliferator-activated Receptor Alpha Genotypes.

BACKGROUND: We determined the blood lipid-lowering effects of eicosapentaenoic acid (EPA) on hypertriglyceridemic subjects with Leu162/Val in exon 5 and G/C in intron7 polymorphism of peroxisome proliferator-activated receptor alpha (PPARα)genotypes that, to our knowledge, have not been previously studied. METHODS: A total of 170 hypertriglyceridemic subjects were enrolled and genotyped for Ala54Thr, Leu162Val, and intron7 polymorphism by the use of a polymerase chain reaction-restriction fragment length polymorphism method. After determination of their genotypes, the first 23 eligible subjects who were found as Ala54 carriers and the first 23 eligible Thr54 carriers were enrolled in the study and stratified for PPARα genotypes. Participants took 2 g of pure EPA daily for 8 weeks. Fasting blood lipid and lipoprotein profiles were determined and changes from baseline were measured. RESULTS: We observed significant difference between EPA supplementation and Leu162 and Val162, Interon 7 (GG and GC) carriers (P < 0.001). We did not observe significant associations between the PPARα L162V single nucleotide polymorphism and multiple lipid and lipoprotein measures. Although EPA consumption lowered lipid and lipoprotein concentrations in Leu162 and Val162 carriers and Interon 7 CC and GC carriers, these differences between the studied groups were not statistically significant. CONCLUSIONS: EPA consumption has a lipid-lowering effect in hypertriglyceridemic subjects in both Leu162 and Val162 carriers. But there was no significant interaction between EPA supplementation and PPARα genotypes. Thus, genetic variation within the PPARα Leu162/Val cannot modulate the association of EPA intakes with lipid and lipoprotein profile. However, we must note that the sample size in this study was small.

Genetics of breast cancer bone metastasis: a sequential multistep pattern.

Bone metastasis accounts for the vast majority of breast cancer (BC) metastases, and is related to a high rate of morbidity and mortality. A number of seminal studies have uncovered gene expression signatures involved in BC development and bone metastasis; each of them points at a distinct step of the 'invasion-metastasis cascade'. In this review, we provide most recently discovered functions of sets of genes that are selected from widely accepted gene signatures that are implicate in BC progression and bone metastasis. We propose a possible sequential pattern of gene expression that may lead a benign primary breast tumor to get aggressiveness and progress toward bone metastasis. A panel of genes which primarily deal with features like DNA replication, survival, proliferation, then, angiogenesis, migration, and invasion has been identified. TGF-ß, FGF, NFκB, WNT, PI3K, and JAK-STAT signaling pathways, as the key pathways involved in breast cancer development and metastasis, are evidently regulated by several genes in all three signatures. Epithelial to mesenchymal transition that is also an important mechanism in cancer stem cell generation and metastasis is evidently regulated by these genes. This review provides a comprehensive insight regarding breast cancer bone metastasis that may lead to a better understanding of the disease and take step toward better treatments.