Search

Breast cancer (BC) patients are frequently at risk of developing other malignancies following treatment. Although studies have been conducted to elucidate the etiology of multiple primary malignancies (MPM) after a BC diagnosis, few studies have investigated other previously diagnosed primary malignancies (OPPM) before BC. Here, genome‐wide profiling was used to identify potential driver DNA copy number alterations and somatic mutations that promote the development of MPMs. To compare the genomic profiles for two primary tumors (BC and OPPM) from the same patient, tumor pairs from 26 young women (≤50 years) diagnosed with one or more primary malignancies before breast cancer were analyzed. Malignant melanoma was the most frequent OPPM, followed by gynecologic‐ and hematologic malignancies. However, significantly more genetic alterations were detected in BC compared to the OPPM. BC also showed more genetic similarity as a group than the tumor pairs. Clonality testing showed that genetic alterations on chromosomes 1, 3, 16, and 19 were concordant in both tumors in 13 patients. TP53 mutations were also found to be prevalent in BC, MM, and HM. Although all samples were classified as genetically unstable, chromothripsis‐like patterns were primarily observed in BC. Taken together, few recurrent genetic alterations were identified in both tumor pairs that can explain the development of MPMs in the same patient. However, larger studies are warranted to further investigate key driver mutations associated with MPMs., Genomic profiles for the tumor pairs for breast cancer patients with multiple primary malignancies.

We present a young male patient with breast cancer having several risk factors likely acting in consort: irradiation of the breast for gynecomastia in adolescence and a life-long administration of phenothiazine for schizophrenia from the age of 16 years, with elevated serum prolactin level resulting in breast cancer development 24 years after irradiation.

Purpose Multiple primary malignancies (MPMs) caused by breast cancer treatment are well described, but only few studies to date describe which other previous primary malignancies (OPPMs) occur before breast cancer. The purpose of the present study was to evaluate the prevalence of OPPMs in patients with breast cancer between 2007 and 2018 in Western Sweden. Methods Patient selection was performed using both pathology reports at Sahlgrenska University Hospital (Sweden) and the Swedish Cancer Registry. All newly diagnosed breast cancer patients were screened for presence of OPPM. Results In total, 8031 breast cancer patients were diagnosed at Sahlgrenska University Hospital between 2007 and 2018. The prevalence of breast cancer patients with OPPMs (n = 414) increased from on average 2.6% to 8.2% during this 12-year period and ranged from 17 to 59 patients annually. The most striking increase in prevalence was found among the gynecological tumors (endometrium and ovarian adenocarcinomas), malignant melanomas and gastrointestinal malignancies. These findings were validated using data of the Swedish Cancer Registry. Conclusions The overall survival rates for cancer patients have improved tremendously during the past 40 years, in part due to individually tailored therapies and screening programs. Our study revealed an increasing trend of OPPMs in breast cancer patients.

Summary Background & aims This study aimed to evaluate the domain-specific physical activity (PA) levels and sitting time of a sample of university students and examine the association of PA with percent body fat. Methods Two hundred and twenty-one students were included in the analysis. We administered the long form of the International Physical Activity Questionnaire (IPAQ) twice within one-month interval. Total PA as well as occupational, transportation-, housework-, and leisure-related PA were assessed, in addition to sitting time. Dietary intake was derived from six non-consecutive 24-hour dietary recalls. Percent body fat (dependent variable) was analyzed using a bioelectrical impedance analyzer (BIA). Multivariate logistic regression, adjusted for potential confounders, examined the associations of domain-specific PA and sitting time with percent body fat. Results Men had higher levels of total and leisure PA than women. All participants had prolonged sitting time, with 48% having a sitting time of more than 10.15 hours/day. In multivariate analysis, moderate leisure PA, compared to vigorous PA was associated with a lower percent body fat. This association remained statistically significant even after adjustment for energy intake and sitting time. Housework-related PA was associated with a higher percent body fat. Conclusion Moderate leisure PA was highly associated with percent body fat even after adjustment for confounding variables. Adequate interventions targeting this kind of leisure should be promoted among universities students.

Cancer drug development has been riddled with high attrition rates, in part, due to poor reproducibility of preclinical models for drug discovery. Poor experimental design and lack of scientific transparency may cause experimental biases that in turn affect data quality, robustness and reproducibility. Here, we pinpoint sources of experimental variability in conventional 2D cell-based cancer drug screens to determine the effect of confounders on cell viability for MCF7 and HCC38 breast cancer cell lines treated with platinum agents (cisplatin and carboplatin) and a proteasome inhibitor (bortezomib). Variance component analysis demonstrated that variations in cell viability were primarily associated with the choice of pharmaceutical drug and cell line, and less likely to be due to the type of growth medium or assay incubation time. Furthermore, careful consideration should be given to different methods of storing diluted pharmaceutical drugs and use of DMSO controls due to the potential risk of evaporation and the subsequent effect on dose-response curves. Optimization of experimental parameters not only improved data quality substantially but also resulted in reproducible results for bortezomib- and cisplatin-treated HCC38, MCF7, MCF-10A, and MDA-MB-436 cells. Taken together, these findings indicate that replicability (the same analyst re-performs the same experiment multiple times) and reproducibility (different analysts perform the same experiment using different experimental conditions) for cell-based drug screens can be improved by identifying potential confounders and subsequent optimization of experimental parameters for each cell line.

Simple Summary Survivin, coded by the BIRC5 gene, is the cell death preventing protein, which is important for cell division in normal and cancer cells. It is intensively studied as a cancer biomarker and target for antitumor therapy. In this study we asked if we could get clinically helpful information on how active BIRC5 is in breast cancer patients? We studied the BIRC5 protein level in tumor samples for breast cancer patients from a West Swedish cohort and its mRNA level in two different public gene expression databases. Survival analysis demonstrated that a higher BIRC5 protein or mRNA level was associated with poor survival in all cohorts and for different cancer subtypes. We show that BIRC5 is a promising independent cancer survival marker. Abstract Breast cancer (BC) histological and molecular classifications significantly improved the treatment strategy and prognosis. Inhibitor of apoptosis BIRC5/survivin is often overexpressed in cancers, however, indications of its importance in BC are inconsistent. We integrate BIRC5 protein and mRNA measures with clinical associates and long-term outcome in three independent cohorts Protein levels of BIRC5 were measured in primary lysates of 845 patients of the West Swedish BC cohort (VGR-BC) and linked to 5- and 27-years survival. The results were externally validated in transcriptomic data from METABRIC and SCAN-B cohorts. Survival analysis showed that high levels of BIRC5 were consistently associated with a poor probability of 5-year overall survival. High BIRC5 in VGR-BC contributed negatively to the disease-specific survival at 5 and 27 years. Subsets with different status by ER (estrogen receptor) expression and presence of nodal metastasis supported independent association of high BIRC5 with poor prognosis in all cohorts. In METABRIC and SCAN-B cohorts, high levels of BIRC5 mRNA were associated with the basal-like and luminal B molecular BC subtypes and with increasing histologic grade. BIRC5 is a sensitive survival marker that acts independent of ER and nodal status, and its levels need to be considered when making treatment decisions.

Background: The ubiquitin-proteasome pathway plays a crucial role in cancer-related processes by inducing cell cycle arrest through the degradation of mitotic cyclins and other cell cycle regulatory proteins. We recently showed that elevated levels of ubiquitin-conjugating enzyme E2C (UBE2C) were associated with aggressive tumor features and unfavorable clinical outcome in breast carcinoma (BC). UBE2C suppression has been achieved using the FDA-approved proteasome inhibitor bortezomib (VELCADE®) in colorectal carcinoma, but little is known about the efficacy of UBE2C-targeted therapy with proteasome inhibitors in breast cancer. Methods: Cell viability assays were used to determine the intrinsic chemosensitivity of five BC cell lines (MCF-7, MDA-MB-436, HCC38, HCC1395, and ZR-75-30; stratified by UBE2C expression and ER status) and the MCF-10A epithelial cell line to proteasome inhibitors (n=8), mitosis inhibitors (n=2), and platinum agents (n=3). UBE2C expression analysis was performed using quantitative real-time PCR and Western blot. IC50 values and growth inhibition metrics (GR50 and GRmax) were calculated for each compound to determine drug potency and efficiency after 24 hour treatment. Proteasome activity was assessed using bortezomib-treated cells. Results: Heterogeneous UBE2C expression levels were found in the different cell lines, with higher UBE2C levels in ER-negative BC cell lines (HCC38, HCC1395, MDA-MB-436) than ER-positive BC (MCF-7 and ZR-75-30) and MCF-10A control cells (ER-negative). Proteasome inhibition levels close to 50% and 100% were seen in all cell lines after 10 nM and 100 - 1000 nM bortezomib, respectively. As expected, bortezomib blocked cell cycle progression by inducing G2/M phase arrest in HCC38 cells. Due to differences in cell growth rates, calculation of the IC50 value was an ineffective method to determine drug potency. In contrast, the normalized growth rate inhibition method with GR50 and GRmax values demonstrated a correlation between sensitivity to proteasome inhibitors in ER-negative BC cell lines and high UBE2C expression levels. However, MDA-MB-436 cells (GR50, range 1.8-286.1 nM; GRmax, range -0.42- -0.93) were generally less sensitive to proteasome inhibitors than HCC38 cells (GR50, range 8.2-936.8 nM; GRmax, range -0.97- -0.99) though both cell lines were ER-negative, which was possibly due to the lower expression of UBE2C in MDA-MB-436 cells. Compared with the other tested drugs, no cell line was sensitive to the mitosis inhibitors and platinum agents were most effective in HCC38 cells. Conclusions: Taken together, these findings suggest an association between UBE2C expression and response to proteasome inhibition, regardless of ER status. Citation Format: Parris TZ, Larsson P, Biermann J, Engqvist H, Werner-Rönnerman E, Kovács A, Karlsson P, Helou K. The effect of UBE2C expression on intrinsic chemosensitivity in breast cancer cell lines [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-19.

Background: Multiple invasive breast tumours may represent either independent primary tumours or clonal recurrences of the first tumour, where the same progenitor cell gives rise to all of the detected tumours. Consequently, the driver events for the progenitor cell need to have been identical in early tumour development. Molecular classification of tumour clonality is not currently evaluated in multiple invasive breast carcinomas, despite evidence suggesting common clonal origins. Furthermore, there is no consensus about which type of biological data (e.g. copy number, mutation, histology) and especially which statistical method is most suitable to distinguish clonal recurrences from independent primary tumours. Methods: Thirty-seven invasive breast tumour pairs were stratified by laterality (bilateral vs. ipsilateral) and the time interval between the diagnoses of the first and second tumours (synchronous vs. metachronous). Both tumours from the same patient were analysed by integrating clinical characteristics (n = 37), DNA copy number (n = 37), DNA methylation (n = 8), gene expression microarray (n = 7), RNA sequencing (n = 3), and SNP genotyping data (n = 3). Different statistical methods, e.g. the diagnostic similarity index (SI), distance measure, shared segment analysis etc., were used to classify the tumours from the same patient as clonally related recurrences or independent primary tumours. Results: The SI applied on DNA copy numbers derived from aCGH (array comparative genomic hybridization) data was determined as the strongest indicator of clonal relatedness as it showed the highest concordance with all other methods. The distance measure was the most conservative method and the shared segment analysis most liberal. Concordant evidence for tumour clonality was found in 46% (17/37) of the patients. Notably, no significant association was found between the clinical characteristics and molecular tumour features. Conclusions: A more accurate classification of clonal relatedness between multiple breast tumours may help to mitigate treatment failure and relapse by integrating tumour-associated molecular features, clinical parameters, and statistical methods. In cases of extremely similar or different tumour pairs, the results showed consistency regardless of the method used. The SI can be easily integrated into clinical routine using FFPE samples to obtain copy number data. However, clinical guidelines with exact thresholds need to be defined to standardize clonality testing in a routine diagnostic setting. Citation Format: Biermann J, Parris TZ, Nemes S, Danielsson A, Engqvist H, Werner Rönnerman E, Forssell-Aronsson E, Kovács A, Karlsson P, Helou K. Tumour clonality in paired invasive breast carcinomas [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-07-09.

Background. Including additional genes in standard immunohistochemical panels might be helpful in determining the prognosis of breast cancer patients. Pevious studies have shown that FOXA1 is a significant predictor of good outcome in breast cancer, while Nestin expression was preferentially found in triple-negative breast cancers, revealing a strong association with germline BRCA1-related breast cancer, a basal-like phenotype, stemness characteristics, high proliferation rates, p53 nuclear expression, increased rate of nodal metastases, and reduced survival (1,2,3,4). ATA3 was not only an important luminal marker, but a reliable immunohistochemical marker, which plays a crucial diagnostic role in verification of breast cancer metastases (Figure 1. and Figure 2). In a cohort containing 164 breast cancer metastases, we found GATA3 to be a reliable and sensitive diagnostic marker. We verified that the metastases originate from breast carcinoma with 95% GATA3-positivity, while mammaglobin showed only 51.2% positivity (5). According to the mammaglobin immunohistochemical prolife, we evaluated the expression of FOXA1, Nestin and GATA3 in mammaglobin-positive (n=84) and mammaglobin-negative (n=80) samples. aterials and method Full-face formalin-fixed paraffin-embedded (FFPE) specimens for 164 breast cancer metastases (from various anatomical sites) diagnosed between 2004 and 2014 were obtained from the Department of Clinical Pathology and Genetics at Sahlgrenska University Hospital (Gothenburg, Sweden). Each FFPE specimen was examined for mammaglobin, ER/PR, CK7, CK20, and HercepTest at the time of diagnosis and retrospectively analyzed for FOXA1, Nestin and GATA3 expression by immunohistochemistry (IHC). The statistical analyses were performed using a .05 P-value cutoff in R/Bioconductor (version 2.15.0) and all P-values are two-sided. The relationship between clinicopathological features and mammaglobin/GATA3 protein expression patterns was evaluated using two-tailed Fisher's exact test. Results In mammaglobin-positive metastases, FOXA1-positivity was associated with ER+ (83%) and negatively associated with triple-negativity (81%; Figure 3.). Moreover, there was no association between Nestin-positivity and the established clinicopathological features in mammaglobin-positive samples (Table 1 and Figure 4). In mammaglobin-negative samples, FOXA1-positivity was associated with GATA3+ (100%), ER+ (77%), HER2+ (36%), and triple-negative status (82% were non-triple negative). In addition, Nestin-positivity was associated with specific metastatic sites (mostly brain, but even gynecological sites and skin), GATA3- (29%), ER- (50%), PR- (79%), and triple-negative status (50% were triple negative) in mammaglobin-negative samples (Table 2). Conclusion In the present study, we found that FOXA1 was expressed mostly in ER-positive breast cancer metastases and Nestin expression was associated with breast cancer metastases with a triple-negative immune profile, where the brain was the most frequent metastatic site. Citation Format: Nyqvist J, de Lara S, Parris TZ, Helou K, Kenne Sarenmalm E, Einbeigi Z, Karlsson P, Kovács A. FOXA1, Nestin, GATA3 and mammaglobin expression in 164 breast cancer metastases – A retrospective immuno-histochemical study of a 10-year period (2004-2014) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-61.

Ovarian cancer is the most lethal gynecological malignancy in the western world. Despite recent efforts to characterize ovarian cancer using molecular profiling, few targeted treatment options are currently available. Here, we examined genetic variants, fusion transcripts, SNP genotyping, and gene expression patterns for early-stage (I and II) ovarian carcinomas (n=96) in relation to clinicopathological characteristics and clinical outcome, thereby identifying novel genetic features of ovarian carcinomas. Furthermore, mutation frequencies of specific genetic variants and/or their gene expression patterns were associated with histotype and overall survival, e.g. SLC28A2 (mucinous ovarian carcinoma histotype), ARCN1 (low expression in 0-2 year survival group), and tumor suppressor MTUS1 (mutation status and overall survival). The long non-coding RNA MALAT1 was identified as a highly promiscuous fusion transcript in ovarian carcinoma. Moreover, gene expression deregulation for 23 genes was associated with tumor aggressiveness. Taken together, the novel biomarkers identified here may improve ovarian carcinoma subclassification and patient stratification according to histotype and overall survival.

In this study, the six indicator non-dioxin-like polychlorinated biphenyls NDL-PCBs (PCB28, PCB52, PCB101, PCB138, PCB153, PCB180), as well as four organochlorine pesticides (OCPs), hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichlorethylene (DDE) were measured in 98 maternal and 49 cord sera samples of a group of Lebanese women who gave birth in three hospitals in Greater Beirut, between March and July 2018. Results showed that the levels of these persistent organic pollutants (POPs) in maternal serum were below critical limits as well as those in other countries (Tunisia, France, Portugal, Spain, Poland, Greenland, Canada, Brazil, and China). The ratios of cord serum concentrations to maternal serum concentrations of analyzed POPs were higher than 1. PCB maternal serum concentrations were found to be linked to illegal incineration (OR = 5.78; p = 0.004) as well as eggs (OR = 4.68; p = 0.027) and fruits and vegetables consumption (OR = 3.92; p = 0.016). OCP concentrations were linked to red meat and cold cuts intake (OR = 3.67–4.59; p = 0.001–0.004). While PCB levels were not correlated to newborns anthropometric measurements, OCP levels in cord serum were found to be positively linked to the birth length of newborns (p = 0.014–0.027).

Background The food frequency questionnaire (FFQ) is the most frequently used method to assess dietary intake in epidemiological studies evaluating diet-disease association. The objective of this study was to validate a FFQ for use among Lebanese adults by evaluating various facets of validity and reproducibility. Methods The quantitative 164-items FFQ was validated against the average of six 24-h dietary recalls (DRs) in a sample of 238 Lebanese adults. Reproducibility of the FFQ was assessed by administering it twice within 1 month’ time interval. Results Positive statistically significant Pearson correlations were observed in most macro and micronutrients between the FFQ and the six 24-h DRs, ranging from 0.16 to 0.65, with two thirds of the correlation coefficients exceeding 0.3. Energy, gender, and age-adjusted statistically significant Pearson correlation coefficients ranged from 0.14 to 0.64, with two thirds of the coefficients exceeding 0.2. Intakes from the FFQ were mostly higher than those of the 24-h DRs. Mean percent difference between nutrient intakes from both dietary methods decreased remarkably after using energy-adjusted mean intakes. Values were acceptable to good for all macronutrients and several micronutrients. Cross-classification analysis revealed that around 64.3 to 83.9% of participants were classified into the same and adjacent quartile whereas grossly misclassified proportions ranged from 3.7 to 12.2%. Weighted kappa values ranged from 0.02 to 0.36 with most of them exceeding 0.2. In indirect validity analysis, key nutrient mean intakes estimated from the six 24-h DRs were significantly positively associated with tertiles of food groups derived from the FFQ. Bland Altman plots showed that the majority of data points fell within the limits of agreement (LOA) for all nutrients. As for reproducibility analysis, ICC values were all statistically significant ranging from 0.645 to 0.959 and Bland Altman plots confirmed these results. Conclusions Based on various aspects of validity and reproducibility, and an extensive range of statistical tests, the present FFQ developed for a Lebanese community is an acceptable tool for dietary assessment and is useful for evaluating diet-disease associations in future studies.

Ovarian cancer comprises multiple subtypes (clear-cell (CCC), endometrioid (EC), high-grade serous (HGSC), low-grade serous (LGSC), and mucinous carcinomas (MC)) with differing molecular and clinical behavior. However, robust histotype-specific biomarkers for clinical use have yet to be identified. Here, we utilized a multi-omics approach to identify novel histotype-specific genetic markers associated with ovarian carcinoma histotypes (CCC, EC, HGSC, and MC) using DNA methylation, DNA copy number alteration and RNA sequencing data for 96 primary invasive early-stage (stage I and II) ovarian carcinomas. More specifically, the DNA methylation analysis revealed hypermethylation for CCC in comparison with the other histotypes. Moreover, copy number imbalances and novel chromothripsis-like rearrangements (n = 64) were identified in ovarian carcinoma, with the highest number of chromothripsis-like patterns in HGSC. For the 1000 most variable transcripts, underexpression was most prominent for all histotypes in comparison with normal ovarian samples. Overall, the integrative approach identified 46 putative oncogenes (overexpressed, hypomethylated and DNA gain) and three putative tumor suppressor genes (underexpressed, hypermethylated and DNA loss) when comparing the different histotypes. In conclusion, the current study provides novel insights into molecular features associated with early-stage ovarian carcinoma that may improve patient stratification and subclassification of the histotypes.

The number of patients with multiple primary malignancies has been increasing steadily in recent years. In the present study, we describe a unique case of an 81-year-old woman with 5 metachronous and synchronous primary malignant neoplasms. The patient was first diagnosed with an endometrium adenocarcinoma in 1997 and a colon adenocarcinoma in 2002. Eleven years after her colon surgery, in 2013, the patient presented with 3 other primary malignancies within a 4-month time span: an invasive malignant melanoma on the lower leg, an invasive mucinous breast carcinoma in the right breast, and a pleomorphic spindle cell sarcoma on the left upper arm. Subsequent routine medical checkups in 2013–2017 revealed no metastases of the primary malignancies. The patient mentioned a familial aggregation of malignant tumors, including 2 sisters with breast cancer and a brother with lung cancer. Interestingly, next-generation sequencing analysis of the patient’s blood sample detected no mutations in the BRCA1, BRCA2, TP53, PTEN, CDH1, PALB2, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, STK11, BMPR1A, SMAD4, PTEN, POLE, POLD1, GREM1, and GALNT12 genes. Therefore, whole genome sequencing is warranted to identify cancer-related genetic alterations in this patient with quintuple primary malignancies.

Background 177Lu-octreotate can be used to treat somatostatin receptor expressing neuroendocrine tumors. It is highly effective in animal models, but clinical studies have so far only demonstrated low cure rates. Hedgehog inhibitors have shown therapeutic effect as monotherapy in neuroendocrine tumor model systems and might be one option to enhance the efficacy of 177Lu-octreotate therapy. The aim of this study was to determine the therapeutic effect of combination therapy using 177Lu-octreotate and the Hedgehog signaling pathway inhibitor sonidegib. Methods GOT1-bearing BALB/c nude mice were treated with either sonidegib (80 mg/kg twice a week via oral gavage), a single injection of 30 MBq 177Lu-octreotate i.v., or a combination of both. Untreated animals served as controls. Tumor size was measured twice-weekly using calipers. The animals were killed 41 d after injection followed by excision of the tumors. Total RNA was extracted from each tumor sample and then subjected to gene expression analysis. Gene expression patterns were compared with those of untreated controls using Nexus Expression 3.0, IPA and Gene Ontology terms. Western blot was carried out on total protein extracted from the tumor samples to analyze activation-states of the Hh and PI3K/AKT/mTOR pathways. Results Sonidegib monotherapy resulted in inhibition of tumor growth, while a significant reduction in mean tumor volume was observed after 177Lu-octreotate monotherapy and combination therapy. Time to progression was prolonged in the combination therapy group compared with 177Lu-octreotate monotherapy. Gene expression analysis revealed a more pronounced response following combination therapy compared with both monotherapies, regarding the number of regulated genes and biological processes. Several cancer-related signaling pathways (i.e. Wnt/β-catenin, PI3K/AKT/mTOR, G-protein coupled receptor, and Notch) were affected by the combination therapy, but not by either monotherapy. Protein expression analysis revealed an activation of the Hh- and PI3K/AKT/mTOR pathways in tumors exposed to 177Lu-octreotate monotherapy and combination therapy. Conclusions A comparative analysis of the different treatment groups showed that combination therapy using sonidegib and 177Lu-octreotate could be beneficial to patients with neuroendocrine tumors. Gene expression analysis revealed a functional interaction between sonidegib and 177Lu-octreotate, i.e. several cancer-related signaling pathways were modulated that were not affected by either monotherapy. Protein expression analysis indicated a possible PI3K/AKT/mTOR-dependent activation of the Hh pathway, independent of SMO.

Diagnostic verification of breast cancer metastasis with histopathology and imaging analysis is essential to determine tumor staging. The aim of this study was to validate the utility of GATA3 immunohistochemistry as a diagnostic marker for breast cancer metastases and metastases of unknown primary origin. Retrospective immunohistochemical analysis of GATA3 expression in 164 breast cancer metastases diagnosed between 2004 and 2014 showed a striking difference between mammaglobin and GATA3 expression (51.2% vs 94% positivity). These findings highlight GATA3 as a more reliable and sensitive diagnostic marker for breast cancer metastases and possibly metastatic tumors of unknown origin than mammaglobin.

Background The International Physical Actvity Questionnaire (IPAQ) is a validated tool for physical activity assessment used in many countries however no Arabic version of the long-form of this questionnaire exists to this date. Hence, the aim of this study was to cross-culturally adapt and validate an Arabic version of the long International Physical Activity Questionnaire (AIPAQ) equivalent to the French version (F-IPAQ) in a Lebanese population. Methods The guidelines for cross-cultural adaptation provided by the World Health Organization and the International Physical Activity Questionnaire committee were followed. One hundred fifty-nine students and staff members from Saint Joseph University of Beirut were randomly recruited to participate in the study. Items of the A-IPAQ were compared to those from the F-IPAQ for concurrent validity using Spearman’s correlation coefficient. Content validity of the questionnaire was assessed using factor analysis for the A-IPAQ’s items. The physical activity indicators derived from the A-IPAQ were compared with the body mass index (BMI) of the participants for construct validity. The instrument was also evaluated for internal consistency reliability using Cronbach’s alpha and Intraclass Correlation Coefficient (ICC). Finally, thirty-one participants were asked to complete the A-IPAQ on two occasions three weeks apart to examine its test–retest reliability. Bland-Altman analyses were performed to evaluate the extent of agreement between the two versions of the questionnaire and its repeated administrations. Results A high correlation was observed between answers of the F-IPAQ and those of the A-IPAQ, with Spearman’s correlation coefficients ranging from 0.91 to 1.00 (p

Organochlorine pesticides (OCPs) were banned by the Stockholm Convention many years ago; however, they are still detected in the environment due to their high persistence, their current illegal use, and their import from countries where they have not been banned. We evaluated the serum concentrations of selected OCPs (hexachlorobenzene (HCB), β-hexachlorocyclohexanes (β-HCH), p,p'-dichlorodiphenyltrichloroethane (DDT) and its metabolite p,p'-dichlorodiphenyldichloroethylene (DDE) in a sample of Lebanese adults using gas chromatography coupled to an ion trap mass spectrometer detector. The mean concentrations of HCB, β-HCH, DDT, and DDE were 7.1, 8.6, 2.1, and 18.9 ng/g of lipids, respectively, and the major contributor among the four OCPs was DDE. The OCP levels in the present study were in general lower than the values observed in several countries worldwide and their concentrations at the 95th percentile were lower than the biomonitoring equivalents (BEs) excluding any appreciable health risk. We observed an inverse association between HCB concentrations and body mass index (BMI) as well as HCB, β-HCH, and DDE levels, and smoking habits. Milk consumption however was positively associated with an increased serum level of β-HCH. This study, which was the first to investigate OCP serum levels in a Lebanese population, provides a baseline to which future measurements can be compared.

Targeted a-therapy is a promising treatment option for various types of malignant tumors. Radiolabeled cancer-seeking agents, however, undergo degradation, resulting in a certain percentage of free radionuclide in the body. The radiohalogen 211At accumulates in various tissues, with specifically high uptake in the thyroid. When normal thyroid function is disturbed because of ionizing radiation (IR) exposure, deleterious effects can occur in tissues that depend on thyroid hormone (TH) regulation for normal physiologic function. However, knowledge of systemic effects is still rudimentary. We previously reported similarities in transcriptomic regulation between the thyroid and other tissues despite large differences in absorbed dose from 211At. Here, we present supportive evidence on systemic effects after 211At administration. Methods: Expression microarray data from the kidney cortex and medulla, liver, lungs, and spleen were used from previous studies in which mice were intravenously injected with 0.064-42 kBq of 211At and killed after 24 h or injected with 1.7 kBq of 211At and killed after 1, 6, or 168 h. Controls were mock-treated and killed after 24 h. Literature-based gene signatures were used to evaluate the relative impact from IR- or TH-induced regulation. Thyroid- and TH-associated upstream regulators as well as thyroid-related diseases and functions were generated using functional analysis software. Results: Responses in IR- or TH-associated gene signatures were tissuespecific and varied over time, and the relative impact of each gene signature differed between the investigated tissues. The liver showed a clear dominance of TH-responding genes. In the kidney cortex, kidney medulla, and lungs, the TH-associated signature was detected to at least an extent similar to the IR-associated signature. The spleen was the single tissue showing regulation of only IR-associated signature genes. Various thyroid-associated diseases and functions were inferred from the data: L-triiodothyronine, TH, TH receptor, and triiodothyronine (reverse) were inferred as upstream regulators with differences in incidence and strength of regulation depending on tissue type. Conclusion: These findings indicate that transcriptional regulation in various nonthyroid tissues was-in part-induced by thyroid (hormone)-dependent signaling. Consideration of the systemic context between tissues could contribute to normal tissue risk assessment and planning of remedial measures.

Background Ovarian cancer is the main cause of gynecological cancer-associated death. However, 5-year survival rates differ dramatically between the five main ovarian carcinoma histotypes. Therefore, we need to have a better understanding of the mechanisms that promote histotype-specific ovarian carcinogenesis and identify novel prognostic biomarkers. Methods Here, we evaluated the prognostic role of 29 genes for early-stage (I and II) ovarian carcinomas (n = 206) using immunohistochemistry (IHC). Results We provide evidence of aberrant protein expression patterns for Collagen type III alpha 1 chain (COL3A1), G protein-coupled receptor 158 (GPR158) and PITH domain containing 1 (PITHD1). Kaplan-Meier survival analysis revealed that COL3A1 expression was associated with shorter overall survival in the four major histotypes of epithelial ovarian carcinoma patients (P value = 0.026, HR = 2.99 (95% CI 1.089–8.19)). Furthermore, GPR158 and PITHD1 were shown to be histotype-specific prognostic biomarkers, with elevated GPR158 expression patterns in mucinous ovarian carcinoma patients with unfavorable overall survival (P value = 0.00043, HR = 6.13 (95% CI 1.98–18.98)), and an association with lower PITHD1 protein expression and unfavorable overall and disease-specific survival in clear-cell ovarian carcinoma patients (P value = 0.012, HR = 0.22 (95% CI 0.058–0.80); P value = 0.003, HR = 0.17 (95% CI 0.043–0.64)). Conclusions The novel biomarkers identified here may improve prognostication at the time of diagnosis and may assist in the development of future individualized therapeutic strategies for ovarian carcinoma patients.

Genomic instability is a hallmark of cancer that plays a pivotal role in breast cancer development and evolution. A number of existing prognostic gene expression signatures for breast cancer are based on proliferation-related genes. Here, we identified a 17-marker panel associated with genome stability. A total of 136 primary breast carcinomas were stratified by genome stability. Matched gene expression profiles showed an innate segregation based on genome stability. We identified a 17-marker panel stratifying the training and validation cohorts into high- and low-risk patients. The 17 genes associated with genomic instability strongly impacted clinical outcome in breast cancer. Pathway analyses determined chromosome organisation, cell cycle regulation, and RNA processing as the underlying biological processes, thereby offering options for drug development and treatment tailoring. Our work supports the applicability of the 17-marker panel to improve clinical outcome prediction for breast cancer patients based on a signature accounting for genomic instability.

Radiation-induced genomic instability (GI) is hypothesized to persist after exposure and ultimately promote carcinogenesis. Based on the absorbed dose to the breast, an increased risk of developing breast cancer was shown in the Swedish hemangioma cohort that was treated with radium-226 for skin hemangioma as infants. Here, we screened 31 primary breast carcinomas for genetic alterations using the OncoScan CNV Plus Assay to assess GI and chromothripsis-like patterns associated with the absorbed dose to the breast. Higher absorbed doses were associated with increased numbers of copy number alterations in the tumor genome and thus a more unstable genome. Hence, the observed dose-dependent GI in the tumor genome is a measurable manifestation of the long-term effects of irradiation. We developed a highly predictive Cox regression model for overall survival based on the interaction between absorbed dose and GI. The Swedish hemangioma cohort is a valuable cohort to investigate the biological relationship between absorbed dose and GI in irradiated humans. This work gives a biological basis for improved risk assessment to minimize carcinogenesis as a secondary disease after radiation therapy.

Background Current prognostic markers cannot adequately predict the clinical outcome of breast cancer patients. Therefore, additional biomarkers need to be included in routine immune panels. FOXA1 was a significant predictor of favorable outcome in primary breast cancer, while Nestin expression is preferentially found in triple-negative tumors with increased rate of nodal metastases, and reduced survival. No studies have investigated the prognostic value of FOXA1 and Nestin expression in breast cancer metastases. Methods Breast cancer metastases (n = 164) from various anatomical sites were retrospectively analyzed by immunohistochemistry for FOXA1, Nestin and GATA3 expression. Cox regression analysis assessed the prognostic value of FOXA1 and Nestin expression. Results In breast cancer metastases, FOXA1 expression was associated with Nestin-negativity, GATA3-positivity, ER-positivity, HER2-positivity and non-triple-negative status (P

Yinglai Huang,1,2,* Lin Pan,3,* Khalil Helou,2 Qisheng Xia,3 Toshima Z Parris,2 Hongyan Li,3 Bo Xu,3 Hon Li3 1Division of Breast and Endocrine Surgery, Department of Surgery, Borås Hospital, Borås, 2Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; 3Department of Biochemistry and Molecular Biology, China-Japan Friendship Hospital, Beijing, People’s Republic of China *These authors contributed equally to this work Background/purpose: The aim of this study was to test the hypothesis that mechanical ventilation (MV) during cancer surgery induces lung stroma/tissue milieu changes, creating a favorable microenvironment for postoperative lung metastatic tumor establishment.Materials and methods: In Protocol A, female BALB/c mice were divided into an MV group and a control (no MV) group, both of which were anesthetized and subjected to intravenous injection of green fluorescent protein (GFP)-labeled mouse mammary carcinoma cell line (4T1) cells. After 24 h, the lung tissue was removed and the number of GFP-labeled 4T1 cells was calculated. In Protocol B, the clinically relevant mouse model of spontaneous breast cancer lung metastasis was used with surgical resection of the primary tumor to investigate the MV event that dictates postoperative lung metastasis. Female BALB/c mice were inoculated in the mammary fat pad with 4T1 cells. After 14-d growth, mice were anesthetized and divided into an MV group and a control (no MV) group during surgical procedures (mastectomy). Metastatic tumor burden was assessed two weeks after mastectomy by both macroscopic metastatic nodule count, hematoxylin–eosin histology, immunohistochemistry for the macrophage marker (CD68), and epithelial cell adhesion molecule (EpCAM).Results: MV was associated with a significant increase in the number of circulating breast tumor cells (GFP-labeled 4T1 cells) remaining in the microvasculature of the lung (P

Genomic instability contributes to the neoplastic phenotype by deregulating key cancer-related genes, which in turn can have a detrimental effect on patient outcome. DNA amplification of the 8p11-p12 genomic region has clinical and biological implications in multiple malignancies, including breast carcinoma where the amplicon has been associated with tumor progression and poor prognosis. However, oncogenes driving increased cancer-related death and recurrent genetic features associated with the 8p11-p12 amplicon remain to be identified. In this study, DNA copy number and transcriptome profiling data for 229 primary invasive breast carcinomas (corresponding to 185 patients) were evaluated in conjunction with clinicopathological features to identify putative oncogenes in 8p11-p12 amplified samples. Illumina paired-end whole transcriptome sequencing and whole-genome SNP genotyping were subsequently performed on 23 samples showing high-level regional 8p11-p12 amplification to characterize recurrent genetic variants (SNPs and indels), expressed gene fusions, gene expression profiles and allelic imbalances. We now show previously undescribed chromothripsis-like patterns spanning the 8p11-p12 genomic region and allele-specific DNA amplification events. In addition, recurrent amplification-specific genetic features were identified, including genetic variants in the HIST1H1E and UQCRHL genes and fusion transcripts containing MALAT1 non-coding RNA, which is known to be a prognostic indicator for breast cancer and stimulated by estrogen. In summary, these findings highlight novel candidate targets for improved treatment of 8p11-p12 amplified breast carcinomas.

Introduction In the present investigation, microarray analysis was used to monitor transcriptional activity in thyroids in mice 24h after 131 I exposure. The aims of this study were to 1) assess the transcriptional patterns associated with 131 I exposure in normal mouse thyroid tissue and 2) propose biomarkers for 131 I exposure of the thyroid. Methods Adult BALB/c nude mice were i.v. injected with 13, 130 or 260kBq of 131 I and killed 24h after injection (absorbed dose to thyroid: 0.85, 8.5, or 17Gy). Mock-treated mice were used as controls. Total RNA was extracted from thyroids and processed using the Illumina platform. Results In total, 497, 546, and 90 transcripts were regulated (fold change ≥1.5) in the thyroid after 0.85, 8.5, and 17Gy, respectively. These were involved in several biological functions, e.g. oxygen access, inflammation and immune response, and apoptosis/anti-apoptosis. Approximately 50% of the involved transcripts at each absorbed dose level were dose-specific, and 18 transcripts were commonly detected at all absorbed dose levels. The Agpat9 , Plau , Prf1 , and S100a8 gene expression displayed a monotone decrease in regulation with absorbed dose, and further studies need to be performed to evaluate if they may be useful as dose-related biomarkers for 131I exposure. Conclusion Distinct and substantial differences in gene expression and affected biological functions were detected at the different absorbed dose levels. The transcriptional profiles were specific for the different absorbed dose levels. We propose that the Agpat9 , Plau , Prf1 , and S100a8 genes might be novel potential absorbed dose-related biomarkers to 131 I exposure of thyroid. Advances in knowledge During the recent years, genomic techniques have been developed; however, they have not been fully utilized in nuclear medicine and radiation biology. We have used RNA microarrays to investigate genome-wide transcriptional regulations in thyroid tissue in mice after low, intermediate, and high absorbed doses from 131 I exposure in vivo. Using this approach, we have identified novel biological responses and potential absorbed dose-related biomarkers to 131 I exposure. Our research shows the importance of embracing technological advances and multi-disciplinary collaboration in order to apply them in radiation therapy, nuclear medicine, and radiation biology. Implications on Patient Care This work may contribute with new knowledge of potential normal tissue effects or complications that may occur after exposure to ionizing radiation in diagnostic and therapeutic nuclear medicine, and due to radioactive fallout or accident with radionuclide spread.

Background: Gene expression profiling has made considerable contributions to our understanding of cancer biology and clinical care. This study describes a novel gene expression signature for breast cancer–specific survival that was validated using external datasets. Methods: Gene expression signatures for invasive breast carcinomas (mainly luminal B subtype) corresponding to 136 patients were analyzed using Cox regression, and the effect of each gene on disease-specific survival (DSS) was estimated. Iterative Bayesian model averaging was applied on multivariable Cox regression models resulting in an 18-marker panel, which was validated using three external validation datasets. The 18 genes were analyzed for common pathways and functions using the Ingenuity Pathway Analysis software. This study complied with the REMARK criteria. Results: The 18-gene multivariable model showed a high predictive power for DSS in the training and validation cohort and a clear stratification between high- and low-risk patients. The differentially expressed genes were predominantly involved in biological processes such as cell cycle, DNA replication, recombination, and repair. Furthermore, the majority of the 18 genes were found to play a pivotal role in cancer. Conclusions: Our findings demonstrated that the 18 molecular markers were strong predictors of breast cancer–specific mortality. The stable time-dependent area under the ROC curve function (AUC(t)) and high C-indices in the training and validation cohorts were further improved by fitting a combined model consisting of the 18-marker panel and established clinical markers. Impact: Our work supports the applicability of this 18-marker panel to improve clinical outcome prediction for breast cancer patients. Cancer Epidemiol Biomarkers Prev; 26(11); 1619–28. ©2017 AACR.

AIM : To examine the burden of cardio- vascular disease (CVD) risk factors and their associa- tion with dietary variables in the Lebanese population while reviewing secular trends in the population's nu- tritional intakes and nutrition-related CVD risk factors. METHODS : Data on CVD risk factors and food con- sumption patterns in Lebanon were collected from scholarly papers, including individual studies and systematic review articles. Electronic databases were searched using combinations of key terms. RESULTS : The prevalence of obesity in Lebanon fol- lowed an alarming increasing trend over time, paral- leled by an escalation in the prevalence of hyperten- sion, diabetes and hyperlipidemia. Food consumption surveys illustrate an increasing trend in energy intake and the proportion of energy derived from fat and animal products, with a concomitant decrease in car- bohydrates and cereals intakes. CONCLUSION : The shift towards an atherogenic diet coupled with the alarming increase in nutrition-related cardiovascular risk factors suggest that the Lebanese population is at an increased risk for CVDs. This should alert to the importance of formulating multi- component intervention strategies at both the indivi- dual and population levels to halt the progression of nutrition-related diseases in the country, while high- lighting the need for immediate public health efforts to promote the adoption of healthy dietary habits. RESUME • OBJECTIFS : Examiner la prevalence des facteurs de risque cardiovasculaires, leur evolution temporelle ainsi que leurs associations avec les facteurs nutritionnels et les changements d'habitudes alimen- taires au sein de la population libanaise. METHODES : Les donnees concernant les facteurs de risque cardiovasculaires et les donnees sur la consom- mation alimentaire au Liban ont ete recueillies a partir des resultats d'etudes individuelles et de revues syste- matiques d'articles scientifiques publies. La recherche des bases de donnees electroniques a ete effectuee en combinant differents mots-cles.

Non-targeted effects can induce responses in tissues that have not been exposed to ionizing radiation. Despite their relevance for risk assessment, few studies have investigated these effects in vivo. In particular, these effects have not been studied in context with thyroid exposure, which can occur e.g. during irradiation of head and neck tumors. To determine the similarity between in-field and out-of-field responses in normal tissue, we used a partial body irradiation setup with female mice where the thyroid region, the thorax and abdomen, or all three regions were irradiated. After 24 h, transcriptional regulation in the kidney cortex, kidney medulla, liver, lungs, spleen, and thyroid was analyzed using microarray technology. Thyroid irradiation resulted in transcriptional regulation in the kidney medulla and liver that resembled regulation upon direct exposure of these tissues regarding both strength of response and associated biological function. The kidney cortex showed fewer similarities between the setups, while the lungs and spleen showed little similarity between in-field and out-of-field responses. Interestingly, effects were generally not found to be additive. Future studies are needed to identify the molecular mechanisms that mediate these systemic effects, so that they may be used as targets to minimize detrimental side effects in radiotherapy.

BACKGROUND/OBJECTIVES To compare five indices of adherence to the Mediterranean Diet (MD) among adults living in the Mediterranean region. SUBJECTS/METHODS A total of 100 healthy Lebanese adults aged between 18 and 65 years. Face-to-face interviews to collect sociodemographic and medical information, to take anthropometric measurements, and to fill a validated, culturally adapted, food frequency questionnaire (FFQ). The score for each item was calculated following the recommendations for each corresponding index. The five MD indices were Mediterranean Diet Scale (MDScale), Mediterranean Food Pattern (MFP), MD Score (MDS), Short Mediterranean Diet Questionnaire (SMDQ), and the MedDiet score. RESULTS Significant correlations were detected between items with P-values < 0.001. Minimal agreement was seen between MDScale and MedDiet score and maximal agreement between MDS and MedDiet score. Univariate and multivariate analyses showed that MDS and MedDiet scores had significant correlations with fiber and olive oil intake, main components of the MD. MDScale showed a significant correlation with waist-to-hip ratio and with total energy intake but none of the five indices was correlated to body mass index (BMI). CONCLUSIONS The indices that showed the highest correlation with variables related to the MD are the MDScale and the MedDiet score; therefore, they can be used to assess our future study populations. Based on the current results, more than half of the study population was non-adherent to the MD and adherence to this diet did not appear to protect against being overweight (BMI ≥ 30).

The deregulation of key cellular pathways is fundamental for the survival and expansion of neoplastic cells, which in turn can have a detrimental effect on patient outcome. To develop effective individualized cancer therapies, we need to have a better understanding of which cellular pathways are perturbed in a genetically defined subgroup of patients. Here, we validate the prognostic value of a 13-marker signature in independent gene expression microarray datasets (n = 1,141) and immunohistochemistry with full-faced FFPE samples (n = 71). The predictive performance of individual markers and panels containing multiple markers was assessed using Cox regression analysis. In the external gene expression dataset, six of the 13 genes (AZGP1, NME5, S100A8, SCUBE2, STC2 and UBE2C) retained their prognostic potential and were significantly associated with disease-free survival (p < 0.001). Protein analyses refined the signature to a four-marker panel [AZGP1, Prolactin-inducible protein (PIP), S100A8 and UBE2C] significantly correlated with cycling, high grade tumors and lower disease-specific survival rates. AZGP1 and PIP were found in significantly lower levels in invasive breast tissue as compared with adjacent normal tissue, whereas elevated levels of S100A8 and UBE2C were observed. A predictive model containing the four-marker panel in conjunction with established clinical variables outperformed a model containing the clinical variables alone. Our findings suggest that deregulated AZGP1, PIP, S100A8 and UBE2C are critical for the aggressive breast cancer phenotype, which may be useful as novel therapeutic targets for drug development to complement established clinical variables.

Despite practical implications we still lack standardized methods for clonality testing of tumor pairs. Each tumor is characterized by a set of chromosomal abnormalities, nonrandom changes preferentially involving specific chromosomes and chromosomal regions. Although tumors accumulate chromosomal abnormalities during their development, the majority of these alterations is specific and characteristic for each individual tumor is not exhibited at the population level. Assumingly, secondary tumors that develop from disseminated cells from the primary tumor inherit not only chromosomal changes specific for the cancerous process but also random chromosomal changes that accumulate during tumor development. Based on this assumption, we adopted an intuitive index for genomic similarities of paired tumors, which ranges between zero (completely different genomic profiles) and one (identical genomic profiles). To test the assumption that two tumors have clonal origins if they share a higher degree of genomic similarity than two randomly paired tumors, we built a permutation-based null-hypothesis procedure. The procedure is demonstrated using two publicly available data sets. The article highlights the complexities of clonality testing and aims to offer an easy to follow blueprint that will allow researchers to test genomic similarities of paired tumors, with the proposed index or any other index that fits their need. V C 2013 Wiley Periodicals, Inc.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a congenital malformation that leads to severe pulmonary hypertension and respiratory failure. It has been associated with deletion of, or mutation in, FOXF1 on 16q24.1, a gene encoding a forkhead transcription factor expressed in the mesenchyme of the developing lung. Here we report on the identification of a pericentric inversion on chromosome 16 (p11.2q24.1) in a case of lethal ACDMPV with atrioventricular septal defect and duodenal atresia. Array-CGH indicated that the inversion is balanced, and FISH showed that the q-arm breakpoint occurs 134 ± 10 kb upstream (5'; centromeric) of FOXF1. This is suggestive of cis-regulatory elements located more than 130 kb 5' of FOXF1, and analysis of genome-wide data sets of chromatin modifications in two different cell types suggested that the FOXF1 regulatory domain covers more than 300 kb, and perhaps up to 433 kb, upstream of the gene, but only 3 kb downstream. The 588 kb gene-free region between FOXF1 and the next gene in the centromeric direction, IRF8, is highly conserved between species and divided into two distinct regulatory domains by an insulator element. Another putative insulator occurs just downstream of FOXF1. Our results further strengthen the association between FOXF1 and a spectrum of malformations that include ACDMPV, atrioventricular septal defects, and gastrointestinal atresia. Furthermore, the presented analysis aids in defining the critical genomic region for this syndrome.

(211)At is a promising therapeutic radionuclide because of the nearly optimal biological effectiveness of emitted α-particles. Unbound (211)At accumulates in the thyroid gland and in other vital normal tissues. However, few studies have been performed that assess the (211)At-induced normal-tissue damage in vivo. Knowledge about the extent and quality of resulting responses in various organs offers a new venue for reducing risks and side effects and increasing the overall well-being of the patient during and after therapy. METHODS: Female BALB/c nude mice were injected intravenously with 0.064-42 kBq of (211)At or mock-treated, and the kidneys, liver, lungs, and spleen were excised 24 h after injection. A transcriptional gene expression analysis was performed in triplicate using RNA microarray technology. Biological processes associated with regulated transcripts were grouped into 8 main categories with 31 subcategories according to gene ontology terms for comparison of regulatory profiles. RESULTS: A substantial decrease in the total number of regulated transcripts was observed between 0.64 and 1.8 kBq of (211)At for all investigated tissues. Few genes were differentially regulated in each tissue at all absorbed doses. In all tissues, most of these genes showed a nonmonotonous dependence on absorbed dose. However, the direction of regulation generally remained uniform for a given gene. Few known radiation-associated genes were regulated on the transcriptional level, and their expression profile generally appeared to be dose-independent and tissue-specific. The regulatory profiles of categorized biological processes were tissue-specific and reflected the shift in regulatory intensity between 0.64 and 1.8 kBq of (211)At. The profiles revealed strongly regulated and nonregulated subcategories. CONCLUSION: The strong regulatory change observed between 0.64 and 1.8 kBq is hypothesized to result not only from low-dose effects in each tissue but also from physiologic responses to ionizing radiation-induced damage to, for example, the (211)At-accumulating thyroid gland. The presented results demonstrate the complexity of responses to radionuclides in vivo and highlight the need for further research to also consider physiology in ionizing radiation-induced responses.

The aim of this study was to identify gene expression profiles distinguishing alpha-particle (211)At and (60)Co irradiation.Gene expression microarray profiling was performed using total RNA from confluent human fibroblasts 5 hours after exposure to (211)At labeled trastuzumab monoclonal antibody (0.25, 0.5, and 1 Gy) and (60)Co (1, 2, and 3 Gy).We report gene expression profiles that distinguish the effect different radiation qualities and absorbed doses have on cellular functions in human fibroblasts. In addition, we identified commonly expressed transcripts between (211)At and (60)Co irradiation. A greater number of transcripts were modulated by (211)At than (60)Co irradiation. In addition, down-regulation was more prevalent than up-regulation following (211)At irradiation. Several biological processes were enriched for both irradiation qualities such as transcription, cell cycle regulation, and cell cycle arrest, whereas mitosis, spindle assembly checkpoint, and apoptotic chromosome condensation were uniquely enriched for alpha particle irradiation.LET-dependent transcriptional modulations were observed in human fibroblasts 5 hours after irradiation exposure. These findings suggest that in comparison with (60)Co, (211)At has the clearest influence on both tumor protein p53-activated and repressed genes, which impose a greater overall burden to the cell following alpha particle irradiation.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that are still routinely detected 30 years after their restriction in many countries. PCBs have been associated with several non-communicable diseases. They are best measured via human biomonitoring (HBM). The concentrations of six indicator PCBs (PCBs 28, 52, 101, 138, 153, and 180) were measured in the serum samples of 316 Lebanese students and employees from Saint Joseph University of Beirut, Lebanon, using gas chromatography coupled to an iron trap mass spectrometer detector. PCBs were detected in 56.3 to 59.2% of the serum samples. The sum of PCB (∑PCBs) levels ranged from