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Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Method(s): We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer. specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Result(s): There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI >=30 versus 18.5.25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age >=30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0.<5 years versus >=10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen.progestin therapy [0.61 (0.54.0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking. Conclusion(s): We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.Copyright © 2021 American Association for Cancer Research.

BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHOD(S): We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP <0.15). RESULT(S): Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSION(S): We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on br

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P=3.19x10-8 and 4.42x10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.Copyright © 2021. The Author(s).

Radboud Universiteit Nijmegen, 25 april 2014, Promotores : Kampman, E., Blom, H.J. Co-promotor : Nagengast, F.M., Contains fulltext : 125589.pdf (publisher's version ) (Open Access)

Contains fulltext : 137784.pdf (publisher's version ) (Closed access), PURPOSE: Dietary intake of B vitamins and methionine, essential components of DNA synthesis and methylation pathways, may influence colorectal tumor (CRT) development. The impact of B vitamins on colorectal carcinogenesis in individuals with Lynch syndrome (LS) is unknown but is important given their high lifetime risk of developing neoplasms. The role of MTHFR C677T genotype in modifying these relationships in LS individuals is also unclear. We investigated associations between dietary intakes of folate, vitamins B2, B6, B12, and methionine and CRT development in a prospective cohort study of 470 mismatch repair gene mutation carriers. METHODS: Dietary intakes were assessed by food frequency questionnaire. Cox regression models with robust sandwich covariance estimation, adjusted for age, sex, physical activity, number of colonoscopies during person-time, NSAID use, and mutual vitamins were used to calculate hazard ratios (HRs) and 95 % confidence intervals (95 % CIs). Analyses were also stratified by MTHFR C677T genotype. RESULTS: During a median person-time of 28.0 months, 131 persons developed a CRT. Fifty-one of these persons developed an incident colorectal adenoma, while there were four persons who developed an incident colorectal carcinoma. Compared to the lowest tertile of intake, adjusted HRs (95 % CIs) for CRT development in the highest tertile were 1.06 (0.59-1.91) for folate, 0.77 (0.39-1.51) for vitamin B2, 0.98 (0.59-1.62) for vitamin B6, 1.24 (0.77-2.00) for vitamin B12, and 1.36 (0.83-2.20) for methionine. Low vitamin B2 and low methionine intake were statistically significantly associated with an increased risk of CRT in MTHFR 677TT individuals compared to a combined reference of persons with low intake and CC genotype. CONCLUSIONS: There was no suggestion that intake of any dietary B vitamin or methionine was associated with CRT development among those with LS.

Contains fulltext : 118083.pdf (publisher's version ) (Open Access), OBJECTIVE: To develop an high resolution computed tomography (HRCT) scoring system for the assessment of bronchopulmonary dysplasia (BPD) and determine its usefulness as compared with the chest radiographic score. MATERIALS AND METHODS: Forty-two very low-birth-weight preterm infants with BPD (25 male, 17 female) were prospectively evaluated with HRCT performed at the mean age of 39.1-week postmenstrual age. Clinical severity of BPD was categorized as mild, moderate or severe. The HRCT score (0-36) of each patient was the sum of the number of bronchopulmonary segments with 1) hyperaeration and 2) parenchymal lesions (linear lesions, segmental atelectasis, consolidation and architectural distortion), respectively. We compared the HRCT scores with the chest radiographic scores (the Toce system) in terms of correlation with clinical severity. RESULTS: The HRCT score had good interobserver (r = 0.969, p < 0.001) and intraobserver (r = 0.986, p < 0.001) reproducibility. The HRCT score showed better correlation (r = 0.646, p < 0.001) with the clinical severity of BPD than the chest radiographic score (r = 0.410, p = 0.007). The hyperaeration score showed better correlation (r = 0.738, p < 0.001) with the clinical severity of BPD than the parenchymal score (r = 0.523, p < 0.001). CONCLUSION: We have developed a new HRCT scoring system for BPD based on the quantitative evaluation of pulmonary abnormalities of BPD consisting of the hyperaeration score and the parenchymal score. The HRCT score shows better correlation with the clinical severity of BPD than the radiographic score.

Contains fulltext : 127315.pdf (publisher's version ) (Open Access), OBJECTIVE: Though a number of CT findings of bowel and mesenteric injuries in blunt abdominal trauma are described in literature, no studies on the specific CT signs of a transected bowel have been published. In the present study we describe the incidence and new CT signs of bowel transection in blunt abdominal trauma. MATERIALS AND METHODS: We investigated the incidence of bowel transection in 513 patients admitted for blunt abdominal trauma who underwent multidetector CT (MDCT). The MDCT findings of 8 patients with a surgically proven complete bowel transection were assessed retrospectively. We report novel CT signs that are unique for transection, such as complete cutoff sign (transection of bowel loop), Janus sign (abnormal dual bowel wall enhancement, both increased and decreased), and fecal spillage. RESULTS: The incidence of bowel transection in blunt abdominal trauma was 1.56%. In eight cases of bowel transection, percentage of CT signs unique for bowel transection were as follows: complete cutoff in 8 (100%), Janus sign in 6 (100%, excluding duodenal injury), and fecal spillage in 2 (25%). The combination of complete cutoff and Janus sign were highly specific findings in patients with bowel transection. CONCLUSION: Complete cut off and Janus sign are the unique CT findings to help detect bowel transection in blunt abdominal trauma and recognition of these findings enables an accurate and prompt diagnosis for emergency laparotomy leading to reduced mortality and morbidity.

Contains fulltext : 127284.pdf (publisher's version ) (Open Access), After maternal intake, nicotine crosses the placental barrier and causes severe embryonic disorders and fetal death. In this study, we investigated whether beta -carotene has a beneficial effect against nicotine-induced teratogenesis in mouse embryos (embryonic day 8.5) cultured for 48 h in a whole embryo culture system. Embryos exposed to nicotine (1 mM) exhibited severe morphological anomalies and apoptotic cell death, as well as increased levels of TNF- alpha , IL-1 beta , and caspase 3 mRNAs, and lipid peroxidation. The levels of cytoplasmic superoxide dismutase (SOD), mitochondrial manganese-dependent SOD, cytosolic glutathione peroxidase (GPx), phospholipid hydroperoxide GPx, hypoxia inducible factor 1 alpha , and Bcl-x L mRNAs decreased, and SOD activity was reduced compared to the control group. However, when beta -carotene (1 x 10(-7) or 5 x 10(-7) muM) was present in cultures of embryos exposed to nicotine, these parameters improved significantly. These findings indicate that beta -carotene effectively protects against nicotine-induced teratogenesis in mouse embryos through its antioxidative, antiapoptotic, and anti-inflammatory activities.

Item does not contain fulltext, SCOPE: Low concentrations of folate, other B vitamins, and methionine are associated with colorectal cancer risk, possibly by changing DNA methylation patterns. Here, we examine whether plasma concentrations of B vitamins and methionine are associated with methylation of long interspersed nuclear element-1 (LINE-1) among those at high risk of colorectal cancer, i.e. patients with at least one histologically confirmed colorectal adenoma (CRA) in their life. METHODS AND RESULTS: We used LINE-1 bisulfite pyrosequencing to measure global DNA methylation levels in leukocytes of 281 CRA patients. Multivariable linear regression was used to assess associations between plasma B vitamin concentrations and LINE-1 methylation levels. Plasma folate was inversely associated with LINE-1 methylation in CRA patients, while plasma methionine was positively associated with LINE-1 methylation. CONCLUSION: This study does not provide evidence that in CRA patients, plasma folate concentrations are positively related to LINE-1 methylation in leukocytes but does suggest a direct association between plasma methionine and LINE-1 methylation in leukocytes.

Contains fulltext : 118282.pdf (publisher's version ) (Open Access), BACKGROUND AND AIMS: Individuals with Lynch syndrome have a high lifetime risk of developing colorectal tumors. In this prospective cohort study of individuals with Lynch syndrome, we examined associations between use of dietary supplements and occurrence of colorectal adenomas. MATERIALS AND METHODS: Using data of 470 individuals with Lynch syndrome in a prospective cohort study, associations between dietary supplement use and colorectal adenoma risk were evaluated by calculating hazard ratios (HR) and 95% confidence intervals (CI) using cox regression models adjusted for age, sex, and number of colonoscopies during person time. Robust sandwich covariance estimation was used to account for dependency within families. RESULTS: Of the 470 mismatch repair gene mutation carriers, 122 (26.0%) developed a colorectal adenoma during an overall median person time of 39.1 months. 40% of the study population used a dietary supplement. Use of any dietary supplement was not statistically significantly associated with colorectal adenoma risk (HR = 1.18; 95%CI 0.80-1.73). Multivitamin supplement use (HR = 1.15; 95%CI 0.72-1.84), vitamin C supplement use (HR = 1.57; 95%CI 0.93-2.63), calcium supplement use (HR = 0.69; 95%CI 0.25-1.92), and supplements containing fish oil (HR = 1.60; 95%CI 0.79-3.23) were also not associated with occurrence of colorectal adenomas. CONCLUSION: This prospective cohort study does not show inverse associations between dietary supplement use and occurrence of colorectal adenomas among individuals with Lynch syndrome. Further research is warranted to determine whether or not dietary supplement use is associated to colorectal adenoma and colorectal cancer risk in MMR gene mutation carriers.

Contains fulltext : 118586.pdf (publisher's version ) (Open Access), We report the case in a 72-year-old man who presented with a right inguinal mass and with a one month history that was initially interpreted as an inguinal hernia. Ultrasonography (US) and computed tomography (CT) demonstrated a right inguinal mass, including myxoid and fat component, extending from the right spermatic cord to the right inguinal subcutaneous layer. Mass excision was performed, and the diagnosis turned out to be angiomyxolipoma. Angiomyxolipoma is a rare tumor and the preoperative diagnosis of this disease is very difficult. However, angiomyxolipoma of the spermatic cord should be considered in the differential diagnosis in patients with an irreducible inguinal mass. Imaging diagnosis, such as US and CT may help to make a preoperative diagnosis.

Item does not contain fulltext, Extraskeletal myxoid chondrosarcoma is a rare malignant soft-tissue tumour that is typically in the deep soft tissues of the lower extremity. The tumour is usually a well-defined, multinodular soft-tissue mass without calcifications. A 62-year-old woman with a history of nasopharyngeal cancer presented with a palpable mass in the anterior neck. Radiologically, the lesion was a well-defined soft-tissue mass with the extensive calcifications on various imaging examinations. Although this lesion was histopathologically diagnosed as extraskeletal myxoid chondrosarcoma, the unusual imaging findings were challenging and very intriguing.

Contains fulltext : 117854.pdf (publisher's version ) (Open Access), OBJECTIVE: To determine whether a routine ultrasonography (US) is necessary for diagnosis of developmental dysplasia of hip (DDH), presenting with congenital muscular torticollis (CMT). METHODS: Cases of 133 patients (81 males, 52 females) diagnosed as CMT were reviewed, retrospectively. We reviewed the medical charts and diagnostic examination. We also assessed the coincidence of CMT and DDH, and investigated the clinical features of CMT related to DDH. RESULTS: Twenty (15.0%) patients out of 133 CMT patients were diagnosed as having DDH by US. Of whom, 8 patients were radiographically positive and 4 patients were both clinically and radiographically positive. Nine patients were treated with a harness and 1 of them needed closed reduction and casting. Out of 9 patients treated with a harness, only 4 were clinically positive. The difference and ratio of the sternocleidomastoid (SCM) muscle thickness between the normal and abnormal side was significantly greater in DDH patients (p=0.014). Further, receiver operating characteristic analysis showed when the SCM ratio is greater than 2.08 and the SCM difference is greater than 6.1 mm, the efficiency of US for the diagnosis of the DDH was found to be the best (p<0.05). CONCLUSION: To evaluate DDH, physical examination showed low sensitivity and radiologic study has limitation for the child before 4 to 6 months of age. Therefore, we recommend that hip is screened by US for the diagnosis of DDH associated with CMT when physical examination is positive or CMT patients with large SCM difference and high SCM ratio.

Contains fulltext : 108382.pdf (publisher's version ) (Open Access), Animals use gustatory information to assess the suitability of potential food sources and make critical decisions on what to consume. For example, the taste of sugar generally signals a potent dietary source of carbohydrates. However, the intensity of the sensory response to a particular sugar, or "sweetness," is not always a faithful reporter of its nutritional value, and recent evidence suggests that animals can sense the caloric content of food independently of taste. Here, we demonstrate that the vinegar fly Drosophila melanogaster uses both taste and calorie sensing to determine feeding choices, and that the relative contribution of each changes over time. Using the capillary feeder assay, we allowed flies to choose between sources of sugars that varied in their ratio of sweetness to caloric value. We found that flies initially consume sugars according to taste. However, over several hours their preference shifts toward the food source with higher caloric content. This behavioral shift occurs more rapidly following food deprivation and is modulated by cAMP and insulin signaling within neurons. Our results are consistent with the existence of a taste-independent calorie sensor in flies, and suggest that calorie-based reward modifies long-term feeding preferences.

Item does not contain fulltext, Nicotine, a major toxic component in tobacco smoke, leads to severe embryonic damage during organogenesis in embryos. We investigated whether resveratrol would positively influence nicotine-induced teratogenesis in mouse embryos (embryonic day 8.5) cultured for 48 h using a whole embryo culture system. Embryos exposed to nicotine (1mM) revealed significantly severe morphological anomalies, increased levels of caspase-3 mRNA and lipid peroxidation, and decreased levels of cytoplasmic superoxide dismutase (SOD), mitochondrial manganese SOD, cytosolic glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, hypoxia-inducible factor 1alpha, Bcl-x(L), and sirtuin1 (SIRT1) mRNAs and SOD activity compared to those in the normal control group. However, when resveratrol (1x10(-8) muM or 1x10(-7) muM) was added concurrently to the embryos exposed to nicotine, all the parameters in above improved conspicuously. These findings indicate that resveratrol has a noted protective effect against nicotine-induced teratogenesis in mouse embryos through its antioxidative and anti-apoptotic effects.

Item does not contain fulltext, Capsaicin and resveratrol as natural products have a variety of beneficial effects. However, capsaicin is also a neurotoxic agent, rendering its effect on the nervous system confusing. The aim of this study was to investigate whether capsaicin and/or resveratrol have a protective effect against glutamate (Glu)-induced neurotoxicity. After exposure to glutamate for 15min, cerebral cortical neurons of ICR mouse fetuses on embryonic days 15-16 were post-treated with capsaicin and/or resveratrol for 24h. Glu induced a significant reduction in cell viability, but the cell viability increased significantly with capsaicin or resveratrol treatment and further was highest in the neurons co-treated with both phytochemicals. Glu-induced reactive oxygen species generation and apoptotic neuronal death also significantly decreased by a combined treatment with both phytochemicals. Due to Glu insults, the reduced mRNA levels of cytoplasmic glutathione peroxidase, copper/zinc and manganese superoxide dismutases, and Bcl-x(L) and the overexpressed mRNA levels of interleukin-1beta and tumor necrosis factor-alpha were significantly restored by post-treatment of capsaicin and/or resveratrol. These findings indicate that capsaicin and resveratrol are neuroprotective against Glu-induced toxicity and that the combined treatment of both phytochemicals can enhance the neuroprotection, suggesting a useful therapeutic application in the treatment of neurodegenerative disorders.

Contains fulltext : 96148.pdf (publisher's version ) (Open Access), A global loss of cytosine methylation in DNA has been implicated in a wide range of diseases. There is growing evidence that modifications in DNA methylation can be brought about by altering the intake of methyl donors such as folate. We examined whether long-term daily supplementation with 0.8 mg of folic acid would increase global DNA methylation compared with placebo in individuals with elevated plasma homocysteine. We also investigated if these effects were modified by MTHFR C677T genotype. Two hundred sixteen participants out of 818 subjects who had participated in a randomized double-blind placebo-controlled trial were selected, pre-stratified on MTHFR C677T genotype and matched on age and smoking status. They were allocated to receive either folic acid (0.8 mg/d; n = 105) or placebo treatment (n = 111) for three years. Peripheral blood leukocyte DNA methylation and serum and erythrocyte folate were assessed. Global DNA methylation was measured using liquid chromatography-tandem mass spectrometry and expressed as a percentage of 5-methylcytosines versus the total number of cytosine. There was no difference in global DNA methylation between those randomized to folic acid and those in the placebo group (difference = 0.008, 95%CI = -0.05,0.07, P = 0.79). There was also no difference between treatment groups when we stratified for MTHFR C677T genotype (CC, n = 76; CT, n = 70; TT, n = 70), baseline erythrocyte folate status or baseline DNA methylation levels. In moderately hyperhomocysteinemic men and women, long-term folic acid supplementation does not increase global DNA methylation in peripheral blood leukocytes.ClinicalTrials.gov NCT00110604.

Contains fulltext : 69076.pdf (publisher's version ) (Closed access), Disturbances in DNA methylation are a characteristic of colorectal carcinogenesis. Folate-mediated one-carbon metabolism is essential for providing one-carbon groups for DNA methylation via DNA methyltransferases (DNMTs). Alcohol, a folate antagonist, could adversely affect one-carbon metabolism. In a case-control study of colorectal polyps, we evaluated three single nucleotide polymorphisms (-149C>T, -283T>C, -579G>T) in the promoter region of the DNMT3b gene, and a functional polymorphism in the coding region of the alcohol dehydrogenase ADH1C gene, ADH1C *2. Cases had a first diagnosis of colorectal adenomatous (n = 530) or hyperplastic (n = 202) polyps at the time of colonoscopy, whereas controls were polyp-free (n = 649). Multivariate logistic regression analysis was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI). There were no significant main associations between the DNMT3b or ADH1C polymorphisms and polyp risk. However, DNMT3b -149TT was associated with an increase in adenoma risk among individuals with low folate and methionine intake (OR, 2.00; 95% CI, 1.06-3.78, P interaction = 0.10). The ADH1C *2/*2 genotype was associated with a possibly elevated risk for adenomatous polyps among individuals who consumed >26 g of alcohol/d (OR, 1.95; 95% CI, 0.60-6.30), whereas individuals who were wild-type for ADH1C were not at increased risk of adenoma (P interaction = 0.01). These gene-diet interactions suggest that polymorphisms relevant to DNA methylation or alcohol metabolism may play a role in colorectal carcinogenesis in conjunction with a high-risk diet.

Contains fulltext : 58061.pdf (publisher's version ) (Closed access), Expression of the urokinase plasminogen activator (uPA) increases during the progression of colorectal tumors from adenomas to carcinomas. The highest amounts of uPA are found at the invasion front of carcinomas, which also displays a strong expression of nuclear beta-catenin and is therefore a region expressing beta-catenin target genes at high levels. Here we show that beta-catenin contributes to the transactivation of uPA. Therefore, beta-catenin might have an impact on the capacity of colorectal tumors for invasion and metastasis, as well as dormancy, which are hallmarks of cancer.