Examining the Relationship between Pre-Malignant Breast Lesions, Carcinogenesis and Tumor Evolution in the Mammary Epithelium Using an Agent-Based Model

Introduction: Breast cancer, the product of numerous rare mutational events that occur over an extended time period, presents numerous challenges to investigators interested in studying the transformation from normal breast epithelium to malignancy using traditional laboratory methods, particularly with respect to characterizing transitional and pre-malignant states. Dynamic computational modeling can provide insight into these pathophysiological dynamics, and as such we use a previously validated agent-based computational model of the mammary epithelium (the DEABM) to investigate the probabilistic mechanisms by which normal populations of ductal cells could transform into states replicating features of both pre-malignant breast lesions and a diverse set of breast cancer subtypes. Methods: The DEABM consists of simulated cellular populations governed by algorithms based on accepted and previously published cellular mechanisms. Cells respond to hormones, undergo mitosis, apoptosis and cellular differentiation. Heritable mutations to 12 genes prominently implicated in breast cancer are acquired via a probabilistic mechanism. 3000 simulations of the 40-year period of menstrual cycling were run in wild-type (WT) and BRCA1-mutated groups. Simulations were analyzed by development of hyperplastic states, incidence of malignancy, hormone receptor and HER-2 status, frequency of mutation to particular genes, and whether mutations were early events in carcinogenesis. Results: Cancer incidence in WT (2.6%) and BRCA1-mutated (45.9%) populations closely matched published epidemiologic rates. Hormone receptor expression profiles in both WT and BRCA groups also closely matched epidemiologic data. Hyperplastic populations carried more mutations than normal populations and mutations were similar to early mutations found in ER+ tumors (telomerase, E-cadherin, TGFB, RUNX3, p Conclusions: The DEABM generates diverse tumors that express tumor markers consistent with epidemiologic data. The DEABM also generates non-invasive, hyperplastic populations, analogous to atypia or ductal carcinoma in situ (DCIS), via mutations to genes known to be present in hyperplastic lesions and as early mutations in breast cancers. The results demonstrate that agent-based models are well-suited to studying tumor evolution through stages of carcinogenesis and have the potential to be used to develop prevention and treatment strategies.</p

Behavior of Reduced Beam Section Moment Connection with Varying Thickness of Continuity Plate

Reduced beam section (RBS) connection is investigated and is widely used in US, Japan and Europe. However, very limited study is conducted with respect to Indian profiles. This study is conducted to give advantageous factors related to RBS connections with continuity plate (CP) and to learn usefulness of those connections for Indian sections. Analytical work of reduced beam section moment connections by providing continuity plates of varying thickness under monotonic drift is presented in this paper. The model is created with finite element method (FEM) and analyzed by ANSYS workbench 16.0 software. Observations were noted for the connections with varying thickness of continuity plates and without continuity plates respectively. Similarity of the results is observed between the, the connections with CP having same thickness of beam flange and with CP having half the thickness of beam flang

COX-2 and PPARγ expression are potential markers of recurrence risk in mammary duct carcinoma in-situ

<p>Abstract</p> <p>Background</p> <p>In women with duct carcinoma in-situ (DCIS) receiving breast conservation therapy (BCT), in-breast recurrences are seen in approximately 10%, but cannot be accurately predicted using clinical and histological criteria. We performed a case-control study to identify protein markers of local recurrence risk in DCIS.</p> <p>Methods</p> <p>Women treated for DCIS with BCT, who later developed in-breast recurrence (cases) were matched by age and year of treatment to women who remained free of recurrence (controls).</p> <p>Results</p> <p>A total of 69 women were included in the study, 31 cases and 38 controls. Immunohistochemical evaluation of DCIS tissue arrays was performed for estrogen receptor, progesterone receptor, HER-2/neu, cyclin D1, p53, p21, cycloxygenase-2 (COX-2) and peroxisome proliferator activated receptor γ (PPARγ). Two markers were significantly different between cases and controls on univariate analysis: strong COX-2 expression was associated with increased risk of recurrence, with 67% vs. 24% positivity in cases and controls p = 0.006; and nuclear expression of PPARγ was associated with protection from recurrence with 4% vs. 27% positivity in cases and controls, p = 0.024. In a multivariate model which included size, grade, COX-2 and PPARγ positivity, we found COX-2 positivity to be a strong independent risk factor for recurrence (OR 7.90, 95% CI 1.72–36.23)., whereas size and grade were of borderline significance. PPARγ expression continued to demonstrate a protective trend, (OR 0.14, 95% CI 0.06–1.84).</p> <p>Conclusion</p> <p>Our findings suggest that COX-2 and PPARγ should be investigated further as biologic markers to predict DCIS recurrence, particularly since they are also potential therapeutic targets.</p

The Case | Ectopic calcifications in a child

The case A nine year old boy, born of third degree consanguinity, presented with a hard left scapular swelling for 6 months. There was no history of fever, trauma or weight loss. There was no pain, redness or discharge. This mass was excised but recurred over the next 6 months (Left panel of Figure 1). A similar swelling had been excised from the left knee one year before presentation, but had recurred over 6 months. Family history was negative for similar lesions. Development was normal for age and he had no other medical problems. On examination, pulse was 84 per minute, blood pressure 96/68 mmHg, weight 22 kg and height 122 cm (both between 10th and 25th percentile). A 6 × 4 cm mass was noted in the right scapular region and a 3 × 3 cm mass at the lateral aspect of the left knee. Both of these masses were firm to hard, globular, nontender, and fixed to the bone. The overlying skin was without erythema or local warmth, though scars from the previous resections were noted. Lymphadenopathy was absent. The rest of the examination was unremarkable. Radiographs of the knee showed a lobular, inhomogenously but densely calcified lesion in the anterolateral region of the left knee (Right panel of Figure 1). Serum calcium was 9.

The expression of TRMT2A, a novel cell cycle regulated protein, identifies a subset of breast cancer patients with HER2 over-expression that are at an increased risk of recurrence

<p>Abstract</p> <p>Background</p> <p>Over-expression of <it>HER2 </it>in a subset of breast cancers (<it>HER2</it>+) is associated with high histological grade and aggressive clinical course. Despite these distinctive features, the differences in response of <it>HER2</it>+ patients to both adjuvant cytotoxic chemotherapy and targeted therapy (e.g. trastuzumab) suggests that unrecognized biologic and clinical diversity is confounding treatment strategies. Furthermore, the small but established risk of cardiac morbidity with trastuzumab therapy compels efforts towards the identification of biomarkers that might help stratify patients.</p> <p>Methods</p> <p>A single institution tissue array cohort assembled at the Clearview Cancer Institute of Huntsville (CCIH) was screened by immunohistochemistry staining using a large number of novel and commercially available antibodies to identify those with a univariate association with clinical outcome in <it>HER2</it>+ patients. Staining with antibody directed at TRMT2A was found to be strongly associated with outcome in <it>HER2</it>+ patients. This association with outcome was tested in two independent validation cohorts; an existing staining dataset derived from tissue assembled at the Cleveland Clinic Foundation (CCF), and in a new retrospective study performed by staining archived paraffin blocks available at the Roswell Park Cancer Institute (RPCI).</p> <p>Results</p> <p>TRMT2A staining showed a strong correlation with likelihood of recurrence at five years in 67 <it>HER2</it>+ patients from the CCIH discovery cohort (HR 7.0; 95% CI 2.4 to 20.1, p < 0.0004). This association with outcome was confirmed using 75 <it>HER2</it>+ patients from the CCF cohort (HR 3.6; 95% CI 1.3 to 10.2, p < 0.02) and 64 patients from the RPCI cohort (HR 3.4; 95% CI 1.3-8.9, p < 0.02). In bivariable analysis the association with outcome was independent of grade, tumor size, nodal status and the administration of conventional adjuvant chemotherapy in the CCIH and RPCI cohorts.</p> <p>Conclusions</p> <p>Studies from three independent single institution cohorts support TRMT2A protein expression as a biomarker of increased risk of recurrence in <it>HER2+ </it>breast cancer patients. These results suggest that TRMT2A expression should be further studied in the clinical trial setting to explore its predictive power for response to adjuvant cytotoxic chemotherapy in combination with <it>HER2 </it>targeted therapy.</p

Dietary Intakes of Total and Specific Lignans Are Associated with Clinical Breast Tumor Characteristics 1-3

. There were significant differences in the contribution to these effects by specific lignans, especially matairesinol and lariciresinol. In summary, in this case-control study of dietary lignan intakes and breast cancer, we found that higher lignan intakes were associated with lower risks of breast cancer with more favorable prognostic characteristics. Future investigations are warranted to explore the strong associations observed with ER 2 cancer in premenopausal women. J. Nutr. 142: 91-98, 2012

Examining the Relationship between Pre-Malignant Breast Lesions, Carcinogenesis and Tumor Evolution in the Mammary Epithelium Using an Agent-Based Model

<div><p>Introduction</p><p>Breast cancer, the product of numerous rare mutational events that occur over an extended time period, presents numerous challenges to investigators interested in studying the transformation from normal breast epithelium to malignancy using traditional laboratory methods, particularly with respect to characterizing transitional and pre-malignant states. Dynamic computational modeling can provide insight into these pathophysiological dynamics, and as such we use a previously validated agent-based computational model of the mammary epithelium (the DEABM) to investigate the probabilistic mechanisms by which normal populations of ductal cells could transform into states replicating features of both pre-malignant breast lesions and a diverse set of breast cancer subtypes.</p><p>Methods</p><p>The DEABM consists of simulated cellular populations governed by algorithms based on accepted and previously published cellular mechanisms. Cells respond to hormones, undergo mitosis, apoptosis and cellular differentiation. Heritable mutations to 12 genes prominently implicated in breast cancer are acquired via a probabilistic mechanism. 3000 simulations of the 40-year period of menstrual cycling were run in wild-type (WT) and BRCA1-mutated groups. Simulations were analyzed by development of hyperplastic states, incidence of malignancy, hormone receptor and HER-2 status, frequency of mutation to particular genes, and whether mutations were early events in carcinogenesis.</p><p>Results</p><p>Cancer incidence in WT (2.6%) and BRCA1-mutated (45.9%) populations closely matched published epidemiologic rates. Hormone receptor expression profiles in both WT and BRCA groups also closely matched epidemiologic data. Hyperplastic populations carried more mutations than normal populations and mutations were similar to early mutations found in ER+ tumors (telomerase, E-cadherin, TGFB, RUNX3, p < .01). ER- tumors carried significantly more mutations and carried more early mutations in BRCA1, c-MYC and genes associated with epithelial-mesenchymal transition.</p><p>Conclusions</p><p>The DEABM generates diverse tumors that express tumor markers consistent with epidemiologic data. The DEABM also generates non-invasive, hyperplastic populations, analogous to atypia or ductal carcinoma <i>in situ</i> (DCIS), via mutations to genes known to be present in hyperplastic lesions and as early mutations in breast cancers. The results demonstrate that agent-based models are well-suited to studying tumor evolution through stages of carcinogenesis and have the potential to be used to develop prevention and treatment strategies.</p></div

Cumulative cancer incidence over time of BRCA-1 mutated simulations in the Duct Epithelium Agent-based Model (DEABM) is compared to the results of five published studies of epidemiologic data.

<p>The cumulative incidence generated by the DEABM over 3,000 simulations was 45.9% by age 54 (95% CI 44.1–47.7%), a figure that fell within the range of published data (18%-58%) and compared favorably to the mean of the five studies (37.2%).</p