Immunohistochemistry profiles of breast ductal carcinoma: factor analysis of digital image analysis data

<p>Abstract</p> <p>Background</p> <p>Molecular studies of breast cancer revealed biological heterogeneity of the disease and opened new perspectives for personalized therapy. While multiple gene expression-based systems have been developed, current clinical practice is largely based upon conventional clinical and pathologic criteria. This gap may be filled by development of combined multi-IHC indices to characterize biological and clinical behaviour of the tumours. Digital image analysis (DA) with multivariate statistics of the data opens new opportunities in this field.</p> <p>Methods</p> <p>Tissue microarrays of 109 patients with breast ductal carcinoma were stained for a set of 10 IHC markers (ER, PR, HER2, Ki67, AR, BCL2, HIF-1α, SATB1, p53, and p16). Aperio imaging platform with the Genie, Nuclear and Membrane algorithms were used for the DA. Factor analysis of the DA data was performed in the whole group and hormone receptor (HR) positive subgroup of the patients (n = 85).</p> <p>Results</p> <p>Major factor potentially reflecting aggressive disease behaviour (i-Grade) was extracted, characterized by opposite loadings of ER/PR/AR/BCL2 and Ki67/HIF-1α. The i-Grade factor scores revealed bimodal distribution and were strongly associated with higher Nottingham histological grade (G) and more aggressive intrinsic subtypes. In HR-positive tumours, the aggressiveness of the tumour was best defined by positive Ki67 and negative ER loadings. High Ki67/ER factor scores were strongly associated with the higher G and Luminal B types, but also were detected in a set of G1 and Luminal A cases, potentially indicating high risk patients in these categories. Inverse relation between HER2 and PR expression was found in the HR-positive tumours pointing at differential information conveyed by the ER and PR expression. SATB1 along with HIF-1α reflected the second major factor of variation in our patients; in the HR-positive group they were inversely associated with the HR and BCL2 expression and represented the major factor of variation. Finally, we confirmed high expression levels of p16 in Triple-negative tumours.</p> <p>Conclusion</p> <p>Factor analysis of multiple IHC biomarkers measured by automated DA is an efficient exploratory tool clarifying complex interdependencies in the breast ductal carcinoma IHC profiles and informative value of single IHC markers. Integrated IHC indices may provide additional risk stratifications for the currently used grading systems and prove to be useful in clinical outcome studies.</p> <p>Virtual Slides</p> <p>The virtual slide(s) for this article can be found here: <url>http://www.diagnosticpathology.diagnomx.eu/vs/1512077125668949</url></p

The growth and phenology patterns of herb Paris (Paris quadrifolia L., Trilliaceae): relation to soil and air temperatures

The phenology and development of Paris quadrifolia L. has been related to variations in soil and air temperatures during four seasons (1997-2000). Its emergence appeared to be strongly dependant on soil temperature. Plants become visible as soon as the daily mean maximum soil temperature reached ca. 7 C. Variations in soil temperatures could delay Paris emergence by almost one month during the study period. The plants needed on average 18 days to develop from 10% to 95% of maximum height, and flowers were developed after ca. 30 days. The growth and phenology pattern of Paris is therefore not typical of a light-demanding early spring plant. Its need for a relatively long developmental period is compensated for by its ability to survive by vegetative growth during low light periods. The investigation showed that the temperature sum is not a useful tool for predicting phenological events in areas where frozen soil occurs. Two populations separated by ca. 6 m had a two-week difference in emergence due to differences in soil temperature. Sterile plants were generally lower than 14 cm and fertile plants were mostly taller than 20 cm. This pattern appeared to be the same in different geographical areas

Influence of body mass index and duration of disease on chromosome damage in lymphocytes of patients with diabetes

It is well-established that patients with diabetes mellitus (DM) have a higher incidence of several types of cancer. The precise mechanisms of this association are still unknown, but obesity and chronic inflammation-induced reactive oxygen species (ROS) are thought to be the main risk factors. ROS may produce different DNA damage, which could eventually lead to cancer. The main objective of this study was to evaluate the relation of chromosome aberrations (CA) with disease status, demographics, and clinical parameters in 33 subjects with type 1 DM (T1DM), 22 subjects with type 2 DM (T2DM), and 21 controls. CAs were analyzed in cultured peripheral blood lymphocytes and subdivided into chromatid (CTA)- and chromosome (CSA)-type aberrations. Compared with controls, higher levels of CTAs and CSAs were observed in T1DM (p = 0.0053 and p = 0.0203, respectively) and T2DM (p = 0.0133 and p = 0.00002, respectively). While there was no difference in CTAs between T1DM and T2DM, CSAs were higher in T2DM (p = 0.0173). A significant positive association between CTAs and disease duration (rs = 0.2938, p = 0.0099) and between CSAs and disease duration (rs = 0.4306, p = 0.0001), age (rs = 0.3932, p = 0.0004), and body mass index (BMI) (rs = 0.3502, p = 0.0019) was revealed. After multiple regression analysis, duration of disease remained significant for CTA, CSA, and CAs (p = 0.0042, p = 0.00003, and p = 0.00002, respectively). For CSA, BMI and the use of statins were the other important confounding variables (p = 0.0105 and p = 0.0763). Thus, this study demonstrated that both T1DM and T2DM patients had a higher number of all types of aberrations than controls, which increases with the prolonged disease duration. Higher BMI was associated with a higher frequency of CSA. The use of statins might be beneficial for reducing chromosome damage, but further investigations are needed to confirm this association

Analysis of DNA polymorphism in wild populations of herb-Paris (Paris quadrifolia L., Trilliaceae) from Lithuania and Norway.

Analysis of random amplified polymorphic DNA (RAPD) was used to determine genetic diversity within the populations of herb-Paris plant from Lithuania and Norway. RAPD analyses have shown 21.9 ± 5.2% of polymorphic loci in the total sample. Polymorphism level in Norwegian sample was 20.3 ± 5.0%, and in the Lithuanian one was 21.9 ± 5.2%. The proportion of distinguishable RAPD phenotypes in Lithuania was 0.52 ± 0.03 and in Norway 0.24 ± 0.03. For the total sample, Shannon?? Information Index was 0.59 and Nei?? gene diversity 0.41. The estimated total proportion of diversity among populations (GST) and gene flow (Nm) were 0.67 and 0.245, respectively. In Norway GST was 0.64 and Nm was 0.28, whereas in Lithuania GST was 0.42 and Nm was 0.68. The UPGMA analyses have revealed that Lithuanian and Norwegian populations of herb-Paris are clearly separated into two clusters. Analysis of molecular variance (AMOVA) showed that the majority of molecular variation (41%) was due to variation between geographical regions (Lithuania and Norway), 37% of molecular variation was due to variation among individuals within the populations, and only 22% of variation was estimated to be due to variation between populations. In Lithuania, 68% of molecular variation was due to variation within populations, 32% due to variation between populations (ФPT = 0.32), whereas in Norway the proportions were 49% and 51% (ФPT = 0.51), respectively. Thus, the estimated parameters indicated a higher genetic diversity in Lithuanian populations of herb-Paris than in Norwegian ones

Evaluation of the Biological Activity of Naturally Occurring 5,8-Dihydroxycoumarin

molecule

Analysis of AR-FL and AR-V1 in Whole Blood of Patients with Castration Resistant Prostate Cancer as a Tool for Predicting Response to Abiraterone Acetate

PURPOSE: Reliable molecular diagnostic tools are still unavailable for making informed treatment decisions and monitoring the response in patients with castration resistant prostate cancer. We evaluated the significance of whole blood circulating androgen receptor transcripts of full length (AR-FL) and splice variants (AR-V1, AR-V3 and AR-V7) as biomarkers of abiraterone acetate treatment resistance in patients with castration resistant prostate cancer. MATERIALS AND METHODS: After retrospective analysis in 112 prostate specimens AR-FL, AR-V1, AR-V3 and AR-V7 were evaluated in 185 serial blood samples, prospectively collected from 102 patients with castration resistant prostate cancer before and during abiraterone acetate therapy via reverse transcription quantitative polymerase chain reaction. RESULTS: AR-FL was present in all samples while AR-V1, AR-V3, AR-V7 and at least 1 of them was detected in 17%, 55%, 65% and 81% of castration resistant prostate cancer blood samples, respectively. The highest amount of AR-V1 was found in blood of patients whose response time was short and medium in comparison to extended. Patients with a higher level of AR-FL and/or AR-V1 had the shortest progression-free survival and overall survival (p <0.0001). CONCLUSIONS: Blood circulating AR-FL or AR-V1 can serve as blood based biomarkers for identification of the primary resistance to abiraterone acetate and the tool to monitor de novo resistance development during abiraterone acetate treatment