Fra-2 Overexpression Upregulates Pro-metastatic Cell-adhesion Molecules, Promotes Pulmonary Metastasis and Reduces Survival in a Spontaneous
The transcription factor Fra-2 affects the invasive potential of breast cancer cells by dysregulating adhesion molecules in vitro. Previous results suggested that it upregulates the expression of E- and P-selectin ligands. Such selectin ligands are important members of the leukocyte adhesion cascade, which govern the adhesion and transmigration of cancer cells into the stroma of the host organ of metastasis. As so far, no in vivo data are available, this study was designed to elucidate the role of Fra-2 expression in a spontaneous breast cancer metastasis xenograft model.
The effect of Fra-2 overexpression in two stable Fra-2 overexpressing clones of the human breast cancer cell line MDA MB231 on survival and metastatic load was studied after subcutaneous injection into scid and E- and P-selectin deficient scid mice.
Fra-2 overexpression lead to a significantly shorter overall survival and a higher amount of spontaneous lung metastases not only in scid mice, but also in E- and P-deficient mice, indicating that it regulates not only selectin ligands, but also selectin-independent adhesion processes.
Thus, Fra-2 expression influences the metastatic potential of breast cancer cells by changing the expression of adhesion molecules, resulting in increased adherence to endothelial cells in a breast cancer xenograft model.
This study is an attempt to obtain reliable data on the natural history of breast cancer growth. The opportunities for using classical mathematical models (exponential and logistic tumor growth models, Gompertz and von Bertalanffy tumor growth models) were analysed in order to describe growth of the primary tumor and the secondary distant metastases of human breast cancer. Our results suggest a new «Consolidated mathematical growth Model of the Primary tumor and the Secondary distant metastases» (CoMPaS). The CoMPaS is based on exponential tumor growth model and consists of a system of determinate nonlinear and linear equations. The CoMPaS describes correctly the primary tumor growth (parameter T) and the secondary distant metastases growth (parameter M). Also, CoMPaS associates with data of 10–15-year survival in patients with the different tumor stage. Analysis of the metastases «nonvisible period» growth indicate the case of discrepancy between 15-year survival depending on tumor stage. In conclusion, the CoMPaS and supporting computer program were build to improve the accuracy of the forecast on survival of breast cancer and facilitate the optimisation of diagnosing secondary distant metastases. This led to completely original results that show how the growth rate of the metastases can change in relation to the growth rate of the primary tumour, taking into consideration its size and diameter of the tumour.
The search for novel parameters to predict the risk of relapse in breast cancer was conducted. Significant correlation between the risk of relapse and α-2A adrenergic receptor (ADRA2A) expression was revealed using public microarray datasets. This relationship was confirmed by validation on independent microarray dataset. It was found that when assessing the risk of BC relapse, the accuracy of prediction based solely on the expression of ADRA2A gene is close to that made using OncotypeDX and MammaPrint test systems. In this case, addition of only one or two supplemental prognostic markers (for instance, expression of SQLE gene or SQLE andDSCC1genes) to ADRA2A ensures the accuracy of prediction not inferior to reliability of these test systems.
Genes with significant differential expression are traditionally used to reveal the genetic background underlying phenotypic differences between cancer cells. We hypothesized that informative marker sets can be obtained by combining genes with a relatively low degree of individual differential expression. We developed a method for construction of highly informative gene combinations aimed at the maximization of the cumulative informative power and identified sets of 2–5 genes efficiently predicting recurrence for ER-positive breast cancer patients. The gene combinations constructed on the basis of microarray data were successfully applied to data acquired by RNA-seq. The developed method provides the basis for the generation of highly efficient prognostic and predictive gene signatures for cancer and other diseases. The identified gene sets can potentially reveal novel essential segments of gene interaction networks and pathways implied in cancer progression.
We propose a new mathematical growth model of primary tumor and primary metastases which may help to improve predicting accuracy of breast cancer process using an original mathematical model referred to CoM-IV and corresponding software. The CoM-IV model and predictive software: a) detect different growth periods of primary tumor and primary metastases; b) make forecast of patient survival; c) have higher average prediction accuracy than the other tools; d) can improve forecasts on survival of BC and facilitate optimisation of diagnostic tests. The CoM-IV enables us, for the first time, to predict the whole natural history of primary tumor and primary metastases growth on each stage (pT1, pT2, pT3, pT4) considering only on primary tumor sizes. Summarising: CoM-IV a) describes correctly primary tumor and primary distant metastases growth of IV (T1-4N0-3M1) stage with (N1-3) or without regional metastases in lymph nodes (N0); b) facilitates the understanding of the appearance period and manifestation of primary metastases.
The Breast is an international, multidisciplinary journal for researchers and clinicians, which focuses on translational and clinical research for the advancement of breast cancer prevention, diagnosis and treatment of all stages. The Editors
welcome the submission of original research articles, systematic reviews, and viewpoint/commentary and debate articles, and correspondence on all areas of pre-malignant and malignant breast disease, including:
• Epidemiology and prevention • Translational research, encompassing the use of new technologies, molecular biology, genetics and pathology • Screening, early diagnosis, follow-up and response assessment: use of imaging, nuclear medicine and other technologies • Medical oncology • Radiation oncology • Breast surgery • Psycho-oncology • Quality of life • Survivorship • Supportive care • Palliative and end-of-life care • Advocacy • Breast Nursing • Breast Units management and organization of breast care, including health economics
PRIMARY THERAPY OF EARLY BREAST CANCER
Evidence, Controversies, Consensus
This paper is devoted to mathematical modelling of the progression and stages of breast cancer. The Consolidated mathematical growth Model of primary tumor (PT) and secondary distant metastases (MTS) in patients with lymph nodes MTS (Stage III) (CoM-III) is proposed as a new research tool. The CoM-III rests on an exponential tumor growth model and consists of a system of determinate nonlinear and linear equations. The CoM-III describes correctly primary tumor growth (parameter T) and distant metastases growth (parameter M, parameter N). The CoM-III model and predictive software: a) detect di erent growth periods of primary tumor and distant metastases in patients with lymph nodes MTS; b) make forecast of the period of the distant metastases appearance in patients with lymph nodes MTS; c) have higher average prediction accuracy than the other tools; d) can improve forecasts on survival of breast cancer and facilitate optimisation of diagnostic tests. The CoM-III enables us, for the rst time, to predict the whole natural history of PT and secondary distant MTS growth of patients with/without lymph nodes MTS on each stage relying only on PT sizes.
An in vitro placental barrier model based on human choriocarcinoma BeWo b30 cell line was considered as a method of preclinical study of the transport and toxicity of antitumor agents and other organic compounds. Low permeabilities were found for 5-fluorouracil as an example of hydrophilic compound and for doxorubicin as an example of a lipophilic compound with a high degree of binding to proteins and DNA and a high permeability was found for cyclophosphamide as an example of lipophilic compound with a low degree of binding to proteins. Using impedance spectrometry and cell viability assessment via reduction of resazurin to resorufin, a pronounced cytotoxic effect of doxorubicin and good tolerance of 5-fluorouracil and cyclophosphamide by the cells were shown for drug concentrations equal to the maximum concentrations in the patients’ blood during the treatment of breast cancer.
This prototype development explains the challenges encountered during the ISO/IEEE 11073 standard implementation process. The complexity of the standard and the consequent heavy requirements, which have not encouraged software engineers to adopt the standard. The developing complexity evaluation drives us to propose two possible implementation strategies that cover almost all possible use cases and eases handling the standard by non-expert users. The first one is focused on medical devices (MD) and proposes a low-memory and low-processor usage technique. It is based on message patterns that allow simple functions to generate ISO/IEEE 11073 messages and to process them easily. MD act as X73 agent. Second one is focused on more powerful device X73 manager, which do not have the MDs' memory and processor usage constraints. The protocol between Agent and Manager is point-to-point and we can distribute the functionality between devices.
Developed both implementation X73 Agent and Manager will cut developing time for applications based on ISO/EEE 11073.
Many environmental stimuli present a quasi-rhythmic structure at different timescales that the brain needs to decompose and integrate. Cortical oscillations have been proposed as instruments of sensory de-multiplexing, i.e., the parallel processing of different frequency streams in sensory signals. Yet their causal role in such a process has never been demonstrated. Here, we used a neural microcircuit model to address whether coupled theta–gamma oscillations, as observed in human auditory cortex, could underpin the multiscale sensory analysis of speech. We show that, in continuous speech, theta oscillations can flexibly track the syllabic rhythm and temporally organize the phoneme-level response of gamma neurons into a code that enables syllable identification. The tracking of slow speech fluctuations by theta oscillations, and its coupling to gamma-spiking activity both appeared as critical features for accurate speech encoding. These results demonstrate that cortical oscillations can be a key instrument of speech de-multiplexing, parsing, and encoding.
In the internal medicine wide spectrum the gastroenterology is one of the chapters, less enlightened by the scientific evidence. It does not mean that the practice of the grasntroenterology may ot be improved by the systematic use of the approaches of the evidence based medicine