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Background:Estrogens play a substantial role in the proliferation, progression and treatment of breast cancer by binding with two estrogen receptors, alpha and beta (ERα and ERβ). Resistance to endocrine therapy is a major problem in the treatment of breast cancers and, in some cases, may be related to loss of ER gene expression. We have already showed that ERα methylation occurs in high frequency and may be one of the important mechanisms for ERα gene silencing in a subset of Iranian primary sporadic breast cancers. In the other hand, the CpG Island methylation status of ERβ and the relationship between clinicopathological features and the pattern of ERβ methylation in sporadic breast cancer are still unknown, especially in Iranian women. Methods: In this study, we examined the exact role of DNA methylation in the estrogen receptors, alpha and beta genes using Combined Bisulfite Restriction enzyme Analysis (COBRA) and Methylation specific polymerase chain reaction (MSP) methods in 34 tissue and 40 peripheral white blood cells in the breast cancers. Results and Conclusions: ERα promoter methylation was identified in 29(72.5%) tissue samples and 35(87.5%) peripheral blood. Among these ERα-methylated cases, the co-occurrentmethylation of ER promoter in peripheral blood and tissue samples was evident in 25 (71.4%) patient (P=0.56). Furthermore, ERβ promoter methylation was detected in 13(32.5%) tissue samples and 4(10.0%) peripheral blood specimens. Of these ERα-methylated cases, the co-ocurrent methylation of ERβ promoter in the peripheral blood and tissue samples was evident in 1(7.7%) patient (P= 0.11). Based on COBRA analysis the percentage of DNA methylation at methylation-sensitive BstUI restriction site of the ERα promoter A ranged from 1% to 91%. The percentages at promoters A region showed a borderline associations with lymph node involvement (P=0.079, r=0.55) and a significant correlation with the grade of tumors (p= 0.27, r=0.65). No significant relation was found between ERα promoter and ERβ promoter methylation (Odds ratio =2.82, 95%, CI =0.28–28.5, P=0.36). The methylation of promoter ON was observed in only a subset of tumors without ER by IHC. In addition, we did not find any significant correlationbetween the prognostic factors such as grade, tumor size, lymph node involvement, and methylation status of this promoter. Our results indicate that methylation of ERβ promoter ON is not responsible for the loss of gene expression in of all breast tumors.

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  Cancer stem cells (CSC) are the tumor-associated cells existed within tumors or hematological cancers which share characteristics similar to normal stem cells. The common characteristics of a normal stem cell and a CSC are their differentiation capacity and self-renewal in tumors. The expression pattern of CSC markers differs depending on the type and location of cancers. CD molecules are probably the most common biomarkers for CSCs. CD molecules such as CD133, CD24, CD44, CD138 and similar CD molecules are well known markers for identification of CSCs. In addition, ATP-Binding Cassette (ABC) transporters such as ABCG2 and ABCB5 as well as EpCAM, ALDH1 and CXCR4 have been used to identify certain CSCs. Therefore these markers may be considered specific for better identification and diagnosis of a specific tumor. Currently studies are in progress to find new cell surface markers which can distinguish specific markers from other markers for isolation and characterization of CSCs. The future of this area of research is promising in developing novel prognostic assays and therapeutic approaches based on cellular and signaling functions of these markers.

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در این مقاله اثر ضد رگ‌ زایی داروی آرتیمیزینین برای مقابله با رشد تومور سرطانی مورد بررسی قرار گرفته است.به این منظور از رویکرد مدلسازی استفاده شده است. ابتدا یکی از مدل‌ های موجود در ادبیات برای انطباق با نتایج تجربی، بهبود داده شده و سپس پارامتر های آن با استفاده از روش بیشترین شیب بر مبنای داده‌ های آزمایشگاهی جمع‌ آوری شده از موش‌ های آزمایشگاهی استخراج شده است. سپس بر مبنای مدل استخراج شده، روش پایداری لیاپانوف برای طراحی برنامه دارو دهی مد نظر قرار گرفته و یک برنامه دارو دهی برای درمان و کنترل رشد تومور سرطانی ارائه گردیده است. با استفاده از شبیه‌ سازی های رایانه ای نشان داده شده است که برنامه دارو دهی ارائه شده مناسب بوده و می‌ تواند منجر به ایجاد بهبود در روند درمان و کنترل رشد تومور سرطانی گردد. در طراحی برنامه دارو دهی مقدار سمیت داروی آرتیمیزینین نیز لحاظ شده است.

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Introduction: Breast cancer is one of the provalent cancers in the world. This cancer as well as other solid tumors, in the course of its development has phases in this order: Epithelial Dysplasia, Carcinoma Insitu, Invassiveness and metastasis. Breast cancer Diagnosis is generally made with pathology methods. In this survey, measuring Angiostatin (which is one of the most important and potent angiogensis inhibitor) in random urine as a noninvassive method was introduced to diagnose the disease. Materials and Methods: In this assay, random urine samples of 15 Breast cancer patient and 15 control urine samples were obtained, and assayed with improved sandwich direct ELISA. Results: Obtained result in statistical T-Test (Pvalue<0.03) showed significant correlation between urine angiostatin and breast cancer, that has coordinace with the result of patients sample pathology. Discussion: Angiostatin dosage in urine of patients of breast cancer is a good marker of non invassive diagnosis.

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Objective: Dendritic cells (DCs) are essential for the activation and polarization of T cells during an adaptive immune response. In this research we investigated the effect of the Lymphoide DCs pulsed with heat-treated tumor lysate (HTL) as a vaccine in tumor immunotherapy. Materials and Methods: The Balb/c mice were injected subcutaneously in the right flank with Wehi-164 fibrosarcoma cells 10 days before immunization with the DCs. Then hsp70 expression in the HTL was detected by using western blot analysis. The mice Lymphoide DCs subset were isolated by magnetic cell sorting (MACS), Then the HTL pulsed Lymphoide DCs, TL pulsed Lymphoide DCs and unpulsed Lymphoide DCs were subcutaneously injected. Tumor growth rate, survival, cytotoxic assay measured. Results: The results showed that HTL-Lymphoide DCs vaccine significantly induced the tumor growth suppression and longer survival than the other immunized mice. Immunotherapy with HTL-Lymphoide DCs led to a significant increase in the activity of cytotoxic T cells in the tumor tissue. Conclusion: The current study suggests that specific anti-tumor immune responses against the fibrosarcoma can be induced by HTL-Lymphoide DCs and may provide a useful therapeutic approach for cancer treatment.

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Objective: The current methods for bladder cancer diagnosis suffer from low sensitivity and specificity. Therefore, finding a novel tumor markers with high specificity and sensitivity is of great interest. MicroRNAs (miRNA, miR) are small endogenously-produced, non-coding RNAs with an important role in regulating gene expression. Recent studies show that miRNAs expression profiles represent significant tumor-specific changes that are unique for most cancers. The aim of this study was to optimize miRNA containing total RNA extraction from urine and use it as a reliable and repeatable technique for miRNA detection in urine of patients with bladder cancer. Materials and Methods: Total RNA was extracted from the urine of patients with bladder cancer and normal individuals using RNX and Trizol solutions with and without modifications of original protocols. Real-time quantitative RT-PCR was then used to detect miRNAs with a potential link to bladder tumorigenesis. Results: RNX and the modified Trizol are practical methods for RNA extraction from urine samples. The mir-21 amplification of the extracted RNAs using modified Trizol method was more efficient than that of RNX method. It is noteworthy that, the levels of miRNAs expression were much higher in the frozen urines compared to the fresh ones. Conclusion: We have succeeded to set-up a protocol to easily amplify miRNAs in urine samples. Based on the data, microRNAs seem to be good biomarkers for early detection and screening of bladder cancer.

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Tumor induced angiogenesis is the bridge between benign and malignant tumor growth stages. In this process, growth and migration of endothelial cells build capillaries to supply the tumor with blood for its further growth. Regarding the importance of capillary formation and blood flow in angiogenesis, simulation of this phenomenon plays important role in tumor growth and cancer development studies. In this work, considering intracellular, cellular, and extracellular scales a mathematical model of tumor-induced angiogenesis is used to consider mechanical effects of extracellular matrix on growth and migration of endothelial cells. These effects are matrix density and its fiber length. In this study, to model cellular dynamics, a discrete lattice based Monte Carlo method is used. Results show that migration of endothelial cells and development of capillaries are possible in a specified range of matrix density and matrix fiber length. Based on the results, medium matrix densities and low fiber length provide a suitable environment for capillaries growth and development. The model is a promising tool for modeling tumor induced angiogenesis and is a base for development of models for loop formation and blood flow in capillaries around tumor.

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Nowadays, solid tumor modeling and simulation results are used to predict how therapeutic drugs are transported to tumor cells by blood flow through capillaries and fluid flow in tissues. This model involves processes such as fluid diffusion, convective transport in extracellular matrix, and extravasation from blood vessels. In this paper, a complete model of interstitial fluid flow in tumor and normal tissue is presented with considering multi scale of solution such as blood flow through a capillary (as the smallest scale) to interstitial flow (as the biggest scale). The advanced mathematical model is used to generate a capillary network induce by tumor with two parent vessel around the tumor for the first time. In the following, the blood flow is modeled through the network with considering the non-continuous behavior of blood rheology and adaptability of capillary diameter to hemodynamics and metabolic stimuli. This flow is simultaneously simulated with interstitial flow which is coupled to blood flow through capillary with extravascular flow. The results predict elevated interstitial pressure in tumor region and heterogeneous capillary network which are introduced as barriers to drug delivery.

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Although chemotherapy is one of the effective methods in cancer treatment its effects may be moderated due to drug resistance. The main objective of this paper is to propose optimal finite cancer treatment duration. In this paper, a mathematical model of tumor growth by adding radiotherapy, chemotherapy and metastasis of cancer cells terms is extended. Stability analysis shows that the tumor free equilibrium point is unstable. Hence, changing the dynamics of the system around this equilibrium point for achieving finite duration treatment method is essential. Therefore, the effects of chemotherapy drug are considered not only on cells populations but also on the dynamics of the system. For this purposes, State Dependent Riccati Equation (SDRE) based optimal control is used. So chemotherapy agent is used as the control input to the extended cancer nonlinear model. Then, in order to show the flexibility in design, two different types of input weighting matrices are selected. Moreover, the robustness of this control method is investigated by simulation. Results show that changing the dynamics of the system is necessary for finite duration cancer treatment method.

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Soft tissue abnormalities are often correlated with a change in the mechanical properties of the soft tissue. New developing non-invasive techniques with the ability of early detection of cancerous tissue with high accuracy is a challenging state of art. In this paper, a new method is proposed to investigate the liver tissue cancers. Hyperelastic behavior of a porcine liver tissue has been extracted from the in vitro stress-strain experimental tests of the tissue. Hyperelastic coefficients have been used as the input of the Abaqus FEM software and the palpation of a physician has been simulated. The soft tissue contains a tumor with specified mechanical and geometrical properties. Artificial tactile sensing capability in tumor detection and localization has been investigated thoroughly. In mass localization we have focused on deeply located tumor which is a challenging area in the medical diagnosis. Moreover, tumor type differentiation which is commonly achieved through pathological investigations is studied by changing the stiffness ratio of the tumor and the tissue. Results show that the new proposed method has a high ability in mass detection, localization and type differentiation.

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Cancer is a disease that begins with abnormal proliferation of cells. Genes inside each cell has issued the necessary orders to the cell. Sometimes these commands in a cell are undefined and cell has abnormal behavior and after a while some of abnormal cells can circulate in blood or change into tumors. In A numerical study was carried out on the heating effect of magnetic nanoparticles used in hyperthermia with the goal of attaining a desired rise of temperature at a particular point of location of the tumor situated inside the muscle. A numerical scheme is proposed to solve the bioheat transfer problem in a two zone tissue in spherical geometry with blood perfusion and metabolism. The analytical solution evidences the accuracy of the numerical scheme and examines the results in the literature. Bio-heat equation is used to predict the temperature rise in term of characteristics of the magnetic nanoparticles, applied magnetic field and the tissue. Results show that the strength of applied AC magnetic field has the minor effect, the volume fraction and the frequency of applied AC magnetic field has moderate effect and the diameter of nanoparticles has the major effect on the temperature rise. among materials investigated in this study, FePt has the most pronounced effect. Also, the temperature rise for a position- independent perfusion rate is larger than that found for a position-dependent perfusion rate. Likewise, the temperature rise for a temperature-dependent metabolism rate is larger than that found for a temperature-independent metabolism rate.

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Soft tissue’s cancers are related to major variations in the mechanical properties of the tissue. In recent years, a number of developing techniques have been introduced for early detection of soft tissue’s cancers. The major advantage of these methods over the common available techniques is while being noninvasive to the body, the accuracy of detection is noticeably increased. This article intends to analyze mechanical behavior of the breast tissue by considering a Mooney-Rivlin hyperelastic model. Coefficients of the model are defined by using a series of experimental mechanical datasets. For this purpose, a mechanical device is designed and fabricated base on a new noninvasive method named Artificial Tactile Sensing (ATS). The device is examined on 8 patients in 20 to 50 age range refer to “Jahad Daneshgahi Breast Diseases Clinic” while considering Helsinki agreement’s protocols. Due to wide anatomical variations of the breast tissue in individuals, 40 specified regions are examined on the tissues of all attended cases. Experimental stress versus strain datasets are collected for 40 test points. To achieve a reliable and optimized model, a genetic algorithm (GA) is used for calculating Mooney-Rivlin’s coefficients. Results confirmed that an accurate model can be afforded to estimate the soft tissue’s mechanical behavior with the least error. The model is suitable for disease diagnosis and follow-up procedure.

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Objective: It is hypothesized that stem cells have the capability to form tumors after transplantation. Spermatogonial stem cells have proliferation potency and colonization ability related to express pluripotency genes such as c-Myc. The primary aim of this study is to investigate tumorigenicity ability of these cells after in vitro cultivation and inoculation in athymic animals. Methods: Spermatogonial stem cells from 3-5 day-old neonatal mice testes (NMRI) were cultured following two-step enzymatic digestion. After one month of culturing the spermatogonial stem cells, the obtained colonies were identified by Oct4 and PLZF markers. Expressions of Nanog, Oct4 and c-Myc pluripotency genes were subsequently studied. We subcutaneously inoculated 5 x 10⁶ cells into athymic mice and assessed tumor formation after 8 weeks. Mouse embryonic stem cells (CCE line) were used as the positive control. Generated tumors were measured by a caliper. Results: The colonies expressed Oct4 and PLZF proteins. Ratio of pluripotency gene expressions in these cells compared to embryonic stem cells significantly decreased (P≤0.05). Mouse embryonic stem cells formed tumors however the spermatogonial colonies did not form any tumors. Conclusion: Mouse spermatogonial stem cells in comparison with embryonic stem cells are not capable of forming tumors in vivo. We have observed that the tumorigenic ability of these cells decreased significantly with down regulation of pluripotency gene expressions, particularly c-Myc. However, this study should be reassessed by using human tissue samples.

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Objective: Recent evidences suggest that tumors arise from a small subpopulation of cells, the cancer stem cells (CSCs) or tumor initiating cells. CSCs are able to resist the conventional methods of cancer therapy due to existence of ABC transporters on their surface. This leads to CSC resistance and maintenance resulting in post-treatment relapse and metastasis. Therefore, precise identification and characterization of these cells as a target for new therapeutic regimens is the goal of numerous studies. This study, with the intent to design a new method of immunotherapy for targeting cancer stem cells in mouse malignant melanoma, initially characterized the cancer stem cells in this malignancy. Methods: In order to identify the CSCs we induced a melanoma tumor using the B16F10 cell line in C57BL/6 mice. The tumor bulk was dissociated by an enzymatic method and homogeneous tumor cells were sorted using anti-CD44 and anti-CD24 antibodies. The sorted tumor cell subpopulations were compared according to their ability to form cell spheres in serum free medium (SFM). We determined the tumor formation ability of all cell subpopulations by transplanting serial dilutions of B16-F10 and all sorted cells sub-populations into C57/BL6 mice. Results: The results showed that although all separated cell subpopulations and B16-F10 cells formed non-adherent spheroids in SFM in the presence of B-27, but the CD24⁺ cells presents a significantly higher ability to produce spheroids. The B16F10 cell line, CD44⁺CD24^- and CD44^-CD24^- cells showed equal potencies in tumor induction (1 in 21730 cells). The CD44^-CD24⁺ cells tumor induction potency was 1 in 17426 and this ability for the double positive cells (CD44⁺CD24⁺) was 1 in 11295. Conclusion: Collectively,the double positive (CD24⁺CD44⁺) cells were more potent in both spheroid formation and tumorogenicity. Hence they might be the CSC population of mouse melanoma.

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Mathematical modeling of tumor growth as modeling of other biological tissues is important since these models enable us to predict and evaluate the parameters that could not be measured easily. The accuracy of a derived model depends upon considering more involved factors and mechanisms and will lead us toward a realistic modelling.
In this study, a finite element model of avascular tumor growth is represented. This model concentrates on the constitutive behavior of tissues and the resulting stresses. The tumor and its host are assumed to behave as a hyperelastic material. The tumor model is supplied with a growth term which is a function of nutrient concentration, solid content of the tumor and rate of cell proliferation and death. The evolved stresses during growth and interactions between tumor and the surrounding host could be evaluated using the presented model. The results show that the exerted stresses on tumor increase as time passes which lead to reduction of tumor growth rate until it gradually reaches an asymptotic radius. The effects of variation of the bulk modulus which is a determinant of compressibility are investigated. Since biological tissues consist mainly of water so we should impose the condition of incompressibility. It is found that the increase of bulk modulus which leads to more incompressibility causes stress elevation.

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In this paper, the diffusion coefficient in a normal tissue and tumor are to be estimated by the method of inverse problems. At the beginning, distribution of drug (with the assumption of uniform and isentropic diffusion coefficient) in the tissue is considered as the direct problem. In the direct problem, the governing equation is the convection–diffusion, which is the generalized form of fick’s law. Here, a source and a sink are defined; the source as the rate of solute transport per unit volume from blood vessels into the interstitial space and the sink as the rate of solute transport per unit volume from the interstitial space into lymph vessels are added to this equation. To solve the direct problem, the finite difference method has been considered. Additionally, the diffusion coefficient of a normal tissue and tumor will be approximated by parameter estimation method of Levenberg-Marquardt. This method is based on minimizing the sum of squared errors which in the present study, considered error is the difference of the estimated concentration and the concentration measured by medical images (simulated numerically). Finally, the results obtained by Levenberg-Marquardt method have provided an acceptable estimation of diffusion coefficient in normal tissue and tumor.

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Today by usage of the simulation of normal tissue and the process of material diffusion in body, the place of tumor can be predicted. By considering the tumor tissue, its growth can be evaluated. The fluid flow in the capillary, its effects on the adjacent tissue and the diffusion of molecules from capillary wall are considered in these kinds of simulation. Cancer cells due to the high rate of dividing cells, have a low level of oxygen. This lack of oxygen is called Hypoxia, so by using of different invasive and noninvasive manners, the amount of oxygen is measured in the body. The PET device indicates the oxygen distribution by use of special tracers in the several parts of body. In this essay by considering a real capillary network, the blood flow had been simulated, then by taking to the account of its effects on the tissue, oxygen pressure and the concentration of tracer had been simulated at the same time. At the end, the concentration of free and bind tracer is shown and its changes by the time is analyzed.

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Cancer is one of the main causes of mortality and morbidity worldwide. Using a single treatment plan for all of the patients is not efficient due to the biological heterogeneity in the individuals. In order to personalize the therapy plan, tumors behavior in each patient must be understood. For this purpose clinical information of the patients are used. Mathematical modeling has gained significant interest in tumor growth investigations, due to its higher flexibility than the other methods. Mass effect and the reaction terms are the key parameters that are investigated in this paper. This is the first time that the effects of these parameters are considered in brain tumor growth modeling and there are few researches that have used only MR images in this area. The mathematical models are used for predicting the growth of brain tumors based on personal MRIs and introducing intracellular fraction into the model. Results of the comparisons show that considering the mass effect in the growth model would improve the prediction. Furthermore, it is necessary to define the optimum formulation for reaction term according to patients' medical information, to be used in the personalized model of tumor growth prediction. The represented approach can be used as a basis for personalizing the therapy plan in patients with brain tumors.

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In a computational modeling of drug delivery and PET tracers to cancer tissues, the most difficult part is a consideration of a complexity of capillaries network. Because of the key role of blood flow in tumor feeding and growth that also carrying radiotracer into both normal and cancerous tissues, there are various studies have been done on the formation of new blood vessels and blood flow around a tumor. In this work, we used an image of a complex capillaries network to simulate FGD tracer distribution within both normal and cancerous tissues. Firstly, one RGB image was imported as an input image which consisted of the capillaries network and has been processed and made ready for creating 2D geometry from it. The creation of 2D geometry from the input image is consisted two areas: Pre-processing and Post-Processing the input image for preparation of it for the creation geometry by capturing the capillaries from a background of whole of the picture. In the next stage, with a usage of the achieved geometry and by coupling blood flow and interstitial flow, pressure and velocity distribution in the capillaries and both tumor and normal tissues were accomplished. Finally, by applying CDR (Convection-Diffusion-Reaction) equations for FDG tracer, distribution of it was acquired within the whole normal and cancerous domain. Observing FDG tracer CDR modeling helped us find tracer distribution with both time and space.