A new exploration on the creation of grafted breast cancer model for MA891 cells in TA2 mice

Animal experimental systems are particularly useful for the study of human breast cancer. An ideal model shoulcl be easy to use, closely mimicking human physiopathology and has a stable tumor morbidity. The cell line MA891 was established from a spontaneous TA2 mouse mammary carcinoma by Cancer Institute of Chinese Academy of Medical Sciences. 3 Some researches indicated that MA891 had a very low immunogenecity and maintained a high metastatic potential in vivo. So it has been used as a better grafted mouse tumor model for studying cancer physiopathology and metastasis in human for years. However, about the biological characteristic and the histopathologic feature of this model there has been a lack of investigations.

Inhibition of growth and metastasis of triple-negative breast cancer targeted by Traditional Chinese Medicine Tubeimu in orthotopic mice models

Objective： Triple-negative breast cancer（TNBC） is highly invasive and metastatic, which is in urgent need of transformative therapeutics. Tubeimu（TBM）, the rhizome of Bolbostemma paniculatum（Maxim.） Franquet, is one of the Chinese medicinal herbs used for breast diseases since the ancient times. The present study evaluated the efficacy, especially the anti-metastatic effects of the dichloromethane extract of Tubeimu（ETBM） on TNBC orthotopic mouse models and cell lines.Methods： We applied real-time imaging on florescent orthotopic TNBC mice model and tested cell migration and invasion abilities with MDA-MB-231 cell line. Digital gene expression sequencing was performed and Kyoto Encyclopedia of Genes and Genomes（KEGG） analysis applied to explore the pathways influenced by ETBM.Moreover, quantitative real-time polymerase chain reactions（q RT-PCR） and Western blot were delivered to confirm the gene expression changes.Results： ETBM exhibited noticeable control on tumor metastasis and growth of TNBC tumors with no obvious toxicity. In compliance with this, it also showed inhibition of cell migration and invasion in vitro. Its impact on the changed biological behavior in TNBC may be a result of decreased expression of integrin β1（ITGβ1）, integrin β8（ITGβ8） and Rho GTPase activating protein 5（ARHGAP5）, which disabled the focal adhesion pathway and caused change in cell morphology.Conclusions： This study reveals that ETBM has anti-metastatic effects on MDA-MB-231-GFP tumor and may lead to a new therapeutic agent for the integrative treatment of highly invasive TNBC.

Progress in research on the application of nursing models for breast cancer patients during the perioperative period

Nursing models at home and abroad for breast cancer patients during the perioperative period were screened, including eight types of models： the nursing model guided by self-care theory, the plan-do-check-act cycle combined with the four-in-one model, the peer support nursing model, the nursing model guided by transcultural theory, the multidisciplinary cooperative nursing model, the knowledge-attitude-practice nursing model, the safe nursing management model, and the case nursing model. These models were analyzed and described with the aim of providing a reference for the clinical breast surgery nursing staff in China and for promoting the development of nursing in China for breast cancer the perioperative period.

A Statistical Model with Non-Linear Effects and Non-Proportional Hazards for Breast Cancer Survival Analysis

The Cox proportional hazard model is being used extensively in oncology in studying the relationship between survival times and prognostic factors. The main question that needs to be addressed with respect to the applicability of the Cox PH model is whether the proportional hazard assumption is met. Failure to justify the subject assumption will lead to misleading results. In addition, identifying the correct functional form of the continuous covariates is an important aspect in the development of a Cox proportional hazard model. The purpose of this study is to develop an extended Cox regression model for breast cancer survival data which takes non-proportional hazards and non-linear effects that exist in prognostic factors into consideration. Non-proportional hazards and non-linear effects are detected using methods based on residuals. An extended Cox model with non-linear effects and time-varying effects is proposed to adjust the Cox proportional hazard model. Age and tumor size were found to have nonlinear effects. Progesterone receptor assay status and age violated the proportional hazard assumption in the Cox model. Quadratic effect of age and progesterone receptor assay status had hazard ratio that changes with time. We have introduced a statistical model to overcome the presence of the proportional hazard assumption violation for the Cox proportional hazard model for breast cancer data. The proposed extended model considers the time varying nature of the hazard ratio and non-linear effects of the covariates. Our improved Cox model gives a better insight on the hazard rates associated with the breast cancer risk factors.

Clinical Study on the Impact of Long-term Survival Quality in 204 Postoperative Patients with Breast Cancer by Cox Proportional Hazard Models

The aim of study was to evaluate clinical characteristics, social support and the association with the prognosis of breast cancer patients. A total of 204 participants were followed from 2003 until the end of 2008. Information about patients with breast cancer was submitted by investigators. Data were analyzed by Cox’s proportional hazard model. The clinical staging of breast cancer we used was the TNM classification. A 'T' score is based upon the size and/or extent of invasion. The 'N' score indicates the extent of lymph node involvement. Age at diagnose was associated with protective factors (HR=0.972;95%CI (0.834-1.130)), T staging (HR=2.075;95%CI (1.424-3.022)), N staging (HR=1.513;95%CI (1.066-2.148)), were associated with risk factor. Two survival graphs of nodes with negative effects by histology and nodes with positive effects by histology was analyzed by log-rank test, there was statistically significant relationship between two survival graphs (χ2 =136.8467, p <.0001). Age at diagnoses, Clinical stage tumor and node could contribute to the development of breast cancer and disease free survival in Chinese women.

Statistical models for predicting number of involved nodes in breast cancer patients

Clinicians need to predict the number of involved nodes in breast cancer patients in order to ascertain severity, prognosis, and design subsequent treatment. The distribution of involved nodes often displays over-dispersion—a larger variability than expected. Until now, the negative binomial model has been used to describe this distribution assuming that over-dispersion is only due to unobserved heterogeneity. The distribution of involved nodes contains a large proportion of excess zeros (negative nodes), which can lead to over-dispersion. In this situation, alternative models may better account for over-dispersion due to excess zeros. This study examines data from 1152 patients who underwent axillary dissections in a tertiary hospital in India during January 1993-January 2005. We fit and compare various count models to test model abilities to predict the number of involved nodes. We also argue for using zero inflated models in such populations where all the excess zeros come from those who have at some risk of the outcome of interest. The negative binomial regression model fits the data better than the Poisson, zero hurdle/inflated Poisson regression models. However, zero hurdle/inflated negative binomial regression models predicted the number of involved nodes much more accurately than the negative binomial model. This suggests that the number of involved nodes displays excess variability not only due to unobserved heterogeneity but also due to excess negative nodes in the data set. In this analysis, only skin changes and primary site were associated with negative nodes whereas parity, skin changes, primary site and size of tumor were associated with a greater number of involved nodes. In case of near equal performances, the zero inflated negative binomial model should be preferred over the hurdle model in describing the nodal frequency because it provides an estimate of negative nodes that are at “high-risk” of nodal involvement.

A progressive processing method for breast cancer detection via UWB based on an MRI-derived model

Ultra-wideband （UWB） microwave imaging is a promising method for breast cancer detection based on the large contrast of electric parameters between the malignant tumor and its surrounded normal breast organisms. In the case of multiple tumors being present, the conventional imaging approaches may be ineffective to detect all the tumors clearly. In this paper, a progressive processing method is proposed for detecting more than one tumor. The method is divided into three stages： primary detection, refocusing and image optimization. To test the feasibility of the approach, a numerical breast model is developed based on the realistic magnetic resonance image （MRI）. Two tumors are assumed embedded in different positions. Successful detection of a 3.6 mm-diameter tumor at a depth of 42 mm is achieved. The correct information of both tumors is shown in the reconstructed image, suggesting that the progressive processing method is promising for multi-tumor detection.

Tumor-Immune Interaction System with the Effect of Time Delay and Hyperglycemia on the Breast Cancer Cells

Breast cancer in women is a complicated and multifaceted disease. Studies have demonstrated that hyperglycemia is one of the most significant risk factors for breast cancer. Hyperglycemia is when the sugar level in human blood is too high, which means excess glucose. Glucose excess can encourage the growth, invasion, and migration of breast cancer cells at the cellular level. Though, the effects of glucose on the dynamics of breast cancer cells have been examined mathematically by a system of ordinary differential equations. However, the non-instantaneous biological occurrences leading to the secretion of immuno-suppressive cytokines by tumors to evade immune surveillance and the immune cells’ derivation of cytokines to attack the tumor cells are not yet discussed. Therefore, investigating the biological process involved in the dynamics of tumors, immune and normal cells with excessive glucose concentration is inviolable to determining the best procedure for controlling tumors’ uncontrollable growth. Time delay, denoted by τ, is used to describe the time tumor cells take to secrete immunosuppressive cytokines to evade immune surveillance and the time immune cells take to recognize and attack the tumor cells. We have studied the local stability analysis of the biological steady states in both delayed and non-delayed system. The Routh-Hurwitz stability criterion is used to analyze the dynamical equilibrium of the cells’ population. Hopf bifurcation was analyzed by using time delay s as a bifurcation parameter. The analytical results suggest an unstable scenario for a tumor-free equilibrium point as normal cells are bound to grow to their carrying capacity. The result predicts a stable system for coexisting equilibrium when the interaction is instantaneous (τ = 0). However, when τ > 0, the coexisting equilibrium point switches from stable to unstable. The numerical results not only validate all the analytical results but also show the case of possible situations when glucose concentration is varied, indicating that both tumor growth and immune system efficiency are highly affected by the level of glucose in the blood. This concluded that the delay in the secretion of cytokines by immune cells and derivation cytokines by the tumors helps to identify the possible chaotic situation under different glucose concentration and the extent to which such delay can have on restoration of the normal cells when glucose concentration is low.

Combination Therapy of Capecitabine with Cyclophosphamide as a Second-Line Treatment after Failure of Paclitaxel plus Bevacizumab Treatment in a Human Triple Negative Breast Cancer Xenograft Model

We examined the antitumor efficacy of the capecitabine (CAPE) plus cyclophosphamide (CPA) combination as a 2nd-line therapy after paclitaxel (PTX) plus bevacizumab (BEV) treatment in a xenograft model of human triple negative breast cancer (TNBC) cell line, MX-1. After tumor growth was confirmed, PTX (20 mg/kg;i.v.) + BEV (5 mg/kg;i.p.) treatment was started (Day 1). Each agent was administered once a week for 5 weeks and tumor regression was observed for at least the first 3 weeks. For 2nd-line treatment, we selected mice in which the tumor volume had increased from day 29 to day 36 and was within 130 - 250 mm3 on day 36. After randomization of mice selected on day 36, CPA (10 mg/kg;p.o.) and CAPE (539 mg/kg;p.o.) were administered daily for 14 days (days 36 - 49), followed by cessation of the drugs for 1 week. The tumor growth on day 57 was significantly suppressed in the CPA, CAPE and CAPE + CPA groups as compared with the control group (p < 0.05). Furthermore, the antitumor activity on day 57 of CAPE + CPA was significantly stronger than that of CPA or CAPE alone (p < 0.05). The thymidine phosphorylase (TP) level in tumor tissue was evaluated by immunohistochemistry on day 50, and was significantly higher in the CPA group than those in the control group (p < 0.05). Upregulation of TP in tumor tissues by CPA treatment would increase the 5-FU level in tumor tissues treated with CAPE. This would explain the possible mechanism that made CAPE + CPA superior to CAPE alone in the 2nd-line treatment. Our preclinical results suggest that the CAPE + CPA combination therapy may be effective as 2nd-line therapy after disease progression in PTX + BEV 1st-line treatment for TNBC patients.

Computational and Structural Investigation of Deleterious Functional SNPs in Breast Cancer BRCA2 Gene

In this work, we have analyzed the genetic variation that can alter the expression and the function in BRCA2 gene using computational methods. Out of the total 534 SNPs, 101 were found to be non synonymous (nsSNPs). Among the 7 SNPs in the untranslated region, 3 SNPs were found in 5′ and 4 SNPs were found in 3′ un-translated regions (UTR). Of the nsSNPs 20.7% were found to be damaging by both SIFT and PolyPhen server among the 101 nsSNPs investigated. UTR resource tool suggested that 2 SNPs in the 5′ UTR region and 4 SNPs in the 3′ UTR regions might change the protein expression levels. The mutation from asparagine to isoleucine at the position 3124 of the native protein of BRCA2 gene was most deleterious by both SIFT and PolyPhen servers. A structural analysis of this mutated protein and the native protein was made which had an RMSD value of 0.301 nm. Based on this work, we proposed that this most deleterious nsSNP with an SNPid rs28897759 is an important candidate for the cause of breast cancer by BRCA2 gene.

Large Scale Analysis of Complex Permittivity of Breast Cancer in Microwave Band

To obtain some prior knowledge of breast cancer detection by microwave imaging, we have measured and analyzed the complex permittivity of tissues extracted from over 140 breast cancer surgeries. The relative permittivity and conductivity of tumor at 1.6 GHz were 17.5% and 16.2% higher than those of mammary gland tissue, respectively. In invasive ductal carcinoma of scirrhous type, 8 out of 64 had higher relative permittivity and conductivity of mammary gland than those of tumor. However, when evaluated by the Debye parameter considering the frequency dependence of the tissue, it is rare that ε∞ and Δε of cancer are simultaneously lower than those of mammary gland. The relative permittivity and conductivity of fibroadenoma are almost the same as those of mammary glands. The relative permittivity and conductivity of each tissue showed strong linearity. Microwave imaging requires accurate reconstruction of ε∞ and Δε to distinguish cancer from normal tissue.

<i>In-Silico</i>Identification of Anticancer Compounds;Ligand-Based Pharmacophore Approach against EGFR Involved in Breast Cancer

Objective: Breast cancer is a public health challenge on a global scale that is caused by environmental or genetic factors. Breast cancer is affecting both males and females, but there is still a lack of effective drugs with improved potency and admissibility against breast cancer as many of the breast cancer drugs have severe side effects. Methods: The docking approach has been used to find a new compound for breast cancer with more efficacy and tolerance and with lesser side effects. A ligand-based pharmacophore approach has been generated for 39 anticancer compounds with significance for the development of new drugs. Result: Through docking, the approach found new lead compounds for breast cancer. The proposed pharmacophore model in this study contains two HBAs and one HYD, one hydrophobic domain and two Aromatic rings and the estimated distance range is minimum to maximum of derived pharmacophore features. Conclusion: Based on this research, it is proposed that these two lead compounds may be able to be used against EGFR in breast cancer. New compounds can be identified based on common features in the Pharmacophore model. 3D pharmacophore triangle could be used for further studies because this pharmacophore has better merging and in the future for more studies can suggest the same distance range of pharmacophore features as this pharmacophore.

Role of ESR Pathway Genes in Breast Cancer: A Review

Breast cancer is the leading cause of death in women. Prognosis of breast cancer is often pessimistic because the tumors are prone to metastasizing to the bone, brain, and lung. The estrogen signaling receptor (ESR) pathway contains 39 main genes and proteins which makes it one of the larger signaling pathways. Predominately this pathway and the proteins within are involved in breast growth and development, making it a prospective area of study for breast cancer. While the healthy ESR pathway has been constructed and is well established, a mechanistic model of mutated genes of ESR pathway has not been delved upon. Such mutated models could be utilized for selecting combinational targets for drug therapies, as well as elucidating crosstalk between other pathways and feedback mechanisms. To construct the mutated models of the ESR pathway it is imperative to assess what is currently understood in the literature and what inconsistencies exist in order to resolve them. Without this information, a model of the ESR pathway will be unreliable and likely unproductive. This review is the detailed literature survey of the biological studies performed on ESR pathways genes, and their respective roles in breast cancer. Furthermore, the details mentioned in the review can be beneficial for the integrated study of the ESR pathway genes, which includes, structural and dynamics study of the genes products, to have a holistic understanding of the cancer mechanism.

基于对比增强CT的影像组学模型可预测乳腺癌患者的肿瘤浸润淋巴细胞水平

目的:基于对比增强CT开发用于预测乳腺癌(BC)患者肿瘤浸润淋巴细胞(TIL)水平的新型影像组学模型。方法:回顾性纳入210名非特殊浸润性BC患者(训练集:147名,验证集:63名),使用Pyradiomics软件包提取患者对比增强CT图像中的高维影像组学特征,然后利用Mann-Whitney U检验、斯皮尔曼相关系数和最小绝对值收敛和选择算子(LASSO)算法进行特征逐步筛选。筛选后的最优特征通过非线性支持向量机(NLSVM)方法在训练集中开发了影像组学模型,并在验证集中对模型的判别能力进行验证。之后利用沙普利加和解释(SHAP)算法对模型进行全局解释与特征重要性排序。结果:模型训练组和验证组的曲线下面积(AUC)分别为0.824(95%CI:0.762~0.886)和0.766(95%CI:0.624~0.909),影像组学模型有3个正向影响特征与4个负向影响特征,其中log-sigma-5-0-mm-3D_firstorder_Maximum对模型的影响力最大,其值越大时,模型输出SHAP值越小。结论:基于对比增强CT的影像组学模型可以帮助临床医生在治疗前准确预测BC患者的肿瘤浸润淋巴细胞水平,促进BC患者的个性化治疗。

基于美学需求的个案护理模式对乳腺癌保乳切除术后患者心理状态和瘢痕的影响

目的:探究基于美学需求的个案护理模式对乳腺癌保乳切除术后患者心理状态和瘢痕的影响。方法:选择2019年2月-2022年2月笔者医院行乳腺癌保乳切除术的106例患者,按随机数表法分为观察组(n=53)和对照组(n=53)。对照组采用常规护理模式,观察组采用基于美学需求的个案护理模式。比较两组护理干预前后心理状态[焦虑自评量表(Selfrating anxiety scale,SAS)、抑郁自评量表(Self-rating depression scale,SDS)、自尊量表(Rosenberg senesteem scale,RSES)]、生活质量[乳腺癌生存质量测评量表(Functional assessment of cancer therapy-breast,FACT-B)]、瘢痕[温哥华瘢痕量表(Vancouver scar scale,VSS)]及并发症发生情况。结果:干预后,两组的SAS、SDS均低于干预前,且观察组均低于对照组(P<0.05),而两组RSES评分高于干预前,且观察组高于对照组(P<0.05);术后1、3、6个月,观察组的VSS评分均低于对照组(P<0.05);干预后,两组的FACT-B各项评分均高于干预前,且观察组的生理状况、社会/家庭状况、情感状况、功能状况、附加关注状况均高于对照组(P<0.05);观察组并发症发生率为22.64%,显著低于对照组的43.40%(P<0.05)。结论:基于美学需求的个案护理模式能够改善乳腺癌保乳切除患者术后心理状态,减轻术后瘢痕,并能提高患者的生活质量。

Competing Risks Analysis of African American Breast Cancer Patients

Purpose: Recent studies showed that African Americans (AA) breast cancer patients experience lower survival than any other race. The knowledge of cause-specific survival of such patients is necessary to investigate the different factors associated with the disease and support the clinical practice. Methods: The parametric competing risk method is applied to build up the survival models and the parametric mixture model is used to study the overall survival of these patients. The Kaplan-Meier survival estimation is also computed to compare the results. Results: The overall death rate decreases sharply immediately after the diagnosis and increases thereafter. The risk of death from breast cancer itself is the highest at the first five years;other causes, however, pose more threats to patients after this period. The patients who received only surgery have higher survival rate in long run. The use of radiation only does not have the significant effect on patients’ survival. Conclusion: Our study shows that the parametric competing risk models are promising in estimating the cause-specific survival of AA breast cancer patients and can be used for clinical practice. We also observed that heart and other diseases pose more threat to breast cancer patients in the long run.

Discovery of Novel Irreversible HER2 Inhibitors for Breast Cancer Treatment

It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb&#174;) has been approved by the U.S. Food and Drug Administration (FDA) as a reversible HER2 inhibitor for treating breast cancer. However, HER2 L755S, T798I and T798M mutations confer drug resistance to lapatinib, restricting its efficacy toward HER2-positive breast cancer. Thus, novel therapy toward mutant HER2 is highly desired. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them were reported to cause severe side effects. In this study, three pharmacophore models based on HER2 L755S, T798I and T798M mutant structures were constructed and then validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Subsequently, these well-validated models were utilized as 3D queries to identify novel irreversible HER2 inhibitors from National Cancer Institute (NCI) database. Finally, two potential irreversible HER2 inhibitor candidates, NSC278329 and NSC718305, were identified and validated through molecular docking, molecular dynamics (MD) simulations and ADMET prediction. Furthermore, the analyses of binding modes showed that both NSC278329 and NSC718305 exhibit good binding interactions with HER2 L755S, T798I and T798M mutants. All together, the above results suggest that both NSC278329 and NSC718305 can serve as novel and effective irreversible HER2 inhibitors for treating breast cancers with HER2 L755S, T798I and T798M mutants. In addition, they may act as lead compounds for designing new irreversible HER2 inhibitors by carrying out structural modifications and optimizations in future studies.

X线联合超声Logistic模型预测乳腺癌腋窝淋巴结转移的价值分析

目的分析与乳腺癌腋窝淋巴结转移相关的X线和超声征象,构建Logistic回归模型并评估其对术前预测腋窝淋巴结状态的临床价值。方法选取2015年1月至2022年1月高密市人民医院收治的312例原发性乳腺癌患者作为研究对象,根据是否发生腋窝淋巴结转移(ALNM)分为转移组(n=141)与未转移组(n=171)。所有患者均行X线及超声检查,比较未转移组与转移组乳腺浸润性导管癌的X线征象、超声征象,采用多因素Logistic回归分析ALNM的影响因素;绘制ROC曲线分析X线、超神征象及Logistic回归模型预测乳腺癌腋窝淋巴结转移的价值。结果两组X线原发灶长径、皮肤增厚、乳头回缩、淋巴结门和淋巴结密度比较差异有统计学意义(P<0.05),两组象限位置、钙化和边缘毛刺比较差异无统计学意义;两组超声原发灶长径、淋巴结皮髓质分界和淋巴结皮质比较差异有统计学意义(P<0.05),两组原发灶高回声晕、后场回声、血流分级和纵横比比较差异无统计学意义。多因素Logistic回归分析结果显示,X线征象的乳房皮肤增厚征象、超声淋巴结皮质增厚征象是乳腺浸润性导管癌患者发生ALNM的独立危险因素(P<0.05)。ROC曲线分析结果显示,X线乳房皮肤增厚征象和超声征象的淋巴结皮质增厚预测淋巴结转移的AUC分别为0.652(95%CI:0.589~0.714)、0.725(95%CI:0.666~0.784),模型预测ALNM的AUC为0.795(95%CI:0.742~0.848),预测效能较好。结论乳腺癌患者的X线皮肤增厚征象和超声腋窝淋巴结皮质增厚征象与ALNM有关,X线联合超声的Logistic模型可较准确地预测乳腺癌患者的腋窝淋巴结状态。

Breast and Ovarian Cancer in Young Women of the Arabian Gulf Region: Relationship to Age

It is widely known that cancer is a disease of “old-age”. However available data show that this is not the case for many types of cancers. Incidences of breast and ovarian cancers have varying rates of change with age. Breast cancer data of Arabian-gulf women, show that the incidence rates increase with age and reach a maximum at 39 year. It then declines linearly with age to about 55 years. The rate of increase and its changes with age are similar to those of many other countries. In the premenopausal phase the relationship between incidence and age could be adequately modeled using a linear model for the logarithmic transformations of age and incidence. Similar observations are made for the ovarian cancer incidences. Results: It is shown that the rate of increase in breast and ovarian cancer incidence with respect to age is increasing in the premenopausal ages. Moreover, the burden of the disease with respect to mortality and “Disability Adjusted Life Years” or DALY, varied considerably among the six gulf countries. Conclusions: We conclude, based on the age incidence relationship that the number of cancer cases may double in the next period that follows our study period (1998-2009). Moreover, if the six countries have identical relationship between age and the two types of cancer, there should be an integrated and unified effort to have a common strategy for prevention and control.