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6,407,725 | StatPearls | Embryogenesis is a complex process and is divided between pre-implantation, embryo, and fetal period. This process is highly susceptible to various external factors such as teratogenic drugs, alcohol, smoking, radiation, and even the lack of appropriate nutrition. Ionizing radiation way more than non-ionizing has known effects in developing fetus with fatal outcomes. Malignancy is relatively uncommon during pregnancy, with a low incidence of 0.02 to 0.1%. The most common malignancies found are breast, skin including melanoma, gynecological (uterine, cervix, and ovarian), and hematological (Hodgkin and non-Hodgkin lymphoma (NHL)). Generally, when rivaled with patients who received surgical monotherapy, survivors who underwent abdominopelvic radiation with or without surgery were more likely to have infants that were premature, low–birth weight, and even associated with perinatal mortality in few cases. Various studies have demonstrated an increased risk of unfavorable pregnancy and neonatal outcomes with prior history of abdominopelvic irradiation, possibly due to radiation-induced uterine damage. Since high-dose uterine irradiation can restrict the pregnant uterus growth and cause vascular changes that impair uterine blood flow, preterm birth, fetal growth restriction, and stillbirth are common. Signorello et al. observed that infants of patients treated with high-dose radiotherapy (>5 Gy) to the uterus were at a heightened risk of preterm delivery, low birth weight, and small for gestational age when compared with offspring of patients who did not receive radiotherapy. Green et al. observed that the incidence of fetal malposition, early or threatened labor, low birth weight, and prematurity were higher with elevated radiation doses. When compared to radiotherapy, chemotherapy does not appear to have harmful effects on the uterus. Hence it generally has favorable pregnancy outcomes in patients treated only with chemotherapy. Those who conceived ≥one year after post-chemotherapy without radiation or ≥two years after chemotherapy with radiation displayed no elevated risks to pregnancy outcomes. |
36,234,844 | Design of Novel IRAK4 Inhibitors Using Molecular Docking, Dynamics Simulation and 3D-QSAR Studies. | Treatment of several autoimmune diseases and types of cancer has been an intense area of research over the past two decades. Many signaling pathways that regulate innate andor adaptive immunity, as well as those that induce overexpression or mutation of protein kinases, have been targeted for drug discovery. One of the serinethreonine kinases, Interleukin-1 Receptor Associated Kinase 4 (IRAK4) regulates signaling through various Toll-like receptors (TLRs) and interleukin-1 receptor (IL1R). It controls diverse cellular processes including inflammation, apoptosis, and cellular differentiation. MyD88 gain-of-function mutations or overexpression of IRAK4 has been implicated in various types of malignancies such as Waldenström macroglobulinemia, B cell lymphoma, colorectal cancer, pancreatic ductal adenocarcinoma, breast cancer, etc. Moreover, over activation of IRAK4 is also associated with several autoimmune diseases. The significant role of IRAK4 makes it an interesting target for the discovery and development of potent small molecule inhibitors. A few potent IRAK4 inhibitors such as PF-06650833, RA9 and BAY1834845 have recently entered phase III clinical trial studies. Nevertheless, there is still a need of selective inhibitors for the treatment of cancer and various autoimmune diseases. A great need for the same intrigued us to perform molecular modeling studies on 4,6-diaminonicotinamide derivatives as IRAK4 inhibitors. We performed molecular docking and dynamics simulation of 50 ns for one of the most active compounds of the dataset. We also carried out MM-PBSA binding free energy calculation to identify the active site residues, interactions of which are contributing to the total binding energy. The final 50 ns conformation of the most active compound was selected to perform dataset alignment in a 3D-QSAR study. Generated RF-CoMFA ( |
36,234,768 | The Role and Regulation of Thromboxane A | Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and colorectal cancers. Several processes involved in cancer development, such as cell growth, migration, and angiogenesis, are regulated by the arachidonic acid derivative thromboxane A |
36,234,755 | Development of Novel Pyridine-Thiazole Hybrid Molecules as Potential Anticancer Agents. | Novel pyridine-thiazole hybrid molecules were synthesized and subjected to physico-chemical characterization and screening of their cytotoxic action towards a panel of cell lines derived from different types of tumors (carcinomas of colon, breast, and lung, glioblastoma and leukemia), and normal human keratinocytes, for comparison. High antiproliferative activity of the 3-(2-fluorophenyl)-1-4-methyl-2-(pyridin-2-ylamino)-thiazol-5-yl-propenone |
36,234,711 | Silver Catalyzed Site-Selective C(sp | Sulfamates are widespread in numerous pharmacologically active molecules. In this paper, SilverBathophenanthroline catalyzed the intramolecular selective amination of primary C(sp |
36,234,680 | DUSP4 Silencing Enhances the Sensitivity of Breast Cancer Cells to Doxorubicin through the Activation of the JNKc-Jun Signalling Pathway. | Doxorubicin (Dox) has limited efficiency in breast cancer (BC) due to drug-acquired resistance. The epithelial-mesenchymal transition (EMT) plays a major role in the survival and drug resistance of cancer cells. It was suggested that the JNK pathway was implicated in the response to Dox by regulating EMT. DUSP4or MKP-2 is a well-known regulator of the JNK pathway and was found to be highly expressed in BC. However, its functional significance is not yet fully understood. In the present study, the possible involvement of MKP-2 in Dox-induced EMT was investigated in breast cancer cells. Immunohistochemistry for tissues obtained from BC patients ( |
36,234,520 | null | The present study aimed to synthesize iron oxide nanoparticles loaded with quinine and alkaloids-rich |
36,234,476 | Uniaxial and Coaxial Nanofibers PCLAlginate or PCLGelatine Transport and Release Tamoxifen and Curcumin Affecting the Viability of MCF7 Cell Line. | Breast cancer is the second cause of cancer death in women worldwide. The search for therapeutic and preventive alternatives has increased in recent years. One synthetic drug for patients with hormone receptor-positive tumours is tamoxifen citrate (TMX). Curcumin (Cur) is a natural compound that is being tested. Both were coupled with nanoscale-controlled and sustained release systems to increase the effectiveness of the treatment and reduce adverse effects. We produced a controlled release system based on uniaxial and coaxial polymeric nanofibers of polycaprolactone (PCL), alginate (Alg) and gelatine (Gel) for the transport and release of TMX and Cur, as a new alternative to breast cancer treatment. Nanofibers combining PCL-Alg and PCL-Gel were fabricated by the electrospinning technique and physicochemically characterised by thermal analysis, absorption spectroscopy in the infrared region and X-ray diffraction. Morphology and size were studied by scanning electron microscopy. Additionally, the release profile of TMX and Cur was obtained by UV-Vis spectroscopy. Additionally, the cytotoxic effect on breast cancer cell line MCF7 and peripheral-blood mononuclear cells (PBMCs) from a healthy donor were evaluated by a Resazurin reduction assay. These assays showed that PCL-TMX nanofiber was highly toxic to both cell types, while PCL-Cur was less toxic. |
36,234,451 | Green Synthesis of Gold Nanoparticles and Study of Their Inhibitory Effect on Bulk Cancer Cells and Cancer Stem Cells in Breast Carcinoma. | Chemo-resistance from cancer stem cells (CSCs) subpopulation is a current issue in cancer treatment. It is important to select alternative therapies to efficiently eradicate both bulk cancer cells and CSCs. Here, gold nanoparticles (AuNPs) have been selected regarding their biocompatibility, facile and controllable synthesis, potent anti-cancer activity and photothermal conversion performance. We reported a green synthesis of functionalized AuNPs using hyaluronic acid (HA) as a reductant, capping, stabilizing and hydrophilic substance. The resultant AuNPs were spherical-shaped with an average diameter of around 30 nm. These AuNPs displayed improved physico-chemical (yield, stability, photothermal effect) and biological properties (cellular uptake, cytotoxicity and apoptotic effect) against bulk MDA-MB-231 cells, in comparison with other organic anti-cancer drugs. The intensified bioactivity was dependent on a mitochondria-mediated cascade, reflected by the damage in mitochondria, oxidative stress, intensified Caspase 3 activity and increaseddecreased expression of certain pro-apoptotic ( |
36,234,382 | Modeling of Electrical Conductivity for Polymer-Carbon Nanofiber Systems. | There is not a simple model for predicting the electrical conductivity of carbon nanofiber (CNF)-polymer composites. In this manuscript, a model is proposed to predict the conductivity of CNF-filled composites. The developed model assumes the roles of CNF volume fraction, CNF dimensions, percolation onset, interphase thickness, CNF waviness, tunneling length among nanoparticles, and the fraction of the networked CNF. The outputs of the developed model correctly agree with the experimentally measured conductivity of several samples. Additionally, parametric analyses confirm the acceptable impacts of main factors on the conductivity of composites. A higher conductivity is achieved by smaller waviness and lower radius of CNFs, lower percolation onset, less tunnel distance, and higher levels of interphase depth and fraction of percolated CNFs in the nanocomposite. The maximum conductivity is obtained at 2.37 Sm by the highest volume fraction and length of CNFs. |
36,233,811 | Survival Analysis in Patients with Lung Cancer and Subsequent Primary Cancer A Nationwide Cancer Registry Study. | With improved survival in patients with cancer, the risk of developing multiple primary malignancies (MPMs) has increased. We aimed to characterize MPMs involving lung cancer and compare these characteristics between patients with single lung cancer and those with lung cancer and subsequent primary cancer (known as lung cancer first LCF). This retrospective study was conducted based on Taiwan Cancer Database from Taiwans National Health Insurance Registry Database. Patients with lung cancer ( MPMs occurred in 10,577 (14.65%) patients with lung cancer, and LCF and other cancer first (OCF) accounted for 35.55% and 64.45% of these patients, with a mean age at lung cancer diagnosis of 65.18 and 68.92 years, respectively. The median interval between primary malignancies in the OCF group was significantly longer than that in the LCF group (3.26 vs. 0.11 years, Survival in patients with MPMs depends on baseline characteristics and treatments. Our findings may contribute to the development of precision medicine for improving personalized treatment and survival as well as the reduction of medical costs. |
36,233,758 | The Present and Future of Clinical Management in Metastatic Breast Cancer. | Regardless of the advances in our ability to detect early and treat breast cancer, it is still one of the common types of malignancy worldwide, with the majority of patients decease upon metastatic disease. Nevertheless, due to these advances, we have extensively characterized the drivers and molecular profiling of breast cancer and further dividing it into subtypes. These subgroups are based on immunohistological markers (Estrogen Receptor-ER Progesterone Receptor-PR and Human Epidermal Growth Factor Receptor 2-HER-2) and transcriptomic signatures with distinct therapeutic approaches and regiments. These therapeutic approaches include targeted therapy (HER-2 |
36,233,640 | Deep Learning and Machine Learning with Grid Search to Predict Later Occurrence of Breast Cancer Metastasis Using Clinical Data. | It is important to be able to predict, for each individual patient, the likelihood of later metastatic occurrence, because the prediction can guide treatment plans tailored to a specific patient to prevent metastasis and to help avoid under-treatment or over-treatment. Deep neural network (DNN) learning, commonly referred to as deep learning, has become popular due to its success in image detection and prediction, but questions such as whether deep learning outperforms other machine learning methods when using non-image clinical data remain unanswered. Grid search has been introduced to deep learning hyperparameter tuning for the purpose of improving its prediction performance, but the effect of grid search on other machine learning methods are under-studied. In this research, we take the empirical approach to study the performance of deep learning and other machine learning methods when using non-image clinical data to predict the occurrence of breast cancer metastasis (BCM) 5, 10, or 15 years after the initial treatment. We developed prediction models using the deep feedforward neural network (DFNN) methods, as well as models using nine other machine learning methods, including naïve Bayes (NB), logistic regression (LR), support vector machine (SVM), LASSO, decision tree (DT), k-nearest neighbor (KNN), random forest (RF), AdaBoost (ADB), and XGBoost (XGB). We used grid search to tune hyperparameters for all methods. We then compared our feedforward deep learning models to the models trained using the nine other machine learning methods. Based on the mean test AUC (Area under the ROC Curve) results, DFNN ranks 6th, 4th, and 3rd when predicting 5-year, 10-year, and 15-year BCM, respectively, out of 10 methods. The top performing methods in predicting 5-year BCM are XGB (1st), RF (2nd), and KNN (3rd). For predicting 10-year BCM, the top performers are XGB (1st), RF (2nd), and NB (3rd). Finally, for 15-year BCM, the top performers are SVM (1st), LR and LASSO (tied for 2nd), and DFNN (3rd). The ensemble methods RF and XGB outperform other methods when data are less balanced, while SVM, LR, LASSO, and DFNN outperform other methods when data are more balanced. Our statistical testing results show that at a significance level of 0.05, DFNN overall performs comparably to other machine learning methods when predicting 5-year, 10-year, and 15-year BCM. Our results show that deep learning with grid search overall performs at least as well as other machine learning methods when using non-image clinical data. It is interesting to note that some of the other machine learning methods, such as XGB, RF, and SVM, are very strong competitors of DFNN when incorporating grid search. It is also worth noting that the computation time required to do grid search with DFNN is much more than that required to do grid search with the other nine machine learning methods. |
36,233,578 | Radiation-Induced Lung Injury Prevention, Diagnostics and Therapy in the Era of the COVID-19 Pandemic. | Thoracic radiotherapy (TRT) plays an integral role in the multimodal treatment of lung cancer, breast cancer, esophageal cancer, thymoma and mesothelioma, having been used as either a definitive, neoadjuvant or adjuvant treatment or for palliative intention to achieve symptom control .... |
36,233,576 | Survival of Breast Cancer by Stage, Grade and Molecular Groups in Mallorca, Spain. | The aims of this study are (1) to determine cause-specific survival by stage, grade, and molecular groups of breast cancer, (2) to identify factors which explain and predict the likelihood of survival and the risk of dying from this cancer and (3) to find out the distribution of breast cancer cases by stage, grade, and molecular groups in females diagnosed in the period 2006-2012 in Mallorca (Spain). We collected data regarding age, date and diagnostic method, histology, laterality, sublocation, pathological or clinical tumor size (T), pathological or clinical regional lymph nodes (N), metastasis (M) and stage, histologic grade, estrogen and progesterone receptors status, HER-2 expression, Ki67 level, molecular classification, date of last follow-up or date of death, and cause of death. We identified 2869 cases. Cause-specific survival for the entire sample was 96% 1 year after diagnosis, 91% at 3 years and 87% at 5 years. Relative survival was 96.9% 1 year after diagnosis, 92.6% at 3 years and 88.5% at 5 years. The competing-risks regression model determined that patients over 65 years of age and patients with triple negative cancer have worse prognoses, and as stages progress, the prognosis for breast cancer worsens, especially from stage III. |
36,233,450 | Capecitabine-A Permanent Mission in Head and Neck Cancers War Council | Capecitabine, an oral pro-drug that is metabolized to 5-FU, has been used in clinical practice for more than 20 years, being part of the therapeutic standard for digestive and breast cancers. The use of capecitabine has been evaluated in many trials including cases diagnosed in recurrent or metastatic settings. Induction regimens or a combination with radiation therapy were evaluated in head and neck cancers, but 5-FU still remained the fluoropyrimidine used as a part of the current therapeutic standard. Quantifications of levels or ratios for enzymes are involved in the capecitabine metabolism to 5-FU but are also involved in its conversion and elimination that may lead to discontinuation, dose reduction or escalation of treatment in order to obtain the best therapeutic ratio. These strategies based on biomarkers may be relevant in the context of the implementation of precision oncology. In particular for head and neck cancers, the identification of biomarkers to select possible cases of severe toxicity requiring discontinuation of treatment, including multi-omics approaches, evaluate not only serological biomarkers, but also miRNAs, imaging and radiomics which will ensure capecitabine a role in both induction and concomitant or even adjuvant and palliative settings. An approach including routine testing of dihydropyrimidine dehydrogenase (DPD) or even the thymidine phosphorylase (TP)DPD ratio and the inclusion of miRNAs, imaging and radiomics parameters in multi-omics models will help implement precision chemotherapy in HNC, a concept supported by the importance of avoiding interruptions or treatment delays in this type of cancer. The chemosensitivity and prognostic features of HPV-OPC cancers open new horizons for the use of capecitabine in heavily pretreated metastatic cases. Vorinostat and lapatinib are agents that can be associated with capecitabine in future clinical trials to increase the therapeutic ratio. |
36,233,396 | PD-L1-Positive High-Grade Triple-Negative Breast Cancer Patients Respond Better to Standard Neoadjuvant Treatment-A Retrospective Study of PD-L1 Expression in Relation to Different Clinicopathological Parameters. | Triple negative breast cancer (TNBC) is typically a high-grade breast cancer with poorest clinical outcome despite available treatment modalities with chemo-, immuno- and radiotherapy. The status of tumor-infiltrating lymphocytes (TILs) is a prognostic factor closely related to programmed death ligand 1 (PD-L1) expressed on T lymphocytes modulating antitumor immunity. Immune-checkpoint inhibitors (ICI) are showing promising results in a subset of breast cancer patients in both neo- and adjuvant settings. Pathologic complete response (pCR) after neoadjuvant treatment was found to be associated with better prognosis. We analyzed the prognostic and predictive significance of PD-L1 (SP142 assay) immunohistochemical expression on TNBC patients samples as illustrated by pCR with regard to its relation to treatment regimen, stage, BRCA mutational status and outcome. Furthermore, we analyzed a few other clinicopathological parameters such as age, TILs and proliferation index. The study highlighted a positive role of PD-L1 evaluation for personalized pCR probability assessment. Although considerable research was made on comparison of PD-L1 level in TNBC with different patient parameters, to our best knowledge, the relation of PD-L1 status to pCR while taking treatment regimen and stage into consideration was so far not investigated. |
36,233,384 | Chest-Wall Tumors and Surgical Techniques State-of-the-Art and Our Institutional Experience. | The chest wall can be involved in both primary and secondary tumors, and even today, their management and treatment continue to be a challenge for surgeons. Primary chest-wall tumors are relatively rare and include a large group of neoplasms that can arise from not only bone or cartilage of the chest wall but also from associated subcutaneous tissue from muscle and blood vessels. Secondary tumors refer to a direct invasion of the chest wall by neoplasms located elsewhere in the body, mainly metastases from breast cancer and lung cancer. En-bloc surgical excision of the lesion should ensure adequate negative margins to avoid local recurrence, and a full thickness surgical resection is often required, and it can result in important chest-wall defects such as skeletal instability or impaired breathing dynamics. The reconstruction of large defects of the chest wall can be complex and often requires the use of prosthetic and biologic mesh materials. This article aims to review the literature on these tumor entities, focusing on the main surgical techniques and the most recent advances in chest-wall resection and reconstruction. We also report on the institutional experience our center. |
36,233,373 | Efficacy of Metformin as Adjuvant Therapy in Metastatic Breast Cancer Treatment. | Metformin has been reported to have an anti-tumorigenic impact against metastatic breast cancer (MBC) cells through several mechanisms. Its effect can be evaluated by using many variables such as the response rate (RR) as well as the progression-free survival (PFS). A prospective study was conducted to investigate and estimate the metformin effect on MBC. About 107 subjects were included in the study and were divided into two groups Group A included non-diabetic MBC patients treated with metformin in conjunction with chemotherapy and group B included those treated with chemotherapy alone. Both PFS and RR were used as a criteria to evaluate the treatment outcome. Associated adverse effects of metformin were also assessed. The average age of the participants in group A and group B was 50 vs. 47.5, respectively. No significant differences were detected between both cohorts concerning RR levels (regression disease (RD) 27.8% vs. 12.5%, stationary disease (SD) 44.4% vs. 41.7%, progression disease (PD) 27.8% vs. 45.8%, respectively, Metformin as an adjuvant therapy to MBC undergoing chemotherapy showed no significant survival benefit as determined by RR and PFS. |
36,233,349 | Nutraceutical-Based Nanoformulations for Breast and Ovarian Cancer Treatment. | Different strategies have been investigated for a more satisfactory treatment of advanced breast cancer, including the adjuvant use of omega-3 polyunsaturated fatty acids (PUFAs). These nutritional compounds have been shown to possess potent anti-inflammatory and antiangiogenic activities, the capacity to affect transduction pathwaysreceptors involved in cell growth and to reprogram tumor microenvironment. Omega-3 PUFA-containing nanoformulations designed for drug delivery in breast cancer were shown to potentiate the effects of enclosed drugs, enhance drug delivery to target sites, and minimize drug-induced side effects. We have critically analyzed here the results of the most recent studies investigating the effects of omega-3 PUFA-containing nanoformulations in breast cancer. The anti-neoplastic efficacy of omega-3 PUFAs has also been convincingly demonstrated by using preclinical in vivo models of ovarian cancer. The results obtained are critically analyzed here and seem to provide a sufficient rationale to move to still lacking interventional clinical trials, as well as to evaluate possible advantages of enclosing omega-3 PUFAs to drug-delivery nanosystems for ovarian cancer. Future perspectives in this area are also provided. |
36,233,281 | A Novel Detection Method of Breast Cancer through a Simple Panel of Biomarkers. | Circulating tumor cells (CTCs) have been identified as responsible for the spread of tumors to other organs of the body. In this sense, the development of sensitive and specific assays for their detection is important to reduce the number of deaths due to metastases. Here, we assessed whether the detection of CTCs in peripheral blood can serve in the construction of a panel of diagnosis and monitoring treatments of breast cancer (BC), focusing on the expression of markers of epithelial-mesenchymal transition. Through analyzing the blood from women without breast alterations (control), women with benign alterations, women with breast cancer without chemotherapy, and women with breast cancer with chemotherapy, we identified the best markers by transcriptional levels and determined three profiles of CTCs (mesenchymal, intermediate, and epithelial) by flow cytometry which, combined, can be used for diagnosis and therapy monitoring with sensitivity and specificity between 80% and 100%. Therefore, we have developed a method for detecting breast cancer based on the analysis of CTC profiles by epithelial-mesenchymal transition markers which, combined, can be used for the diagnosis and monitoring of therapy. |
36,233,245 | Intratumoral Treatment with 5-Androstene-3β, 17α-Diol Reduces Tumor Size and Lung Metastasis in a Triple-Negative Experimental Model of Breast Cancer. | Breast cancer treatment failure is related to low response rates, high costs, and long-term toxicities. Thus, it is necessary to find less toxic, cheaper, and more effective treatments. In situ administration ensures drug delivery to tumor cells and decreases systemic toxic effects. The androstene-3β, 17α-diol (α-AED) reduces breast tumor cell proliferation and is an ideal candidate to treat mammary tumors. This study aims to identify the in vitro and in vivo effects of α-AED on a triple-negative mammary tumor model. An in vitro biphasic steroid effect was observed in mouse and human mammary tumor cells treated with α-AED. In this sense, cells treated with higher doses (100 and 200 μM) showed an antiproliferative effect. The α-AED administrated intratumorally reduced average tumor weight and increased the percentage of natural killer cells (NK), plasmatic, and plasmablast cells in mice tumors. Of note, VEGF levels in all α-AED-treated tumors was lower than in the control and vehicle groups. The tumor in situ increased response was reflected systemically by higher anti-4T1 IgG concentration in serum from α-AED-treated mice, but no other associated systemic changes were detected. The reduction in tumor size for the local injection of α-AED is associated with the anti-proliferative effect of this steroid, and the lower local levels of VEGF may be related to the imperceptible macroscopic metastasis in α-AED-treated mice. The above suggests that α-AED may be used in clinical studies to prove its efficacy as an alternative breast tumor treatment or in conjunction with already established therapies. |
36,233,219 | Characteristics of the Cytotoxicity of | Breast cancer is a highly heterogeneous disease that has been clinically divided into three main subtypes estrogen receptor (ER)- and progesterone receptor (PR)-positive, human epidermal growth factor receptor 2 (HER 2)-positive, and triple-negative breast cancer (TNBC). With its high metastatic potential and resistance to endocrine therapy, HER 2-targeted therapy, and chemotherapy, TNBC represents an enormous clinical challenge. The genus |
36,233,194 | Identification of Candidate Genes in Breast Cancer Induced by Estrogen Plus Progestogens Using Bioinformatic Analysis. | Menopausal hormone therapy (MHT) was widely used to treat menopause-related symptoms in menopausal women. However, MHT therapies were controversial with the increased risk of breast cancer because of different estrogen and progestogen combinations, and the molecular basis behind this phenomenon is currently not understood. To address this issue, we identified differentially expressed genes (DEGs) between the estrogen plus progestogens treatment (EPT) and estrogen treatment (ET) using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data. As a result, a total of 96 upregulated DEGs were first identified. Seven DEGs related to the cell cycle ( |
36,233,192 | Crosstalk between CXCR4ACKR3 and EGFR Signaling in Breast Cancer Cells. | A better understanding of the complex crosstalk among key receptors and signaling pathways involved in cancer progression is needed to improve current therapies. We have investigated in cell models representative of the major subtypes of breast cancer (BC) the interplay between the chemokine CXCL12CXCR4ACKR3 and EGF receptor (EGFR) family signaling cascades. These cell lines display a high heterogeneity in expression profiles of CXCR4ACKR3 chemokine receptors, with a predominant intracellular localization and different proportions of cell surface CXCR4, ACKR3 or double-positive cell subpopulations, and display an overall modest activation of oncogenic pathways in response to exogenous CXCL12 alone. Interestingly, we find that in MDA-MB-361 (luminal B subtype, Her2-overexpressing), but not in MCF7 (luminal A) or MDA-MB-231 (triple negative) cells, CXCR4ACKR3 and EGFR receptor families share signaling components and crosstalk mechanisms to concurrently promote ERK12 activation, with a key involvement of the G protein-coupled receptor kinase 2 (GRK2) signaling hub and the cytosolic tyrosine kinase Src. Our findings suggest that in certain BC subtypes, a relevant cooperation between CXCR4ACKR3 and growth factor receptors takes place to integrate concurrent signals emanating from the tumor microenvironment and foster cancer progression. |
36,233,156 | The Effect of Aflatoxin B1 on Tumor-Related Genes and Phenotypic Characters of MCF7 and MCF10A Cells. | The fungal toxin aflatoxin B1 (AB1) and its reactive intermediate, aflatoxin B1-8, 9 epoxide, could cause liver cancer by inducing DNA adducts. AB1 exposure can induce changes in the expression of several cancer-related genes. In this study, the effect of AB1 exposure on breast cancer MCF7 and normal breast MCF10A cell lines at the phenotypic and epigenetic levels was investigated to evaluate its potential in increasing the risk of breast cancer development. We hypothesized that, even at low concentrations, AB1 can cause changes in the expression of important genes involved in four pathways, i.e., p53, cancer, cell cycle, and apoptosis. The transcriptomic levels of |
36,233,102 | A Computational QSAR, Molecular Docking and In Vitro Cytotoxicity Study of Novel Thiouracil-Based Drugs with Anticancer Activity against Human-DNA Topoisomerase II. | Computational chemistry, molecular docking, and drug design approaches, combined with the biochemical evaluation of the antitumor activity of selected derivatives of the thiouracil-based dihydroindeno pyrido pyrimidines against topoisomerase I and II. The IC50 of other cell lines including the normal human lung cell line W138, lung cancer cell line, A549, breast cancer cell line, MCF-7, cervical cancer, HeLa, and liver cancer cell line HepG2 was evaluated using biochemical methods. The global reactivity descriptors and physicochemical parameters were computed, showing good agreement with the Lipinski and Vebers rules of the drug criteria. The molecular docking study of the ligands with the topoisomerase protein provides the binding sites, binding energies, and deactivation constant for the inhibition pocket. Various biochemical methods were used to evaluate the IC50 of the cell lines. The QSAR model was developed for colorectal cell line HCT as a case study. Four QSAR statistical models were predicted between the IC50 of the colorectal cell line HCT to correlate the anticancer activity and the computed physicochemical and quantum chemical global reactivity descriptors. The predictive power of the models indicates a good correlation between the observed and the predicted activity. |
36,233,090 | Moderate-Risk Genes for Hereditary Ovarian Cancers Involved in the Homologous Recombination Repair Pathway. | Approximately 20% of cases of epithelial ovarian cancer (EOC) are hereditary, sharing many causative genes with breast cancer. The lower frequency of EOC compared to breast cancer makes it challenging to estimate absolute or relative risk and verify the efficacy of risk-reducing surgery in individuals harboring germline pathogenic variants (GPV) in EOC predisposition genes, particularly those with relatively low penetrance. Here, we review the molecular features and hereditary tumor risk associated with several moderate-penetrance genes in EOC that are involved in the homologous recombination repair pathway, i.e., |
36,233,075 | null | In recent years, malignant breast cancer metastasis has caused a great increase in mortality. Research on the genetic and molecular mechanisms of malignant breast cancer has continued to deepen, and targeted therapy has become the general trend. Among them, competing endogenous RNA (ceRNA)-related molecules have received much attention. Homeobox transcript antisense RNA |
36,233,074 | Selectively Targeting Breast Cancer Stem Cells by 8-Quinolinol and Niclosamide. | Cancer maintenance, metastatic dissemination and drug resistance are sustained by cancer stem cells (CSCs). Triple negative breast cancer (TNBC) is the breast cancer subtype with the highest number of CSCs and the poorest prognosis. Here, we aimed to identify potential drugs targeting CSCs to be further employed in combination with standard chemotherapy in TNBC treatment. The anti-CSC efficacy of up to 17 small drugs was tested in TNBC cell lines using cell viability assays on differentiated cancer cells and CSCs. Then, the effect of 2 selected drugs (8-quinolinol -8Q- and niclosamide -NCS-) in the cancer stemness features were evaluated using mammosphere growth, cell invasion, migration and anchorage-independent growth assays. Changes in the expression of stemness genes after 8Q or NCS treatment were also evaluated. Moreover, the potential synergism of 8Q and NCS with PTX on CSC proliferation and stemness-related signaling pathways was evaluated using TNBC cell lines, CSC-reporter sublines, and CSC-enriched mammospheres. Finally, the efficacy of NCS in combination with PTX was analyzed in vivo using an orthotopic mouse model of MDA-MB-231 cells. Among all tested drug candidates, 8Q and NCS showed remarkable specific anti-CSC activity in terms of CSC viability, migration, invasion and anchorage independent growth reduction in vitro. Moreover, specific 8QPTX and NCSPTX ratios at which both drugs displayed a synergistic effect in different TNBC cell lines were identified. The sole use of PTX increased the relative presence of CSCs in TNBC cells, whereas the combination of 8Q and NCS counteracted this pro-CSC activity of PTX while significantly reducing cell viability. In vivo, the combination of NCS with PTX reduced tumor growth and limited the dissemination of the disease by reducing circulating tumor cells and the incidence of lung metastasis. The combination of 8Q and NCS with PTX at established ratios inhibits both the proliferation of differentiated cancer cells and the viability of CSCs, paving the way for more efficacious TNBC treatments. |
36,233,063 | RYBP Sensitizes Cancer Cells to PARP Inhibitors by Regulating ATM Activity. | Ring1 and YY1 Binding Protein (RYBP) is a member of the non-canonical polycomb repressive complex 1 (PRC1), and like other PRC1 members, it is best described as a transcriptional regulator. Previously, we showed that RYBP, along with other PRC1 members, is also involved in the DNA damage response. RYBP inhibits recruitment of breast cancer gene 1(BRCA1) complex to DNA damage sites through its binding to K63-linked ubiquitin chains. In addition, ataxia telangiectasia mutated (ATM) kinase serves as an important sensor kinase in early stages of DNA damage response. Here, we report that overexpression of RYBP results in inhibition in both ATM activity and recruitment to DNA damage sites. Cells expressing RYBP show less phosphorylation of the ATM substrate, Chk2, after DNA damage. Due to its ability to inhibit ATM activity, we find that RYBP sensitizes cancer cells to poly-ADP-ribose polymerase (PARP) inhibitors. Although we find a synergistic effect between PARP inhibitor and ATM inhibitor in cancer cells, this synergy is lost in cells expressing RYBP. We also show that overexpression of RYBP hinders cancer cell migration through, at least in part, ATM inhibition. We provide new mechanism(s) by which RYBP expression may sensitize cancer cells to DNA damaging agents and inhibits cancer metastasis. |
36,233,061 | Cardiolipin for Enhanced Cellular Uptake and Cytotoxicity of Thermosensitive Liposome-Encapsulated Daunorubicin toward Breast Cancer Cell Lines. | Daunorubicin (DNR) and cardiolipin (CL) were co-delivered using thermosensitive liposomes (TSLs). 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine (MSPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 or DSPE-mPEG (2000) and CL were used in the formulation of liposomes at a molar ratio of 574030320, respectively. CL forms raft-like microdomains that may relocate and change lipid organization of the outer and inner mitochondrial membranes. Such transbilayer lipid movement eventually leads to membrane permeabilization. TSLs were prepared by thin-film hydration (druglipid ratio 15) where DNR was encapsulated within the aqueous core of the liposomes and CL acted as a component of the lipid bilayer. The liposomes exhibited high drug encapsulation efficiency (gt90%), small size (115 nm), narrow size distribution (polydispersity index 0.12), and a rapid release profile under the influence of mild hyperthermia. The liposomes also exhibited 4-fold higher cytotoxicity against MDA-MB-231 cells compared to DNR or liposomes similar to DaunoXome |
36,232,997 | New Oxazolo5,4- | Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo5,4- |
36,232,989 | An Insight into Molecular Targets of Breast Cancer Brain Metastasis. | Brain metastasis is one of the major reasons of death in breast cancer (BC) patients, significantly affecting the quality of life, physical activity, and interdependence on several individuals. There is no clear evidence in scientific literature that depicts an exact mechanism relating to brain metastasis in BC patients. The tendency to develop breast cancer brain metastases (BCBMs) differs by the BC subtype, varying from almost half with triple-negative breast cancer (TNBC) (HER2 |
36,232,922 | Molecular Pathogenesis of Colorectal Cancer Impact of Oncogenic Targets Regulated by Tumor Suppressive | We recently determined the RNA sequencing-based microRNA (miRNA) expression signature of colorectal cancer (CRC). Analysis of the signature showed that the expression of both strands of pre- |
36,232,888 | LC-PDA-MS and GC-MS Analysis of | null |
36,232,858 | Naked and Decorated Nanoparticles Containing H | Several semisynthetic, low-cardiotoxicity doxorubicin (DOXO) conjugated have been extensively described, considering the risk of cytotoxicity loss against resistant tumor cells, which mainly present drug efflux capacity. Doxorubicin 14-4-(4-phenyl-5-thioxo-5H-1,2dithiol-3-yl)-benzoate (H |
36,232,840 | Deep Learning Approaches for Detection of Breast Adenocarcinoma Causing Carcinogenic Mutations. | Genes are composed of DNA and each gene has a specific sequence. Recombination or replication within the gene base ends in a permanent change in the nucleotide collection in a DNA called mutation and some mutations can lead to cancer. Breast adenocarcinoma starts in secretary cells. Breast adenocarcinoma is the most common of all cancers that occur in women. According to a survey within the United States of America, there are more than 282,000 breast adenocarcinoma patients registered each 12 months, and most of them are women. Recognition of cancer in its early stages saves many lives. A proposed framework is developed for the early detection of breast adenocarcinoma using an ensemble learning technique with multiple deep learning algorithms, specifically Long Short-Term Memory (LSTM), Gated Recurrent Units (GRU), and Bi-directional LSTM. There are 99 types of driver genes involved in breast adenocarcinoma. This study uses a dataset of 4127 samples including men and women taken from more than 12 cohorts of cancer detection institutes. The dataset encompasses a total of 6170 mutations that occur in 99 genes. On these gene sequences, different algorithms are applied for feature extraction. Three types of testing techniques including independent set testing, self-consistency testing, and a 10-fold cross-validation test is applied to validate and test the learning approaches. Subsequently, multiple deep learning approaches such as LSTM, GRU, and bi-directional LSTM algorithms are applied. Several evaluation metrics are enumerated for the validation of results including accuracy, sensitivity, specificity, Mathews correlation coefficient, area under the curve, training loss, precision, recall, F1 score, and Cohens kappa while the values obtained are 99.57, 99.50, 99.63, 0.99, 1.0, 0.2027, 99.57, 99.57, 99.57, and 99.14 respectively. |
36,232,807 | Association of Common Variants in | Reactive oxygen species impair the blood vessels, leading to the initiation of atherosclerosis, and migration and proliferation of vascular smooth muscle cells and neovascularization by endothelial cells of vasa vasorum are essential for atherosclerosis development. Obg-like ATPase 1 (OLA1), a negative regulator in cellular responses to oxidative stress, binds to breast cancer susceptibility gene 1 (BRCA1), which protects vascular endothelial and smooth muscle cells against reactive oxygen species. However, it is not known whether OLA1 is genetically correlated with atherosclerosis. Here, we conducted two independent population-based case-control studies to explore the effects of variants in |
36,232,793 | Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes A Consequence of Multigene Panel Genetic Testing | The probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes for hereditary breast and ovarian cancer and lynch syndromes in the same patient is uncommon, except in populations where founder effects exist. Two breast cancer women that are double heterozygotes (DH) for both |
36,232,784 | Pro-Apoptotic and Anti-Invasive Properties Underscore the Tumor-Suppressing Impact of Myoglobin on a Subset of Human Breast Cancer Cells. | The expression of myoglobin (MB), well known as the oxygen storage and transport protein of myocytes, is a novel hallmark of the luminal subtype in breast cancer patients and correlates with better prognosis. The mechanisms by which MB impacts mammary tumorigenesis are hitherto unclear. We aimed to unravel this role by using CRISPRCas9 technology to generate MB-deficient clones of MCF7 and SKBR3 breast cancer cell lines and subsequently characterize them by transcriptomics plus molecular and functional analyses. As main findings, loss of MB at normoxia upregulated the expression of cell cyclins and increased cell survival, while it prevented apoptosis in MCF7 cells. Additionally, MB-deficient cells were less sensitive to doxorubicin but not ionizing radiation. Under hypoxia, the loss of MB enhanced the partial epithelial to mesenchymal transition, thus, augmenting the migratory and invasive behavior of cells. Notably, in human invasive mammary ductal carcinoma tissues, MB and apoptotic marker levels were positively correlated. In addition, MB protein expression in invasive ductal carcinomas was associated with a positive prognostic value, independent of the known tumor suppressor p53. In conclusion, we provide multiple lines of evidence that endogenous MB in cancer cells by itself exerts novel tumor-suppressive roles through which it can reduce cancer malignancy. |
36,232,774 | null | Androgen receptor (AR) expression is frequently observed in breast cancer, but its association with estrogen receptor (ER) expression in breast cancer remains unclear. This study analyzed the clinicopathological and molecular features associated with AR negativity in both ER-positive and ER-negative breast cancer, trying to elucidate the molecular correlation between AR and ER. Our results showed that AR negativity was associated with different clinicopathological characteristics and molecular features in ER-positive and ER-negative breast cancer. Moreover, AR-positive breast cancer has better clinicopathological features than AR-negative breast cancer, especially in the ER-negative subtype. These results suggest that the role of AR in ER-negative breast cancer is distinctive from that in ER-positive breast cancer. |
36,232,754 | Novel Thieno 2,3- | Due to the role of cancer stem cells (CSCs) in tumor resistance and glycosphingolipid (GSL) involvement in tumor pathogenesis, we investigated the effect of a newly synthesized compound (3-amino- |
36,232,751 | Exploring Amodiaquines Repurposing Potential in Breast Cancer Treatment-Assessment of In-Vitro Efficacy Mechanism of Action. | Due to the heterogeneity of breast cancer, current available treatment options are moderately effective at best. Hence, it is highly recommended to comprehend different subtypes, understand pathogenic mechanisms involved, and develop treatment modalities. The repurposing of an old FDA approved anti-malarial drug, amodiaquine (AQ) presents an outstanding opportunity to explore its efficacy in treating majority of breast cancer subtypes. Cytotoxicity, scratch assay, vasculogenic mimicry study, and clonogenic assay were employed to determine AQs ability to inhibit cell viability, cell migration, vascular formation, and colony growth. 3D Spheroid cell culture studies were performed to identify tumor growth inhibition potential of AQ in MCF-7 and MDAMB-231 cell lines. Apoptosis assays, cell cycle analysis, RT-qPCR assays, and Western blot studies were performed to determine AQs ability to induce apoptosis, cell cycle changes, gene expression changes, and induction of autophagy marker proteins. The results from in-vitro studies confirmed the potential of AQ as an anti-cancer drug. In different breast cancer cell lines tested, AQ significantly induces cytotoxicity, inhibit colony formation, inhibit cell migration, reduces 3D spheroid volume, induces apoptosis, blocks cell cycle progression, inhibit expression of cancer related genes, and induces LC3BII protein to inhibit autophagy. Our results demonstrate that amodiaquine is a promising drug to repurpose for breast cancer treatment, which needs numerous efforts from further studies. |
36,232,692 | Overview of MicroRNAs as Diagnostic and Prognostic Biomarkers for High-Incidence Cancers in 2021. | MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) about 22 nucleotides in size, which play an important role in gene regulation and are involved in almost all major cellular physiological processes. In recent years, the abnormal expression of miRNAs has been shown to be associated with human diseases including cancer. In the past ten years, the link between miRNAs and various cancers has been extensively studied, and the abnormal expression of miRNAs has been reported in various malignant tumors, such as lung cancer, gastric cancer, colorectal cancer, liver cancer, breast cancer, and prostate cancer. Due to the high malignancy grade of these cancers, it is more necessary to develop the related diagnostic and prognostic methods. According to the study of miRNAs, many potential cancer biomarkers have been proposed for the diagnosis and prognosis of diseases, especially cancer, thus providing a new theoretical basis and perspective for cancer screening. The use of miRNAs as biomarkers for diagnosis or prognosis of cancer has the advantages of being less invasive to patients, with better accuracy and lower price. In view of the important clinical significance of miRNAs in human cancer research, this article reviewed the research status of miRNAs in the above-mentioned cancers in 2021, especially in terms of diagnosis and prognosis, and provided some new perspectives and theoretical basis for the diagnosis and treatment of cancers. |
36,232,660 | Evaluation of Circulating MicroRNAs and Adipokines in Breast Cancer Survivors with Arm Lymphedema. | Breast cancer-related lymphedema (BCRL) is a form of secondary lymphedema that is characterized by abnormal swelling of one or both arms due to the accumulation of lymph fluid in the interstitial tissue spaces, resulting from obstruction of the lymphatic vessels due to surgery insults, radiotherapy, or chemotherapy. Due to the multifactorial nature of this condition, the pathogenesis of secondary lymphedema remains unclear and the search for molecular factors associated with the condition is ongoing. This study aimed to identify serum microRNAs and adipokines associated with BCRL. Blood was collected from 113 breast cancer survivors and processed to obtain serum for small RNA-sequencing (BCRL vs. non-BCRL, |
36,232,636 | Effects of Combined Pentadecanoic Acid and Tamoxifen Treatment on Tamoxifen Resistance in MCF-7SC Breast Cancer Cells. | Estrogen receptors are indicators of breast cancer adaptability to endocrine therapies, such as tamoxifen. Deficiency or absence of estrogen receptor α (ER-α) in breast cancer cells results in reduced efficacy of endocrine therapy. Here, we investigated the effect of combined tamoxifen and pentadecanoic acid therapy on ER-α-under-expressing breast cancer cells. Drug resistance gene expression patterns were determined by RNA sequencing analysis and in vitro experiments. For the first time, we demonstrate that the combined treatment of pentadecanoic acid, an odd-chain fatty acid, and tamoxifen synergistically suppresses the growth of human breast carcinoma MCF-7 stem cells (MCF-7SCs), which were found to be tamoxifen-resistant and showed reduced ER-α expression compared with the parental MCF-7 cells. In addition, the combined treatment synergistically induced apoptosis and accumulation of sub-G1 cells and suppressed epithelial-to-mesenchymal transition (EMT). Exposure to this combination induces re-expression of ER-α at the transcriptional and protein levels, along with suppression of critical survival signal pathways, such as ERK12, MAPK, EGFR, and mTOR. Collectively, decreased ER-α expression was restored by pentadecanoic acid treatment, resulting in reversal of tamoxifen resistance. Overall, pentadecanoic acid exhibits the potential to enhance the efficacy of endocrine therapy in the treatment of ER-α-under-expressing breast cancer cells. |
36,232,621 | Knock-Out of the Five Lysyl-Oxidase Family Genes Enables Identification of Lysyl-Oxidase Pro-Enzyme Regulated Genes. | The five lysyl-oxidase genes share similar enzymatic activities and contribute to tumor progression. We have knocked out the five lysyl-oxidase genes in MDA-MB-231 breast cancer cells using CRISPRCas9 in order to identify genes that are regulated by LOX but not by other lysyl-oxidases and in order to study such genes in more mechanistic detail in the future. Re-expression of the full-length cDNA encoding LOX identified four genes whose expression was downregulated in the knock-out cells and rescued following LOX re-expression but not re-expression of other lysyl-oxidases. These were the AGR2, STOX2, DNAJB11 and DNAJC3 genes. AGR2 and STOX2 were previously identified as promoters of tumor progression. In addition, we identified several genes that were not downregulated in the knock-out cells but were strongly upregulated following LOX or LOXL3 re-expression. Some of these, such as the DERL3 gene, also promote tumor progression. There was very little proteolytic processing of the re-expressed LOX pro-enzyme in the MDA-MB-231 cells, while in the HEK293 cells, the LOX pro-enzyme was efficiently cleaved. We introduced point mutations into the known BMP-1 and ADAMTS214 cleavage sites of LOX. The BMP-1 mutant was secreted but not cleaved, while the LOX double mutant dmutLOX was not cleaved or secreted. However, even in the presence of the irreversible LOX inhibitor β-aminoproprionitrile (BAPN), these point-mutated LOX variants induced the expression of these genes, suggesting that the LOX pro-enzyme has hitherto unrecognized biological functions. |
36,232,614 | Novel Strategies against Cancer Dexibuprofen-Loaded Nanostructured Lipid Carriers. | The aim of this work was to design innovative nanostructured lipid carriers (NLCs) for the delivery of dexibuprofen (DXI) as an antiproliferative therapy against tumoral processes, and overcome its side effects. DXI-NLC samples were prepared with beeswax, Miglyol 812 and Tween 80 using high-pressure homogenization. A two-level factorial design 2 |
36,232,567 | Efficacy and Safety of Ginger on the Side Effects of Chemotherapy in Breast Cancer Patients Systematic Review and Meta-Analysis. | Cancer is one of the leading causes of death in the world, with breast cancer being the most prevalent cancer. Chemotherapy-induced nausea and vomiting (CINV) is one of the most serious side effects of chemotherapy. Because the current CINV treatment option has several flaws, alternative treatment options are required. Ginger has traditionally been used to treat nausea and vomiting, and it also has anticancer properties in breast cancer cells. Based on these findings, researchers investigated whether using ginger to treat CINV in breast cancer patients is both effective and safe. We searched PubMed, Embase, Cochrane Library, CNKI, and Wanfang from inception to June 2022. Outcomes included Rhodes Index Scores of Nausea, Vomiting, and Retching, severity and frequency of CINV. Five RCTs were included. We pooled all included data and performed subgroup analysis by types of CINV. Overall, authors found that ginger was associated with a reduction in CINV. Subgroup and sensitivity analysis revealed that managing severity of acute CINV in breast cancer patients with ginger was efficient. In terms of managing delayed CINV in breast cancer patients, ginger was also statistically significant. The authors concluded that ginger may be helpful in lowering both acute and delayed CINV in breast cancer patients. Since there were no serious side effects, ginger is thought to be safe. |
36,232,564 | Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing A Clinic-Based, Observational Study. | Breast cancer (BC) is associated with hereditary components, and some deleterious germline variants have been regarded as effective therapeutic targets. We conducted a clinic-based, observational study to better understand the distribution of deleterious germline variants and assess any clinicopathological predictors related to the variants among Chinese BC patients using a 32 cancer-related genes next-generation sequencing panel. Between November 2020 and February 2022, a total of 700 BC patients were recruited, and 13.1% (92700) of them carried deleterious germline variants in 15 cancer-related genes, including 37 (37700, 5.3%) in |
36,232,534 | Phytochemicals with Chemopreventive Activity Obtained from the Thai Medicinal Plant | With the aim of searching for phytochemicals with aromatase inhibitory activity, five new prenylcoumarins, mammeasins K ( |
36,232,480 | Emerging Roles of Ceramides in Breast Cancer Biology and Therapy. | One of the classic hallmarks of cancer is the imbalance between elevated cell proliferation and reduced cell death. Ceramide, a bioactive sphingolipid that can regulate this balance, has long been implicated in cancer. While the effects of ceramide on cell death and therapeutic efficacy are well established, emerging evidence indicates that ceramide turnover to downstream sphingolipids, such as sphingomyelin, hexosylceramides, sphingosine-1-phosphate, and ceramide-1-phosphate, is equally important in driving pro-tumorigenic phenotypes, such as proliferation, survival, migration, stemness, and therapy resistance. The complex and dynamic sphingolipid network has been extensively studied in several cancers, including breast cancer, to find key sphingolipidomic alterations that can be exploited to develop new therapeutic strategies to improve patient outcomes. Here, we review how the current literature shapes our understanding of how ceramide synthesis and turnover are altered in breast cancer and how these changes offer potential strategies to improve breast cancer therapy. |
36,232,400 | Evaluation of the Sensitivity of Breast Cancer Cell Lines to Cardiac Glycosides Unveils ATP1B3 as a Possible Biomarker for the Personalized Treatment of ERα Expressing Breast Cancers. | The molecular classification of breast cancer (BC) dictates pharmacological treatment. Estrogen receptor α (ERα) expressing tumors are treated with 4OH-tamoxifen or fulvestrant, which inhibits the receptor, or with aromatase inhibitors (i.e., anastrozole, letrozole, and exemestane) that reduce the 17β-estradiol (E2) circulating blood levels. Besides such endocrine therapy (ET) drugs, ERα-positive BCs can be treated with epidermal growth factor receptor (EGF-R) inhibitors (i.e., gefitinib, erlotinib, and lapatinib) according to HER2 expression. Notwithstanding these anti-BC drugs, novel personalized approaches for BC treatment are required because prolonged administration of those pharmaceutics determines resistant phenotypes, which result in metastatic BC. We have recently reported that the cardiac glycoside (CG) (i.e., NaK ATPase inhibitor) ouabain could be repurposed for ERα-positive primary and metastatic BC treatment as it induces ERα degradation and kills BC cells. Here, we evaluated if other CGs could represent additional treatment options for ERα-positive BCs and if the NaK ATPase could be considered a biomarker for ERα-positive BC treatment. The results indicate that the ATP1B3 NaK ATPase isoform can educate the choice for the personalized treatment of ERα-positive BC with CGs and that CGs could be more efficacious if they are administered in association with gefitinib. |
36,232,369 | Analysis of Tumor-Infiltrating T-Cell Transcriptomes Reveal a Unique Genetic Signature across Different Types of Cancer. | CD8 and CD4 T-cells play a key role in cellular immune responses against cancer by cytotoxic responses and effector lineages differentiation, respectively. These subsets have been found in different types of cancer however, it is unclear whether tumor-infiltrating T-cell subsets exhibit similar transcriptome profiling across different types of cancer in comparison with healthy tissue-resident T-cells. Thus, we analyzed the single cell transcriptome of five tumor-infiltrating CD4-T, CD8-T and Treg cells obtained from different types of cancer to identify specific pathways for each subset in malignant environments. An in silico analysis was performed from single-cell RNA-sequencing data available in public repositories (Gene Expression Omnibus) including breast cancer, melanoma, colorectal cancer, lung cancer and head and neck cancer. After dimensionality reduction, clustering and selection of the different subpopulations from malignant and nonmalignant datasets, common genes across different types of cancer were identified and compared to nonmalignant genes for each T-cell subset to identify specific pathways. Exclusive pathways in CD4 cells, CD8 cells and Tregs, and common pathways for the tumor-infiltrating T-cell subsets were identified. Finally, the identified pathways were compared with RNAseq and proteomic data obtained from T-cell subsets cultured under malignant environments and we observed that cytokine signaling, especially Th2-type cytokine, was the top overrepresented pathway in Tregs from malignant samples. |
36,232,349 | Current Molecular Combination Therapies Used for the Treatment of Breast Cancer. | Breast cancer is the second leading cause of death for women worldwide. While monotherapy (single agent) treatments have been used for many years, they are not always effective, and many patients relapse after initial treatment. Moreover, in some patients the response to therapy becomes weaker, or resistance to monotherapy develops over time. This is especially problematic for metastatic breast cancer or triple-negative breast cancer. Recently, combination therapies (in which two or more drugs are used to target two or more pathways) have emerged as promising new treatment options. Combination therapies are often more effective than monotherapies and demonstrate lower levels of toxicity during long-term treatment. In this review, we provide a comprehensive overview of current combination therapies, including molecular-targeted therapy, hormone therapy, immunotherapy, and chemotherapy. We also describe the molecular basis of breast cancer and the various treatment options for different breast cancer subtypes. While combination therapies are promising, we also discuss some of the challenges. Despite these challenges, the use of innovative combination therapy holds great promise compared with traditional monotherapies. In addition, the use of multidisciplinary technologies (such as nanotechnology and computer technology) has the potential to optimize combination therapies even further. |
36,232,335 | Immune State Conversion of the Mesenteric Lymph Node in a Mouse Breast Cancer Model. | Secondary lymphoid tissues, such as the spleen and lymph nodes (LNs), contribute to breast cancer development and metastasis in both anti- and pro-tumoral directions. Although secondary lymphoid tissues have been extensively studied, very little is known about the immune conversion in mesenteric LNs (mLNs) during breast cancer development. Here, we demonstrate inflammatory immune conversion of mLNs in a metastatic 4T1 breast cancer model. Splenic T cells were significantly decreased and continuously suppressed IFN-γ production during tumor development, while myeloid-derived suppressor cells (MDSCs) were dramatically enriched. However, T cell numbers in the mLN did not decrease, and the MDSCs only moderately increased. T cells in the mLN exhibited conversion from a pro-inflammatory state with high IFN-γ expression to an anti-inflammatory state with high expression of IL-4 and IL-10 in early- to late-stages of breast cancer development. Interestingly, increased migration of CD103 |
36,232,223 | How Do Healthy Women Perceive the Risk of Breast Cancer The Role of Illness Perceptions and Compared Risk between Portugal and the U.A.E. | (1) Background Breast cancer (BC) shows significant epidemiological differences between Eastern and Western countries. These may arise from socio-cultural factors influencing how healthy young women perceive this condition, their risk of getting cancer, and the implications for preventive screening behaviors. In this study, the illness perceptions, individual risk perception, compared risk, and beliefs about preventive behaviors for BC of female university students were compared using an anonymous online survey between a European country (Portugal) and the United Arab Emirates. (2) Method A structural equation model (SEM) was developed to investigate the hypothetical relationship between illness perceptions and compared risk as predictors of perceived risk for BC. (3) Results There were significant differences between the study variables. The SEM was invariant, but the differences between regression coefficients in both countries were highly statistically significant. Mediation analyses revealed a significant indirect effect of compared risk on individual risk and a significantly stronger direct effect for the Emirati sample. (4) Conclusions These findings suggest that cultural research may help to explain factors that may shape social comparison of individual risk characteristics and influence perceived risk. Moreover, providing culturally appropriate strategies to be designed and implemented can promote early detection behaviors for BC. |
36,232,107 | Demoralization and Its Association with Quality of Life, Sleep Quality, Spiritual Interests, and Suicide Risk in Breast Cancer Inpatients A Cross-Sectional Study. | With decreasing mortality, the quality of life, spiritual needs, and mental health of breast cancer patients have become increasingly important. Demoralization is a poor prognostic factor for cancer patients. The extent of demoralization in breast cancer patients and its association with these factors remains unclear. This cross-sectional study was conducted at a Taiwanese medical center. We enrolled 121 participants (34 with high demoralization and 87 with low demoralization, as per the Mandarin Version of Demoralization Scale). High demoralization was associated with reduced quality of life, sleep quality, and spiritual interests. Multivariate analyses revealed that the scores of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire ≥ 62.5 (OR 0.21, |
36,232,105 | Intersectionality Impacts Survivorship Identity-Informed Recommendations to Improve the Quality of Life of African American Breast Cancer Survivors in Health Promotion Programming. | (1) Background African American women breast cancer survivors face unique experiences that impact their quality of life as they transition beyond treatments. Experiences may be complicated by living at the intersection of systemically oppressed identities, including gender, race, social class, and cancer-related disability. Using the Black Feminist Thought (BFT) framework and the PEN-3 cultural model, this qualitative study sought to (a) understand African American women breast cancer survivors lived experiences (b) examine how the multiple intersecting factors of race, gender, social classsocioeconomic status, and cancer-related disability impact their quality of life and (c) inform future health promotion programming that is culturally relevant to AAWBCS to improve their quality of life. (2) Methods Seven focus groups were conducted with 30 African American breast cancer survivors in a Midwestern metropolitan region. Focus groups were audiotaped and transcribed verbatim. Framework analyses were conducted to identify themes with NVivo qualitative analysis software. (3) Results Four themes emerged (a) caregiving roles provide both support and challenges for survivors, (b) the strong Black woman is inherent in survivor experiences, (c) intersectionality impacts survivorship, and (d) African American women resist oppression through culturally specific supports and advocacy. (4) Conclusions The intervention point of entry should be at the peer support group level and centered on family and provide community-based support and services. Future research should move upstream to address social determinants of health, including racism, sexism, and ableism there is a critical need to discuss how structural racism affects health care and develop interventions to address racial discrimination and racial bias in health care. |
36,232,036 | The Impact of IT-Based Healthcare Communication on Mammography Screening Utilization among Women in the United States National Health Interview Survey (2011-2018). | Effective patient-provider communication improves mammography utilization. Using information technology (IT) promotes health outcomes. However, there are disparities in access to IT that could contribute to disparities in mammography utilization. This study aims to assess the association between IT-based health care communication and mammography utilization and to evaluate if this effect is modified by raceethnicity and age. To this end, this study was conducted using the National Health Interview Survey from 2011 to 2018. A total of 94,290 women aged 40 years and older were included. Multiple logistic regression models were used, and odds ratios were reported. The study found that all IT-based healthcare communication strategies were significantly associated with mammography utilization in all years from 2011 to 2018. In 2018, women who looked up health information on the internet, scheduled a medical appointment on the internet, and communicated with providers by email had a significantly higher chance to use mammography ( |
36,232,029 | Polish Adaptation of the Modified Tampa Scale of Kinesiophobia for Fatigue (TSK-F) and the Revision of the Tampa Scale in Terms of Pain for Cancer Patients. | The aim of this study was to create a Polish adaptation of the Tampa Scale of Kinesiophobia considering fatigue, and to verify the usefulness of the scale in the context of pain in cancer patients. The study was conducted at the Breast Cancer Unit, operating at the Greater Poland Cancer Centre, and at the Poznan Centre for Specialist Medical Services in Poznan. After considering the exclusion criteria, 100 people qualified for the interviews for the final study 50 breast cancer patients and 50 healthy respondents (without cancer). Statistical analysis of the CFA score showed that the chi-square test was not significant (χ |
36,232,027 | Breast Cancer Treatment in Integrated Care Process in Andalusia The Challenge of Multidisciplinarity. | Despite the increasing trend in the incidence of breast cancer in recent decades, mortality has decreased in developed countries. The general objective of the study is to analyse the functioning and organisation of the care process for breast cancer treatment in Andalusia (Spain) in order to identify possible barriers and facilitators that may be affecting its effectiveness and, therefore, the survival of the disease. A qualitative method was adopted based on 19 semi-structured interviews with health professionals from different specialities in two Andalusian provinces Huelva (mortality rate higher than the national average) and Granada (mortality rate similar to the national average). Results show the existence of barriers (seasonal delays, low frequency of multidisciplinary meetings, lack of human and technical resources, difficulties in accessing treatment in certain populations, etc.) and facilitators (creation of multidisciplinary units and committees for breast pathology, standardisation of treatments, assignment of professionals with preferential attention to breast pathology, etc.) in the care process of breast cancer treatment. The combination of these barriers can have an impact on the accessibility, quality, and efficacy of the treatment, and in the long term, on survival from the disease. |
36,232,004 | The Role of Emotion-Related Abilities in the Quality of Life of Breast Cancer Survivors A Systematic Review. | Breast cancer survivors have to deal with notable challenges even after successful treatment, such as body image issues, depression and anxiety, the stress related to changes in lifestyle, and the continual challenges inherent to health management. The literature suggests that emotional abilities, such as emotional intelligence, emotion management, mood repair, and coping play a fundamental role in such challenges. We performed a systematic review to systematize the evidence available on the role of emotional abilities in quality of life and health management in breast cancer survivors. The search was performed on three scientific databases (Pubmed, Scopus, and PsycINFO) and, after applying exclusion criteria, yielded 33 studies, mainly of a cross-sectional nature. The results clearly support the hypothesis that emotional abilities play multiple important roles in breast cancer survivors quality of life. Specifically, the review highlighted that copingemotional management plays multiple roles in breast cancer survivors well-being and health management, affecting vitality and general adjustment to cancer positivity and promoting benefit findings related to the cancer experience however, rare negative results exist in the literature. This review highlights the relevance of emotional abilities to promoting quality of life in breast cancer survivors. Future review efforts may explore other breast cancer survivors emotional abilities, aiming at assessing available instruments and proposing tailored psychological interventions. |
36,231,913 | A Comprehensive Review on Multifaceted Mechanisms Involved in the Development of Breast Cancer Following Adverse Childhood Experiences (ACEs). | Adverse Childhood Experiences (ACEs) may give rise to harmful effects on health throughout life. Epigenetic changes explain how preexisting risk factors may contribute to produce altered biological responses and cancer risk. The main aim of the review is to summarize studies examining the means in which Adverse Childhood Experiences (ACEs) can modulate individual vulnerability to breast cancer (BC) development through multifaceted mechanisms. Studies selection, data extraction, and assessments agreed to PRISMA criteria. We included original research with clinical samples following BC interventions, investigating potential mechanisms linking ACEs and BC in adults. From the 3321 papers found, nine articles involving 2931 participants were selected. All studies included ACEs retrospective assessments and psychological measures, and seven of them considered biomarkers. Individuals exposed to greater ACEs were at increased BC risk compared with individuals with no ACEs. Associations were found between child abuse andor neglect, depression, perceived stress, fatigue, and plasma levels of cytokines interleukin (IL-6), C-reactive protein (CRP), soluble tumor necrosis factor receptor type II (sTNF-RII), interleukin IL-1 receptor antagonist (IL-1ra), and psycho-physiological adjustments that may lead to BC. Exposure to multiple ACEs appears a risk factor for BC development in adulthood. Although the clinical relevance of findings such as this is ambiguous, the review added evidence for a link between the presence of childhood adversity and BC occurrence, pointing to psychological, hormonal, and immunological dysregulations. |
36,231,811 | The Body after Cancer A Qualitative Study on Breast Cancer Survivors Body Representation. | The relationship with the body is a relevant issue for breast cancer survivors. Oncological treatments damage their bodies due to scars, weight gain, and other side effects. Starting from the efficacy of psychological interventions for breast cancer survivors, a tailored psychological support program was provided to promote overall well-being after illness dealing with bodily signals and related emotions and thoughts. This study presents changes in the description of the relationship with their bodies as well as participants emotions and thoughts before and after a psychological intervention. Eighteen women answered questions related to their bodies before and after the psychological intervention. Results were analyzed in accordance with the procedure of the Word Association Analysis through the T-Lab software and the Qualitative Thematic Analysis. Participants reported a great awareness of their bodies and the desire to take care of them daily. In particular, the body is now perceived as a helper to sustain breast cancer survivors in their everyday activities. The words and the themes that characterized the participants reports highlighted the impact of cancer diagnosis and oncological therapies on breast cancer survivors. The participation in the psychological intervention focused on self-compassion towards their body helps women to create an improved body perception. |
36,231,809 | South Korean Early Cancer Patients Perceptions of Difficulties in Fighting Their Disease A Q Methodological Approach. | This study applied the Q methodology to explore breast cancer patients perceived difficulties in their fight against the disease. We used literature analysis and in-depth interviews and selected 162 statements for the Q population. Then, we chose 40 universal and representative statements for the Q samples from the Q population. The P sample included 13 breast cancer patients in the early stage of the disease who participated in the Q sorting. We interviewed the study participants with high factor weights by type of P sample. The studys results showed three types of breast cancer patients perceptions of difficulties in the initial fight against the disease. Type 1 showed fear of the future, Type 2 showed helplessness against what cannot be controlled, and Type 3 showed frustration due to difficulties in role performance. Based on these results, we discuss the characteristics, meanings, and significance of individual types of breast cancer patients perceptions of the disease, including suggestions for follow-up studies. |
36,231,805 | The Technology-Oriented Pathway for Auxiliary Diagnosis in the Digital Health Age A Self-Adaptive Disease Prediction Model. | The advent of the digital age has accelerated the transformation and upgrading of the traditional medical diagnosis pattern. With the rise of the concept of digital health, the emerging information technologies, such as machine learning (ML) and data mining (DM), have been extensively applied in the medical and health field, where the construction of disease prediction models is an especially effective method to realize auxiliary medical diagnosis. However, the existing related studies mostly focus on the prediction analysis for a certain disease, using models with which it might be challenging to predict other diseases effectively. To address the issues existing in the aforementioned studies, this paper constructs four novel strategies to achieve a self-adaptive disease prediction process, i.e., the hunger-state foraging strategy of producers (PHFS), the parallel strategy for exploration and exploitation (EEPS), the perturbation-exploration strategy (PES), and the parameter self-adaptive strategy (PSAS), and eventually proposes a self-adaptive disease prediction model with applied universality, strong generalization ability, and strong robustness, i.e., multi-strategies optimization-based kernel extreme learning machine (MsO-KELM). Meanwhile, this paper selects six different real-world disease datasets as the experimental samples, which include the Breast Cancer dataset (cancer), the Parkinson dataset (Parkinsons disease), the Autistic Spectrum Disorder Screening Data for Children dataset (Autism Spectrum Disorder), the Heart Disease dataset (heart disease), the Cleveland dataset (heart disease), and the Bupa dataset (liver disease). In terms of the prediction accuracy, the proposed MsO-KELM can obtain ACC values in analyzing these six diseases of 94.124%, 84.167%, 91.079%, 72.222%, 70.184%, and 70.476%, respectively. These ACC values have all been increased by nearly 2-7% compared with those obtained by the other models mentioned in this paper. This study deepens the connection between information technology and medical health by exploring the self-adaptive disease prediction model, which is an intuitive representation of digital health and could provide a scientific and reliable diagnostic basis for medical workers. |
36,231,664 | The Interplay of GPER1 with 17β-Aminoestrogens in the Regulation of the Proliferation of Cervical and Breast Cancer Cells A Pharmacological Approach. | The G-protein-coupled receptor for estrogen (GPER1) is a transmembrane receptor involved in the progression and development of various neoplasms whose ligand is estradiol (E2). 17β-aminoestrogens (17β-AEs) compounds, analogs to E2, are possible candidates for use in hormone replacement therapy (HRT), but our knowledge of their pharmacological profile is limited. Thus, we explored the molecular recognition of GPER1 with different synthetic 17β-AEs prolame, butolame, and pentolame. We compared the structure and ligand recognition sites previously reported for a specific agonist (G1), antagonists (G15 and G36), and the natural ligand (E2). Then, the biological effects of 17β-AEs were analyzed through cell viability and cell-cycle assays in two types of female cancer. In addition, the effect of 17β-AEs on the phosphorylation of the oncoprotein c-fos was evaluated, because this molecule is modulated by GPER1. Molecular docking analysis showed that 17β-AEs interacted with GPER1, suggesting that prolame joins GPER1 in a hydrophobic cavity, similarly to G1, G15, and E2. Prolame induced cell proliferation in breast (MCF-7) and cervical cancer (SIHA) cells meanwhile, butolame and pentolame did not affect cell proliferation. Neither 17β-AEs nor E2 changed the activation of c-fos in MCF-7 cells. Meanwhile, in SIHA cells, E2 and 17β-AEs reduced c-fos phosphorylation. Thus, our data suggest that butolame and pentolame, but not prolame, could be used for HRT without presenting a potential risk of inducing breast- or cervical-cancer-cell proliferation. The novelty of this work lies in its study of compound analogs to E2 that may represent important therapeutic strategies for women in menopause, with non-significant effects on the cell viability of cancer cells. The research focused on the interactions of GPER1, a molecule recently associated with promoting and maintaining various neoplasms. |
36,231,542 | Web-Based Personalized Intervention to Improve Quality of Life and Self-Efficacy of Long-Term Breast Cancer Survivors Study Protocol for a Randomized Controlled Trial. | Long-term breast cancer survivors (>5 years free of disease) may suffer late sequelae of cancer that impact on their quality of life. The use of telehealth for cancer care is recommended but little is known about the effectiveness of digital interventions for long-term cancer survivors. This study aims to evaluate the effectiveness of a web-based personalized intervention based on artificial intelligence instead of usual primary health care to improve the quality of life of long-term survivors of breast cancer and self-efficacy for the management of late sequelae. A randomized controlled trial will be conducted. The sample will consist of long-term breast cancer survivors recruited from primary health centers. Women will be randomly assigned to the intervention group to receive a web-based personalized intervention or to the control group to receive standard primary health care by nurses. Data on quality of life of cancer survivors and self-efficacy for the management of late sequelae of cancer will be collected and assessed at preintervention, and at 3, 6, and 9 months. It is expected that, at the end of the programme, the experimental group will have improved quality of life and improved self-efficacy for the management of late sequelae of cancer. |
36,231,355 | Hereditary Ovarian Cancer Towards a Cost-Effective Prevention Strategy. | Ovarian cancer (OC) is the most lethal gynaecological malignancy. The search for a widely affordable and accessible screening strategy to reduce mortality from OC is still ongoing. This coupled with the late-stage presentation and poor prognosis harbours significant health-economic implications. OC is also the most heritable of all cancers, with an estimated 25% of cases having a hereditary predisposition. Advancements in technology have detected multiple mutations, with the majority affecting the |
36,231,235 | An Evidence-Based Somatic Acupressure Intervention Protocol for Managing the Breast Cancer Fatigue-Sleep Disturbance-Depression Symptom Cluster Development and Validation following the Medical Research Council Framework. | Somatic acupoint stimulation (SAS) has been frequently utilised as a promising intervention for individual cancer-related symptom management, such as fatigue, sleep disturbance and depression. However, research evidence regarding the role of SAS in mitigating the fatigue-sleep disturbance-depression symptom cluster (FSDSC) has been scant. This study was conducted to develop an evidence-based SAS intervention protocol that can be further implemented in a Phase II randomized controlled trial (RCT) to manage the FSDSC in breast cancer survivors. The Medical Research Council Framework for Developing and Evaluating Complex Intervention (MRC framework) was employed to guide the development procedures of the SAS intervention protocol, including the identification of an existing evidence base, the identification of theories and practice standards, and the validation of the SAS intervention protocol. A content validity study was performed through an expert panel to assess the scientific and practical appropriateness of the SAS intervention protocol. The content validity index (CVI), including item-level CVI and protocol-level CVI, were calculated to evaluate the consensus level of the expert panel. Key components of the SAS protocol, including the acupoint formula, the SAS modality, technique, intensity and frequency were identified for both a true and placebo SAS intervention based on the best available research evidence retrieved from systematic reviews, clinical trials, and relevant theories, particularly regarding the inflammatory process, A research-informed, theory-driven and practically feasible SAS intervention protocol for the FSDSC management in breast cancer survivors was developed following the MRC framework. The feasibility and acceptability of the SAS intervention will be further tested in breast cancer survivors through a Phase II RCT. |
36,231,221 | Sexual Dysfunction in Women with Cancer A Systematic Review of Longitudinal Studies. | Several factors affect sexual function, including cancer development and treatment. This study summarized the risk of women with cancer of developing sexual dysfunctions. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched the EMBASE, PubMed, LILACS, SciELO, CINAHL, Scopus, and Web of Science databases using the descriptors cancer, neoplasms, sexual dysfunction, sexual function, and women. The Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies assessed the quality of studies. Sixteen studies were included in this review. Women with cancer presented sexual dysfunctions in 14 out of 16 included studies. The incidence of sexual dysfunctions ranged from 30% to 80%, while the risk of developing sexual dysfunction increased 2.7- and 3.5-fold in women with cervical and breast cancer, respectively. Different cancer treatments increase the risk of developing sexual dysfunction in women, especially desire, arousal, and orgasm, leading to biopsychosocial changes in the health of this population. |
36,231,127 | Investigating Two Modes of Cancer-Associated Antigen Heterogeneity in an Agent-Based Model of Chimeric Antigen Receptor T-Cell Therapy. | Chimeric antigen receptor (CAR) T-cell therapy has been successful in treating liquid tumors but has had limited success in solid tumors. This work examines unanswered questions regarding CAR T-cell therapy using computational modeling, such as, what percentage of the tumor must express cancer-associated antigens for treatment to be successful The model includes cancer cell and vascular and CAR T-cell modules that interact with each other. We compare two different models of antigen expression on tumor cells, binary (in which cancer cells are either susceptible or are immune to CAR T-cell therapy) and gradated (where each cancer cell has a probability of being killed by a CAR T-cell). We vary the antigen expression levels within the tumor and determine how effective each treatment is for the two models. The simulations show that the gradated antigen model eliminates the tumor under more parameter values than the binary model. Under both models, shielding, in which the lownon-antigen-expressing cells protect high antigen-expressing cells, reduced the efficacy of CAR T-cell therapy. One prediction is that a combination of CAR T-cell therapies that targets the general population of cells as well as one that specifically targets cancer stem cells should increase its efficacy. |
36,231,082 | Platelet-Derived Extracellular Vesicles Stimulate Migration through Partial Remodelling of the Ca | Platelets can support cancer progression via the release of microparticles and microvesicles that enhance the migratory behaviour of recipient cancer cells. We recently showed that platelet-derived extracellular vesicles (PEVs) stimulate migration and invasiveness in highly metastatic MDA-MB-231 cells by stimulating the phosphorylation of p38 MAPK and the myosin light chain 2 (MLC2). Herein, we assessed whether the pro-migratory effect of PEVs involves the remodelling of the Ca PEVs were isolated from human blood platelets, and Fura-2AM Ca Pretreating MDA-MB-231 cells with PEVs for 24 h caused an increase in Ca PEVs stimulate migration in the highly metastatic MDA-MB-231 breast cancer cell line by inducing a partial remodelling of the Ca |
36,231,059 | The Interplay between the Cellular Response to DNA Double-Strand Breaks and Estrogen. | Cancer development is often connected to impaired DNA repair and DNA damage signaling pathways. The presence of DNA damage in cells activates DNA damage response, which is a complex cellular signaling network that includes DNA repair, activation of the cell cycle checkpoints, cellular senescence, and apoptosis. DNA double-strand breaks (DSBs) are toxic lesions that are mainly repaired by the non-homologous end joining and homologous recombination repair (HRR) pathways. Estrogen-dependent cancers, like breast and ovarian cancers, are frequently associated with mutations in genes that play a role in HRR. The female sex hormone estrogen binds and activates the estrogen receptors (ERs), ERα, ERβ and G-protein-coupled ER 1 (GPER1). ERα drives proliferation, while ERβ inhibits cell growth. Estrogen regulates the transcription, stability and activity of numerus DDR factors and DDR factors in turn modulate ERα expression, stability and transcriptional activity. Additionally, estrogen stimulates DSB formation in cells as part of its metabolism and proliferative effect. In this review, we will present an overview on the crosstalk between estrogen and the cellular response to DSBs. We will discuss how estrogen regulates DSB signaling and repair, and how DDR factors modulate the expression, stability and activity of estrogen. We will also discuss how the regulation of HRR genes by estrogen promotes the development of estrogen-dependent cancers. |
36,231,046 | Endothelial | null |
36,231,027 | CUEDC2 Drives β-Catenin Nuclear Translocation and Promotes Triple-Negative Breast Cancer Tumorigenesis. | Hyperactivation of Wnt signaling is crucial in tumor formation. Fully elucidating the molecular details of how the cancer-specific Wnt signaling pathway is activated or contributes to tumorigenesis will help in determining future treatment strategies. Here, we aimed to explore the contribution of CUEDC2, a novel CUE-domain-containing protein, to the activation of Wnt signaling and the tumorigenesis of triple-negative breast cancer (TNBC) and to determine the underlying mechanisms. TNBC patient samples and disease-free survival (DFS) data were used to determine the association between CUEDC2 and TNBC progression. The effects of CUEDC2 on TNBC were examined in TNBC cells in vitro and in subcutaneous xenograft tumors in vivo. Gene knockdown, immunoprecipitation plus liquid chromatography-tandem mass spectrometry, pull-down, co-immunoprecipitation, localized surface plasmon resonance, and nuclear translocation analysis were used to uncover the mechanisms of CUEDC2 in regulating Wnt signaling and TNBC development. CUEDC2 is sufficient to maintain the hyperactivation of Wnt signaling required for TNBC tumorigenesis. The contribution of CUEDC2 plays a major role in determining the outcome of oncogenic Wnt signaling both in vitro and in vivo. Mechanistically, the CUE domain in CUEDC2 directly bound to the ARM (7-9) domain in β-catenin, promoted β-catenin nuclear translocation and enhanced the expression of β-catenin targeted genes. More importantly, an 11-amino-acid competitive peptide targeting the CUE domain in CUEDC2 blocked the interactions of CUEDC2 and β-catenin and abrogated the malignant phenotype of TNBC cells in vitro and in vivo. We observed that TNBC patients who exhibited higher levels of CUEDC2 showed marked hyperactivation of the Wnt signaling pathway and poor clinical outcomes, highlighting the clinical relevance of our findings. CUEDC2 promotes TNBC tumor growth by enhancing Wnt signaling through directly binding to β-catenin and accelerating its nuclear translocation. Targeting the interactions of CUEDC2 and β-catenin may be a valuable strategy for combating TNBC. |
36,230,969 | Hypoxia-Inducible Expression of Annexin A6 Enhances the Resistance of Triple-Negative Breast Cancer Cells to EGFR and AR Antagonists. | Physiological changes such as hypoxia in the tumor microenvironment (TME) endow cancer cells with malignant properties, leading to tumor recurrence and rapid progression. Here, we assessed the effect of hypoxia (1% Oxygen) on the tumor suppressor Annexin A6 (AnxA6) and the response of triple-negative breast cancer (TNBC) cells to epidermal growth factor receptor (EGFR) and androgen receptor (AR) targeted therapies. We demonstrate that brief exposure of TNBC cells to hypoxia (within 24 h) is associated with down regulation of AnxA6 while > 24 h exposure cell type dependently stimulated the expression of AnxA6. Hypoxia depicted by the expression and stability of HIF-12α led to up regulation of the HIF target genes |
36,230,951 | Combination Treatment of Retinoic Acid Plus Focal Adhesion Kinase Inhibitor Prevents Tumor Growth and Breast Cancer Cell Metastasis. | All-trans retinoic acid (RA), the primary metabolite of vitamin A, controls the development and homeostasis of organisms and tissues. RA and its natural and synthetic derivatives, both known as retinoids, are promising agents in treating and chemopreventing different neoplasias, including breast cancer (BC). Focal adhesion kinase (FAK) is a crucial regulator of cell migration, and its overexpression is associated with tumor metastatic behavior. Thus, pharmaceutical FAK inhibitors (FAKi) have been developed to counter its action. In this work, we hypothesize that the RA plus FAKi (RA FAKi) approach could improve the inhibition of tumor progression. By in silico analysis and its subsequent validation by qPCR, we confirmed RARA, SRC, and PTK2 (encoding RARα, Src, and FAK, respectively) overexpression in all breast cells tested. We also showed a different pattern of genes updown-regulated between RA-resistant and RA-sensitive BC cells. In addition, we demonstrated that both RA-resistant BC cells (MDA-MB-231 and MDA-MB-468) display the same behavior after RA treatment, modulating the expression of genes involved in Src-FAK signaling. Furthermore, we demonstrated that although RA and FAKi administered separately decrease viability, adhesion, and migration in mammary adenocarcinoma LM3 cells, their combination exerts a higher effect. Additionally, we show that both drugs individually, as well as in combination, induce the expression of apoptosis markers such as active-caspase-3 and cleaved-PARP1. We also provided evidence that RA effects are extrapolated to other cancer cells, including T-47D BC and the human cervical carcinoma HeLa cells. In an orthotopic assay of LM3 tumor growth, whereas RA and FAKi administered separately reduced tumor growth, the combined treatment induced a more potent inhibition increasing mice survival. Moreover, in an experimental metastatic assay, RA significantly reduced metastatic lung dissemination of LM3 cells. Overall, these results indicate that RA resistance could reflect deregulation of most RA-target genes, including genes encoding components of the Src-FAK pathway. Our study demonstrates that RA plays an essential role in disrupting BC tumor growth and metastatic dissemination in vitro and in vivo by controlling FAK expression and localization. RA plus FAKi exacerbate these effects, thus suggesting that the sensitivity to RA therapies could be increased with FAKi coadministration in BC tumors. |
36,230,935 | Metabolic Pathways in Breast Cancer Reprograming An Insight to Non-Coding RNAs. | Cancer cells reprogram their metabolisms to achieve high energetic requirements and produce precursors that facilitate uncontrolled cell proliferation. Metabolic reprograming involves not only the dysregulation in glucose-metabolizing regulatory enzymes, but also the enzymes engaging in the lipid and amino acid metabolisms. Nevertheless, the underlying regulatory mechanisms of reprograming are not fully understood. Non-coding RNAs (ncRNAs) as functional RNA molecules cannot translate into proteins, but they do play a regulatory role in gene expression. Moreover, ncRNAs have been demonstrated to be implicated in the metabolic modulations in breast cancer (BC) by regulating the metabolic-related enzymes. Here, we will focus on the regulatory involvement of |
36,230,929 | Micro-RNA193a-3p Inhibits Breast Cancer Cell Driven Growth of Vascular Endothelial Cells by Altering Secretome and Inhibiting Mitogenesis Transcriptomic and Functional Evidence. | Breast cancer (BC) cell secretome in the tumor microenvironment (TME) facilitates neo-angiogenesis by promoting vascular endothelial cell (VEC) growth. Drugs that block BC cell growth or angiogenesis can restrict tumor growth and are of clinical relevance. Molecules that can target both BC cell and VEC growth as well as BC secretome may be more effective in treating BC. Since small non-coding microRNAs (miRs) regulate cell growth and miR193a-3p has onco-suppressor activity, we investigated whether miR193a-3p inhibits MCF-7-driven growth (proliferation, migration, capillary formation, signal transduction) of VECs. Using BC cells and VECs grown in monolayers or 3D spheroids and gene microarrays, we demonstrate that pro-growth effects of MCF-7 and MDA-MB231 conditioned medium (CM) are lost in CM collected from MCF-7MDA-MB231 cells pre-transfected with miR193a-3p (miR193a-CM). Moreover, miR193a-CM inhibited MAPK and Akt phosphorylation in VECs. In microarray gene expression studies, miR193a-CM upregulated 553 genes and downregulated 543 genes in VECs. Transcriptomic and pathway enrichment analysis of differentially regulated genes revealed downregulation of interferon-associated genes and pathways that induce angiogenesis and BCtumor growth. An angiogenesis proteome array confirmed the downregulation of 20 pro-angiogenesis proteins by miR193a-CM in VECs. Additionally, in MCF-7 cells and VECs, estradiol (E2) downregulated miR193a-3p expression and induced growth. Ectopic expression of miR193a-3p abrogated the growth stimulatory effects of estradiol E2 and serum in MCF-7 cells and VECs, as well as in MCF-7 and MCF-7VEC 3D spheroids. Immunostaining of MCF-7VEC spheroid sections with ki67 showed miR193a-3p inhibits cell proliferation. Taken together, our findings provide first evidence that miR193a-3p abrogates MCF-7-driven growth of VECs by altering MCF-7 secretome and downregulating pro-growth interferon signals and proangiogenic proteins. Additionally, miR193a-3p inhibits serum and E2-induced growth of MCF-7, VECs, and MCF-7VEC spheroids. In conclusion, miRNA193a-3p can potentially targetinhibit BC tumor angiogenesis via a dual mechanism (1) altering proangiogenic BC secretomeTME and (2) inhibiting VEC growth. It may represent a therapeutic molecule to target breast tumor growth. |
36,230,903 | Advances in Biomarkers and Endogenous Regulation of Breast Cancer Stem Cells. | Breast cancer is one of the most common cancers. Even if breast cancer patients initially respond to treatment, developed resistance can lead to a poor prognosis. Cancer stem cells (CSCs) are a group of undifferentiated cells with self-renewal and multipotent differentiation characteristics. Existing evidence has shown that CSCs are one of the determinants that contribute to the heterogeneity of primary tumors. The emergence of CSCs causes tumor recurrence, metastasis, and therapeutic resistance. Previous studies indicated that different stemness-associated surface markers can identify other breast cancer stem cell (BCSC) subpopulations. Deciphering the critical signaling networks that are involved in the induction and maintenance of stemness is essential to develop novel BCSC-targeting strategies. In this review, we reviewed the biomarkers of BCSCs, critical regulators of BCSCs, and the signaling networks that regulate the stemness of BCSCs. |
36,230,902 | Long Noncoding RNAs and Circular RNAs Regulate AKT and Its Effectors to Control Cell Functions of Cancer Cells. | AKT serine-threonine kinase (AKT) and its effectors are essential for maintaining cell proliferation, apoptosis, autophagy, endoplasmic reticulum (ER) stress, mitochondrial morphogenesis (fissionfusion), ferroptosis, necroptosis, DNA damage response (damage and repair), senescence, and migration of cancer cells. Several lncRNAs and circRNAs also regulate the expression of these functions by numerous pathways. However, the impact on cell functions by lncRNAs and circRNAs regulating AKT and its effectors is poorly understood. This review provides comprehensive information about the relationship of lncRNAs and circRNAs with AKT on the cell functions of cancer cells. the roles of several lncRNAs and circRNAs acting on AKT effectors, such as FOXO, mTORC12, S6K12, 4EBP1, SREBP, and HIF are explored. To further validate the relationship between AKT, AKT effectors, lncRNAs, and circRNAs, more predicted AKT- and AKT effector-targeting lncRNAs and circRNAs were retrieved from the LncTarD and circBase databases. Consistently, using an in-depth literature survey, these AKT- and AKT effector-targeting database lncRNAs and circRNAs were related to cell functions. Therefore, some lncRNAs and circRNAs can regulate several cell functions through modulating AKT and AKT effectors. This review provides insights into a comprehensive network of AKT and AKT effectors connecting to lncRNAs and circRNAs in the regulation of cancer cell functions. |
36,230,901 | Locus-Specific Enrichment Analysis of 5-Hydroxymethylcytosine Reveals Novel Genes Associated with Breast Carcinogenesis. | An imbalance in DNA methylation is a hallmark epigenetic alteration in cancer. The conversion of 5-methylcytosine (5-mC) to 5-hydroxymethyl cytosine (5-hmC), which causes the imbalance, results in aberrant gene expression. The precise functional role of 5-hydroxymethylcytosine in breast cancer remains elusive. In this study, we describe the landscape of 5-mC and 5-hmC and their association with breast cancer development. We found a distinguishable global loss of 5-hmC in the localized and invasive types of breast cancer that strongly correlate with |
36,230,886 | Molecular Mechanisms Driving the Formation of Brain Metastases. | Targeted therapies for cancers have improved primary tumor response rates, but concomitantly, brain metastases (BM) have become the most common brain tumors in adults and are associated with a dismal prognosis of generally less than 6 months, irrespective of the primary cancer type. They most commonly occur in patients with primary breast, lung, or melanoma histologies however, they also appear in patients with other primary cancers including, but not limited to, prostate cancer, colorectal cancer, and renal cell carcinoma. Historically, molecular biomarkers have normally been identified from primary tumor resections. However, clinically informative genomic alterations can occur during BM development and these potentially actionable alterations are not always detected in the primary tumor leading to missed opportunities for effective targeted therapy. The molecular mechanisms that facilitate and drive metastasis to the brain are poorly understood. Identifying the differences between the brain and other extracranial sties of metastasis, and between primary tumors and BM, is essential to improving our understanding of BM development and ultimately patient management and survival. In this review, we present the current data on the genomic landscape of BM from various primary cancers which metastasize to the brain and outline potential mechanisms which may play a role in promoting the formation of the distant metastases in the brain. |
36,230,863 | LINC01526 Promotes Proliferation and Metastasis of Gastric Cancer by Interacting with TARBP2 to Induce GNG7 mRNA Decay. | Gastric cancer is the most common malignancy of the human digestive system. Long noncoding RNAs (lncRNAs) influence the occurrence and development of gastric cancer in multiple ways. However, the function and mechanism of LINC01526 in gastric cancer remain unknown. Herein, we investigated the function of LINC01526 with respect to the malignant progression of gastric cancer. We found that LINC01526 was upregulated in gastric cancer cells and tissues. The function experiments in vitro and the Xenograft mouse model in vivo proved that LINC01526 could promote gastric cancer cell proliferation and migration. Furthermore, LINC01526 interacted with TAR (HIV-1) RNA-binding protein 2 (TARBP2) and decreased the mRNA stability of G protein gamma 7 (GNG7) through TARBP2. Finally, the rescue assay showed that downregulating GNG7 partially rescued the cell proliferation inhibited by LINC01526 or TARBP2 silencing. In summary, LINC01526 promoted gastric cancer progression by interacting with TARBP2, which subsequently degraded GNG7 mRNA. This study not only explores the role of LINC01526 in gastric cancer, but also provides a laboratory basis for its use as a new biomarker for diagnosis and therapeutic targets. |
36,230,857 | Hypoxia and ERα Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast Cancer. | Estrogen receptor-alpha (ERα) is the driving transcription factor in 70% of breast cancers and its activity is associated with hormone dependent tumor cell proliferation and survival. Given the recurrence of hormone resistant relapses, understanding the etiological factors fueling resistance is of major clinical interest. Hypoxia, a frequent feature of the solid tumor microenvironment, has been described to promote endocrine resistance by triggering ERα down-regulation in both in vitro and in vivo models. Yet, the consequences of hypoxia on ERα genomic activity remain largely elusive. In the present study, transcriptomic analysis shows that hypoxia regulates a fraction of ERα target genes, underlying an important regulatory overlap between hypoxic and estrogenic signaling. This gene expression reprogramming is associated with a massive reorganization of ERα cistrome, highlighted by a massive loss of ERα binding sites. Profiling of enhancer acetylation revealed a hormone independent enhancer activation at the vicinity of genes harboring hypoxia inducible factor (HIFα) binding sites, the major transcription factors governing hypoxic adaptation. This activation counterbalances the loss of ERα and sustains hormone-independent gene expression. We describe hypoxia in luminal ERα () breast cancer as a key factor interfering with endocrine therapies, associated with poor clinical prognosis in breast cancer patients. |
36,230,854 | Risk of Presenting with Poor-Prognosis Metastatic Cancer in Adolescents and Young Adults A Population-Based Study. | Having metastatic disease at diagnosis poses the great risk of death among AYAs with cancer from all sociodemographic subgroups. This landscape study utilized United States Surveillance, Epidemiology, and End Results Program data from 2000-2016 to identify subgroups of AYAs at highest risk for presenting with metastases across twelve cancer sites having a poor-prognosis (5-year survival lt50% with metastases). Adjusted odds ratios for risk of metastatic disease presentation were compared for AYAs in aggregate and by sociodemographic subgroup (raceethnicity, sex, socioeconomic status SES). In general, AYAs who were male, racialethnic minorities, or low SES were at consistently greatest risk of metastases. Strikingly, having metastatic melanoma was independently associated with multiple AYA sociodemographic subgroups, including males (aOR 3.11 95% CI 2.64-3.66), non-Hispanic Blacks (4.04 2.32-7.04), Asian Pacific Islanders (2.99 1.75-5.12), Hispanics (2.37 1.85-3.04), and low SES (2.30 1.89-2.80). Non-Hispanic Blacks were more likely to present with metastatic cancer in all sites, except for bone, rhabdomyosarcoma, and stomach. Low SES AYAs are more likely to present with metastatic melanoma, bone tumors, soft tissue sarcomas, breast, cervical, lung, and stomach carcinomas. Building on these results, future cancer-specific studies should investigate the connection between sociodemographic risk factors and biological drivers of metastases. This line of research has potential to inform targeted public health and screening efforts to facilitate risk reduction and earlier detection of these deadly diseases. |
36,230,841 | Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice. | At diagnosis, about 35% of pancreatic cancers are at the locally invasive yet premetastatic stage. Surgical resection is not a treatment option, leaving patients with a largely incurable disease that often evolves to the polymetastatic stage despite chemotherapeutic interventions. In this preclinical study, we hypothesized that pancreatic cancer metastasis can be prevented by inhibiting mitochondrial redox signaling with MitoQ, a mitochondria-targeted antioxidant. Using four different cancer cell lines, we report that, at clinically relevant concentrations (100-500 nM), MitoQ selectively repressed mesenchymal pancreatic cancer cell respiration, which involved the inhibition of the expression of PGC-1α, NRF1 and a reduced expression of electron-transfer-chain complexes I to III. MitoQ consequently decreased the mitochondrial membrane potential and mitochondrial superoxide production by these cells. Phenotypically, MitoQ further inhibited pancreatic cancer cell migration, invasion, clonogenicity and the expression of stem cell markers. It reduced by 50% the metastatic homing of human MIA PaCa-2 cells in the lungs of mice. We further show that combination treatments with chemotherapy are conceivable. Collectively, this study indicates that the inhibition of mitochondrial redox signaling is a possible therapeutic option to inhibit the metastatic progression of pancreatic cancer. |
36,230,821 | Targeting Triple Negative Breast Cancer Stem Cells by Heat Shock Protein 70 Inhibitors. | Triple negative breast cancer (TNBC) is considered the most aggressive breast cancer with high relapse rates and poor prognosis. Although great advances in the development of cancer therapy have been witnessed over the past decade, the treatment options for TNBC remain limited. In this study, we investigated the effect and potential underlying mechanism of the Hsp70 inhibitors, compound 1 and compound 6, on breast cancer stem cells (BCSCs) in TNBC cells. Our results showed that compound 1 and 6 exhibited potent tumor suppressive effects on cell viability and proliferation, and effectively inhibited BCSC expansion in TNBC cells. Reminiscent with the effect of Hsp70 inhibitors, Hsp70 knockdown effectively suppressed mammosphere formation and the expressions of BCSCs surface markers. Mechanistically, evidence showed that the Hsp70 inhibitors inhibited BCSCs by down-regulating β-catenin in TNBC cells. Moreover, we used the Hsp70 inhibitors treated TNBC cells and a stable Hsp70 knockdown clone of MDA-MB-231 cells to demonstrate the in vivo efficacy of Hsp70 inhibition in suppressing tumorigenesis and xenograft tumor growth. Together, these findings suggest the potential role of Hsp70 as a target for TNBC therapy and foster new therapeutic strategies to eliminate BCSCs by targeting Hsp70. |
36,230,808 | Multiplexed In Situ Spatial Protein Profiling in the Pursuit of Precision Immuno-Oncology for Patients with Breast Cancer. | Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many solid tumors. In breast cancer (BC), immunotherapy is currently approved in combination with chemotherapy, albeit only in triple-negative breast cancer. Unfortunately, most patients only derive limited benefit from ICIs, progressing either upfront or after an initial response. Therapeutics must engage with a heterogeneous network of complex stromal-cancer interactions that can fail at imposing cancer immune control in multiple domains, such as in the genomic, epigenomic, transcriptomic, proteomic, and metabolomic domains. To overcome these types of heterogeneous resistance phenotypes, several combinatorial strategies are underway. Still, they can be predicted to be effective only in the subgroups of patients in which those specific resistance mechanisms are effectively in place. As single biomarker predictive performances are necessarily suboptimal at capturing the complexity of this articulate network, precision immune-oncology calls for multi-omics tumor microenvironment profiling in order to identify unique predictive patterns and to proactively tailor combinatorial treatments. Multiplexed single-cell spatially resolved tissue analysis, through precise epitope colocalization, allows one to infer cellular functional states in view of their spatial organization. In this review, we discuss-through the lens of the cancer-immunity cycle-selected, established, and emerging markers that may be evaluated in multiplexed spatial protein panels to help identify prognostic and predictive patterns in BC. |
36,230,801 | Subpathway Analysis of Transcriptome Profiles Reveals New Molecular Mechanisms of Acquired Chemotherapy Resistance in Breast Cancer. | Chemoresistance has been a major challenge in the treatment of patients with breast cancer. The diverse omics platforms and small sample sizes reported in the current studies of chemoresistance in breast cancer limit the consensus regarding the underlying molecular mechanisms of chemoresistance and the applicability of these study findings. Therefore, we built two transcriptome datasets for patients with chemotherapy-resistant breast cancers-one comprising paired transcriptome samples from 40 patients before and after chemotherapy and the second including unpaired samples from 690 patients before and 45 patients after chemotherapy. Subsequent conventional pathway analysis and new subpathway analysis using these cohorts uncovered 56 overlapping upregulated genes (false discovery rate FDR, 0.018) and 36 downregulated genes (FDR, 0.016). Pathway analysis revealed the activation of several pathways in the chemotherapy-resistant tumors, including those of drug metabolism, MAPK, ErbB, calcium, cGMP-PKG, sphingolipid, and PI3K-Akt, as well as those activated by Cushings syndrome, human papillomavirus (HPV) infection, and proteoglycans in cancers, and subpathway analysis identified the activation of several more, including fluid shear stress, Wnt, FoxO, ECM-receptor interaction, RAS signaling, Rap1, mTOR focal adhesion, and cellular senescence (FDR lt 0.20). Among these pathways, those associated with Cushings syndrome, HPV infection, proteoglycans in cancer, fluid shear stress, and focal adhesion have not yet been reported in breast cancer chemoresistance. Pathway and subpathway analysis of a subset of triple-negative breast cancers from the two cohorts revealed activation of the identical chemoresistance pathways. |
36,230,790 | Neuraminidase-1 A Sialidase Involved in the Development of Cancers and Metabolic Diseases. | Sialidases or neuraminidases (NEU) are glycosidases which cleave terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides. Four types of mammalian sialidases, which are encoded by different genes, have been described with distinct substrate specificity and subcellular localization NEU-1, NEU-2, NEU-3 and NEU-4. Among them, NEU-1 regulates many membrane receptors through desialylation which results in either the activation or inhibition of these receptors. At the plasma membrane, NEU-1 also associates with the elastin-binding protein and the carboxypeptidase protective proteincathepsin A to form the elastin receptor complex. The activation of NEU-1 is required for elastogenesis and signal transduction through this receptor, and this is responsible for the biological effects that are mediated by the elastin-derived peptides (EDP) on obesity, insulin resistance and non-alcoholic fatty liver diseases. Furthermore, NEU-1 expression is upregulated in hepatocellular cancer at the mRNA and protein levels in patients, and this sialidase regulates the hepatocellular cancer cells proliferation and migration. The implication of NEU-1 in other cancer types has also been shown notably in the development of pancreatic carcinoma and breast cancer. Altogether, these data indicate that NEU-1 plays a key role not only in metabolic disorders, but also in the development of several cancers which make NEU-1 a pharmacological target of high potential in these physiopathological contexts. |
36,230,784 | Novel Insights into Redox-Based Mechanisms for Auranofin-Induced Rapid Cancer Cell Death. | Auranofin (Ridaura |
36,230,782 | Development of a High-Affinity Antibody against the Tumor-Specific and Hyperactive 611-p95HER2 Isoform. | The expression of human epidermal growth factor receptor 2 (HER2) is a key classification factor in breast cancer. Many breast cancers express isoforms of HER2 with truncated carboxy-terminal fragments (CTF), collectively known as p95HER2. A common p95HER2 isoform, 611-CTF, is a biomarker for aggressive disease and confers resistance to therapy. Contrary to full-length HER2, 611-p95HER2 has negligible normal tissue expression. There is currently no approved diagnostic assay to identify this subgroup and no therapy targeting this mechanism of tumor escape. The purpose of this study was to develop a monoclonal antibody (mAb) against 611-CTF-p95HER2. Hybridomas were generated from rats immunized with cells expressing 611-CTF. A hybridoma producing a highly specific Ab was identified and cloned further as a mAb. This mAb, called Oslo-2, gave strong staining for 611-CTF and no binding to full-length HER2, as assessed in cell lines and tissues by flow cytometry, immunohistochemistry and immunofluorescence. No cross-reactivity against HER2 negative controls was detected. Surface plasmon resonance analysis demonstrated a high binding affinity (equilibrium dissociation constant 2 nM). The target epitope was identified at the N-terminal end, using experimental alanine scanning. Further, the mAb paratope was identified and characterized with hydrogen-deuterium-exchange, and a molecular model for the (Oslo-2 mAb611-CTF-p95HER2) complex was generated by an experimental-information-driven docking approach. We conclude that the Oslo-2 mAb has a high affinity and is highly specific for 611-CTF-p95HER2. The Ab may be used to develop potent and safe therapies, overcoming p95HER2-mediated tumor escape, as well as for developing diagnostic assays. |
36,230,780 | Anti-Apoptotic c-FLIP Reduces the Anti-Tumour Activity of Chimeric Antigen Receptor T Cells. | CAR T cell treatment of solid tumours is limited by poor persistence partly due to CD95 ligand (CD95L)-induced apoptosis. Both T cells and cells within the tumour microenvironment (TME) may express CD95L, triggering apoptosis in CD95-receptor-positive CAR T cells. Tonic signalling of CAR T cells may also increase CD95-dependent AICD. Because the intracellular protein c-FLIP protects T cells from AICD, we expressed c-FLIPp43 within a Her-2 targeted CAR cassette and evaluated the potential of c-FLIPp43 through in vitro functional assays and in vivo tumour-bearing xenograft model. cFLIP expression protected against CD95L-induced cell death in the Jurkat T cell lines. However, in primary human CAR T cells containing CAR-CD28 domains, c-FLIPp43 overexpression had minimal additional impact on resistance to CD95L-induded cell death. In vitro cytotoxicity against a breast cancer tumour cell line was not altered by c-FLIPp43 expression, but the expression of c-FLIPp43 in Her2-CAR T cells lowered interferon-γ secretion, without markedly affecting IL-2 levels, and c-FLIPp43-Her2-CAR T cells showed reduced anti-tumour activity in immunodeficient mice with breast cancer. The findings of this study provide a new understanding of the effects of controlling extrinsic apoptosis pathway suppression in CAR T cells, suggesting that c-FLIPp43 expression reduces anti-tumour immunity through the modulation of effector T cell pathways. |
36,230,779 | Cholesterol-Inulin Conjugates for Efficient SN38 Nuclear Delivery Nanomedicines for Precision Cancer Therapy. | An amphiphilic inulin-thiocholesterol conjugate (INU-Cys-TC) was strategically designed as a biodegradable core-shell nanocarrier of 7-ethyl-10-hydroxy-camptothecin (SN38) to enhance its solubility and stability in aqueous media, thus exploiting its brilliant anticancer effect. INU-Cys-TC was designed to have the hydrophilic inulin backbone (external shell) partially functionalized with hydrophobic thiocholesterol moieties (internal core) through a biodegradable disulfide bond due to cysteamine bridges. Thiocholesterol moieties impair redox-sensitive self-assembling abilities, yielding to nano-sized micelles in aqueous media capable of efficiently encapsulating a high amount of SN38 (DL 8.1%). Micelles (INU-Cys-TCSN38) were widely characterized, demonstrating an effective and stable delivery strategy to overcome the poor water-solubility of SN38. SN38-loaded micelles showed a gradual and prolonged release of SN38 over time, and a cell- and time-dependent cytotoxicity. In particular, we show that micelles efficiently deliver SN38 inside cell nuclei, and, compared to normal cell lines, they can also enter cancer cells by endo-lysosomes, where a complete degradation can occur releasing the drug payload. Overall, the proposed micelles appear potentially effective as nanomedicines for precision cancer therapies of colorectal and breast cancer, thus improving the SN38 therapeutic index and extending its use in a huge plethora of cancers. |
36,230,778 | Spatial Transcriptomic Analysis Reveals Associations between Genes and Cellular Topology in Breast and Prostate Cancers. | Cancer is the leading cause of death worldwide with breast and prostate cancer the most common among women and men, respectively. Gene expression and image features are independently prognostic of patient survival but until the advent of spatial transcriptomics (ST), it was not possible to determine how gene expression of cells was tied to their spatial relationships (i.e., topology). We identify topology-associated genes (TAGs) that correlate with 700 image topological features (ITFs) in breast and prostate cancer ST samples. Genes and image topological features are independently clustered and correlated with each other. Themes among genes correlated with ITFs are investigated by functional enrichment analysis. Overall, topology-associated genes (TAG) corresponding to extracellular matrix (ECM) and Collagen Type I Trimer gene ontology terms are common to both prostate and breast cancer. In breast cancer specifically, we identify the ZAG-PIP Complex as a TAG. In prostate cancer, we identify distinct TAGs that are enriched for GI dysmotility and the IgA immunoglobulin complex. We identified TAGs in every ST slide regardless of cancer type. These TAGs are enriched for ontology terms, illustrating the biological relevance to our image topology features and their potential utility in diagnostic and prognostic models. |
36,230,772 | Intestinal Microbiota Influence Doxorubicin Responsiveness in Triple-Negative Breast Cancer. | Triple-negative breast cancer (TNBC) is highly aggressive with a poor 5-year survival rate. Targeted therapy options are limited and most TNBC patients are treated with chemotherapy. This study aimed to determine whether doxorubicin (Dox) shifts the gut microbiome and whether gut microbiome populations influence chemotherapeutic responsiveness. Female BALBc mice (n 115) were injected with 4T1-luciferase cells (a murine syngeneic TNBC model) and treated with Dox andor antibiotics, high-fat diet-derived fecal microbiota transplant (HFD-FMT), or exogenous lipopolysaccharide (LPS). Metagenomic sequencing was performed on fecal DNA samples. Mice that received Dox were stratified into Dox responders or Dox nonresponders. Mice from the Dox responders and antibiotics Dox groups displayed reduced tumor weight and metastatic burden. Metagenomic analysis showed that Dox was associated with increased |
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