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Iron metabolism, ferroptosis, and lncRNA in cancer knowns and unknowns.

Cancer cells undergo substantial metabolic alterations to sustain increased energy supply and uncontrolled proliferation. As an essential trace element, iron is vital for many biological processes. Evidence has revealed that cancer cells deploy various mechanisms to elevate the cellular iron concentration to accelerate proliferation. Ferroptosis, a form of cell death caused by iron-catalyzed excessive peroxidation of polyunsaturated fatty acids (PUFAs), is a promising therapeutic target for therapy-resistant cancers. Previous studies have reported that long noncoding RNA (lncRNA) is a group of critical regulators involved in modulating cell metabolism, proliferation, apoptosis, and ferroptosis. In this review, we summarize the associations among iron metabolism, ferroptosis, and ferroptosis-related lncRNA in tumorigenesis. This information will help deepen understanding of the role of lncRNA in iron metabolism and raise the possibility of targeting lncRNA and ferroptosis in cancer combination therapy.

Tumor immune checkpoints and their associated inhibitors.

Immunological evasion is one of the defining characteristics of cancers, as the immune modification of an immune checkpoint (IC) confers immune evasion capabilities to tumor cells. Multiple ICs, such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), can bind to their respective receptors and reduce tumor immunity in a variety of ways, including blocking immune cell activation signals. IC blockade (ICB) therapies targeting these checkpoint molecules have demonstrated significant clinical benefits. This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers. Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment. In this review, we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels, including epigenetic regulation, transcriptional regulation, and post-translational modifications. In addition, we provide a summary of the medications targeting various nodes in the regulatory pathway, and highlight the potential of newly identified IC molecules, focusing on their potential implications for cancer diagnostics and immunotherapy.

Management of nipple-areolar complex anomalies.

Nipple-areolar complex anomalies may be secondary to many etiologies from simple anatomic variations to malignant processes as Paget disease or invasive breast cancer, passing through benign locally aggressive processes as erosive adenomatosis of the nipple. Differential diagnosis is not always simple. If clinical exam and standard radiological checkup cant confirm the benignity of the lesion, a biopsy specimen will be obtained to allow an anatomopathological examination. A precise diagnosis can then be made leading to optimal management. This paper describes how to explore nipple-areolar complex anomalies through an uncommon clinical case associating independently an invasive retro-areolar cancer and a dermatological disease of the areola mimicking a Paget disease. Les anomalies de la plaque aréolo-mamelonnaire peuvent être secondaires à de nombreuses étiologies, allant de simples variantes anatomiques à des pathologies malignes telles que la maladie de Paget ou un cancer invasif, tout en passant par des pathologies bénignes localement agressives comme l’adénomatose érosive du mamelon. Le diagnostic différentiel n’est pas toujours aisé. Si l’examen clinique et le bilan radiologique standard ne permettent pas d’affirmer la bénignité de la lésion, un prélèvement biopsique sera réalisé afin de permettre une analyse anatomopathologique. Un diagnostic précis pourra alors être posé pour guider la prise en charge optimale. Cet article a pour but de détailler la mise au point d’une atteinte de la plaque aréolo-mamelonnaire par l’intermédiaire d’un cas clinique peu fréquent associant de manière indépendante un cancer invasif rétro-aréolaire et une atteinte dermatologique de l’aréole mimant une maladie de Paget.

Breast Cancer Screening Rates Among Medicaid Beneficiaries With Schizophrenia.

Women with serious mental illness are more likely to be diagnosed as having late-stage breast cancer than women without serious mental illness, suggesting a disparity in screening mammography. This study aimed to compare screening mammography rates in a nationally representative sample of Medicaid beneficiaries with and without schizophrenia. Medicaid Analytic eXtract files, 2007-2012, were used to identify a cohort of women ages 40-64 with schizophrenia who were eligible for Medicaid but not Medicare (N87,572 in 2007 and N114,341 in 2012) and a cohort without schizophrenia, frequency-matched by age, race-ethnicity, and state (N97,003 in 2007 and N126,461 in 2012). Annual screening mammography rates were calculated and adjusted for demographic characteristics and comorbid conditions. Multivariable logistic regression was used to estimate the association between beneficiary characteristics and screening mammography rates. In 2012, 27.2% of women with schizophrenia completed screening mammography, compared with 26.8% of the control cohort. In the schizophrenia cohort, American IndianAlaskan Native women had significantly lower odds of receiving mammography (OR0.82, p0.02) than White women, whereas HispanicLatina women had higher odds (OR1.16, p<0.001). Women with schizophrenia and a nonalcohol-related substance use disorder had lower odds of receiving mammography (OR0.74, p<0.001) than women without a substance use disorder. Having at least one medical visit in the past year (vs. no visits) increased the odds of receiving screening mammography (OR5.08, p<0.001). Screening mammography rates were similar between Medicaid-insured women with and those without schizophrenia. Interventions to increase uptake may need to focus on improving socioeconomic conditions and primary care engagement for vulnerable populations, regardless of psychiatric condition.

YAP Overexpression in Breast Cancer Cells Promotes Angiogenesis through Activating YAP Signaling in Vascular Endothelial Cells.

The YAP signaling pathway is altered and implicated as oncogenic in human mammary cancers. However, roles of YAP signaling that regulate the breast tumor angiogenesis have remained elusive. Tumor angiogenesis is coordinated by the activation of both cancer cells and vascular endothelial cells. Whether the YAP signaling pathway can regulate the intercellular interaction between cancer cells and endothelial cells is essentially unknown. The effects of YAP on tumor angiogenesis, migration, and proliferation of vascular endothelial cells were evaluated in vitro. Expression of proteins and phosphorylating proteins involved in YAP, G13-RhoA, and PI3KAkt signaling pathways was evaluated using the Western blotting, immunofluorescence staining, and immunohistochemistry analysis. In addition, the effects of YAP on breast cancer angiogenesis were evaluated in vivo by tumor xenograft mice. We showed here that conditioned media from YAP overexpressed breast cancer cells (CM-YAP) could promote angiogenesis, accompanied by increased tube formation, migration, and proliferation of human umbilical vein endothelial cells (HUVECs). Down regulation of YAP in HUVECs reversed CM-YAP induced angiogenesis. CM-YAP time-dependently activated YAP in HUVECs by dephosphorylating YAP and increasing nuclear translocation. We also identified that both G YAP-YAP interaction between breast cancer cells and endothelial cells could promote tumor angiogenesis, supporting that YAP is a potential marker and target for developing novel therapeutic strategies against breast cancer.

The cuproptosis-related signature predicts prognosis and indicates immune microenvironment in breast cancer.

Breast cancer (BC) is the most diagnosed cancer in women. Cuproptosis is new regulated cell death, distinct from known death mechanisms and dependent on copper and mitochondrial respiration. However, the comprehensive relationship between cuproptosis and BC is still blank until now. In the present study, we acquired 13 cuproptosis-related regulators (CRRs) from the previous research and downloaded the RNA sequencing data of TCGA-BRCA from the UCSC XENA database. The 13 CRRs were all differently expressed between BC and normal samples. Using consensus clustering based on the five prognostic CRRs, BC patients were classified into two cuproptosis-clusters (C1 and C2). C2 had a significant survival advantage and higher immune infiltration levels than C1. According to the Cox and LASSO regression analyses, a novel cuproptosis-related prognostic signature was developed to predict the prognosis of BC effectively. The high- and low-risk groups were divided based on the risk scores. Kaplan-Meier survival analysis indicated that the high-risk group had shorter overall survival (OS) than the low-risk group in the training, test and entire cohorts. GSEA indicated that the immune-related pathways were significantly enriched in the low-risk group. According to the CIBERSORT and ESTIMATE analyses, patients in the high-risk group had higher infiltrating levels of antitumor lymphocyte cell subpopulations and higher immune score than the low-risk group. The typical immune checkpoints were all elevated in the high-risk group. Furthermore, the high-risk group showed a better immunotherapy response than the low-risk group based on the Tumor Immune Dysfunction and Exclusion (TIDE) and Immunophenoscore (IPS). In conclusion, we identified two cuproptosis-clusters with different prognoses using consensus clustering in BC. We also developed a cuproptosis-related prognostic signature and nomogram, which could indicate the outcome, the tumor immune microenvironment, as well as the response to immunotherapy.

Comprehensive analysis of PTPN gene family revealing PTPN7 as a novel biomarker for immuno-hot tumors in breast cancer.

Diagnosis and management of breast implant capsule recurrence following mastectomy and subpectoral implant - innovative use of ADM for reconstruction.

It is well reported that patients who have undergone breast augmentation and subsequently develop breast cancer can successfully undergo breast-conserving therapy with preservation of their implants. However, there is a paucity of literature on the radiological investigations and surgical techniques in postmastectomy implant-reconstructed patients who develop recurrences to enable preservation of their implant-based reconstruction whilst effectively treating the local recurrence. The wide adoption of acellular dermal matrix use in prosthetic breast reconstruction in recent years has made radiological evaluation of such patients challenging. Herein presented is a case of a 37-year-old woman where wide local excision of a local recurrence abutting a peri-implant capsule following previous mastectomy and implant-acellular dermal matrix (ADM) reconstruction was performed with successful preservation of reconstruction volume (and shape) using an ADM patch to repair the capsular defect whilst retaining the implant

Identification of tumor antigens and immune subtypes in breast cancer for mRNA vaccine development.

Poor prognosis, resistance to chemotherapy, insensitivity to radiotherapy, and a high prevalence of adverse drug reactions remain urgent issues for breast cancer (BC) patients. Increased knowledge of tumor immunobiology and vaccine development suggests the possibility of cancer vaccination. Here, we investigated potential BC-associated antigens for the development of an anti-BC mRNA vaccine and populations suitable for mRNA vaccination. Gene expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). The single-cell sequencing data were obtained from the Single Cell Portal platform. cBioPortal was used to visualize and compare genetic alterations. Correlations between immune cell infiltration and antigen expression were visualized with the Tumor Immune Estimation Resource (TIMER). Immune subtypes were identified by consensus clustering and analysis of immune infiltration. Biomarkers for the assessment of mRNA vaccination suitability were investigated. Three tumor-associated antigens, CD74, IRF1, and PSME2, that showed overexpression, amplification, and mutation and were linked with prognosis and immune cell infiltration, were identified. Single-cell sequencing analysis showed the expression of the three tumor-associated antigens in different cells of BC. Three immune subtypes were identified among BC patients, with Cluster B patients having a tumor microenvironment conducive to immunotherapy. These subtypes also showed different expression patterns of immune checkpoints, immune cell death-promoting genes, and response to immune checkpoint inhibitor (ICI) therapy. Thus, we identified five biomarkers that could be applied for assessing vaccination suitability and predicted drugs that would be appropriate for patients unsuited for vaccination. Our findings suggest new directions for the development of mRNA vaccines against breast cancer.

Conducive target range of breast cancer Hypoxic tumor microenvironment.

Breast cancer is a kind of malignant tumor disease that poses a serious threat to human health. Its biological characteristics of rapid proliferation and delayed angiogenesis, lead to intratumoral hypoxia as a common finding in breast cancer. HIF as a transcription factor, mediate a series of reactions in the hypoxic microenvironment, including metabolic reprogramming, tumor angiogenesis, tumor cell proliferation and metastasis and other important physiological and pathological processes, as well as gene instability under hypoxia. In addition, in the immune microenvironment of hypoxia, both innate and acquired immunity of tumor cells undergo subtle changes to support tumor and inhibit immune activity. Thus, the elucidation of tumor microenvironment hypoxia provides a promising target for the resistance and limited efficacy of current breast cancer therapies. We also summarize the hypoxic mechanisms of breast cancer treatment related drug resistance, as well as the current status and prospects of latest related drugs targeted HIF inhibitors.

A vicious circle in breast cancer The interplay between inflammation, reactive oxygen species, and microRNAs.

Breast cancer (BC) is the most common cancer in women worldwide. This highly heterogeneous disease is molecularly stratified into luminal A, luminal B, HER2, triple-negativebasal-like, and normal-like subtypes. An important aspect in BC progression is the activation of inflammatory processes. The activation of CD8Th1, NK, and M1 tumor associated macrophages (TAMs), leads to tumor destruction. In contrast, an anti-inflammatory response mediated by CD4Th2 and M2 TAMs will favor tumor progression. Inflammation also stimulates the production of inflammatory mediators like reactive oxygen species (ROS). In chronic inflammation, ROS activates oxidative stress and endothelial dysfunction. In cancer, ROS plays a dual role with anti-tumorigenic and pro-tumorigenic effects in cell signaling pathways that control proliferation, survival, apoptosis, and inflammation. MicroRNAs (miRNAs), which are known to be involved in BC progression and inflammation, can be regulated by ROS. At the same time, miRNAs regulate the expression of genes modulating oxidative stress. In this review, we will discuss the interplay between inflammation, ROS, and miRNAs as anticancer and tumor promoter molecules in BC. A clear understanding of the role of miRNAs in the regulation of ROS production and inflammation, may lead to new opportunities for therapy in BC.

Interpreting Breast Cancer Mortality Trends Related to Introduction of Mammography Screening A Simulation Study.

Population-level mammography screening effects on breast cancer mortality emerge gradually following screening introduction, resulting in very low statistical power of trend analysis.Researchers and policy makers evaluating mammography screening should avoid relying on population-wide breast cancer mortality trends.Expected mammography screening effects at population level are lower than those from screening trials, as many cases of breast cancer fall outside the screening age range.

Integrating a Patient Decision Aid into the Electronic Health Record A Case Report on the Implementation of BREASTChoice at 2 Sites.

Patient decision aids can support shared decision making and improve decision quality. However, decision aids are not widely used in clinical practice due to multiple barriers. Integrating patient decision aids into the electronic health record (EHR) can increase their use by making them more clinically relevant, personalized, and actionable. In this article, we describe the procedures and considerations for integrating a patient decision aid into the EHR, based on the example of BREASTChoice, a decision aid for breast reconstruction after mastectomy. BREASTChoices unique features include 1) personalized risk prediction using clinical data from the EHR, 2) clinician- and patient-facing components, and 3) an interactive format. Integrating a decision aid with patient- and clinician-facing components plus interactive sections presents unique deployment issues. Based on this experience, we outline 5 key implementation recommendations 1) engage all relevant stakeholders, including patients, clinicians, and informatics experts 2) explicitly and continually map all persons and processes 3) actively seek out pertinent institutional policies and procedures 4) plan for integration to take longer than development of a stand-alone decision aid or one with static components and 5) transfer knowledge about the software programming from one institution to another but expect local and context-specific changes. Integration of patient decision aids into the EHR is feasible and scalable but requires preparation for specific challenges and a flexible mindset focused on implementation. Integrating an interactive decision aid with patient- and clinician-facing components into the electronic health record could advance shared decision making but presents unique implementation challenges.We successfully integrated a decision aid for breast reconstruction after mastectomy called BREASTChoice into the electronic health record.Based on this experience, we offer these implementation recommendations 1) engage relevant stakeholders, 2) explicitly and continually map persons and processes, 3) seek out institutional policies and procedures, 4) plan for it to take longer than for a stand-alone decision aid, and 5) transfer software programming from one site to another but expect local changes.

Time tracking and multidimensional influencing factors analysis on female breast cancer mortality Evidence from urban and rural China between 1994 to 2019.

There are huge differences in female breast cancer mortality between urban and rural China. In order to better prevent breast cancer equally in urban and rural areas, it is critical to trace the root causes of past inequities and predict how future differences will change. Moreover, carcinogenic factors from micro-individual to macro-environment also need to be analyzed in detail. However, there is no systematic research covering these two aspects in the current literature. Breast cancer mortality data in urban and rural China from 1994 to 2019 are collected, which from China Health Statistical Yearbook. The Age-Period-Cohort model is used to examine the effects of different age groups, periods, and birth cohorts on breast cancer mortality. Nordpred project is used to predict breast cancer mortality from 2020 to 2039. The age effect gradually increases and changes from negative to positive at the age of 40-44. The period effect fluctuates very little and shows the largest difference between urban and rural areas in 2019. The birth cohort effect gradually decreases with urban-rural effects alternating between strong and weak. In the predicted results, the urban-rural mortality gap becomes first narrow and then wide and shows a trend of younger death. From the perspective of a temporal system, the changing trend of breast cancer mortality is highly consistent with the history of social and economic structural changes in China. From the perspective of the theory of social determinants of health, individuals, families, institutions and governments need to participate in the prevention of breast cancer.

Machine learning predicts the prognosis of breast cancer patients with initial bone metastases.

Bone is the most common metastatic site of patients with advanced breast cancer and the survival time is their primary concern however, we lack accurate predictive models in clinical practice. In addition to this, primary surgery for breast cancer patients with bone metastases is still controversial. The data used for analysis in this study were obtained from the SEER database (2010-2019). We made a COX regression analysis to identify prognostic factors of patients with bone metastatic breast cancer (BMBC). Through cross-validation, we constructed an XGBoost model to predicting survival in patients with BMBC. We also investigated the prognosis of patients treated with neoadjuvant chemotherapy plus surgical and chemotherapy alone using propensity score matching and K-M survival analysis. Our validation results showed that the model has high sensitivity, specificity, and correctness, and it is the most accurate one to predict the survival of patients with BMBC (1-year AUC 0.818, 3-year AUC 0.798, and 5-year survival AUC 0.791). The sensitivity of the 1-year model was higher (0.79), while the specificity of the 5-year model was higher (0.86). Interestingly, we found that if the time from diagnosis to therapy was ≥1 month, patients with BMBC had even better survival than those who started treatment immediately (HR 0.920, 95%CI 0.869-0.974, We constructed an AI model to provide a quantitative method to predict the survival of patients with BMBC, and our validation results indicate that this model should be highly reproducible in a similar patient population. We also identified potential prognostic factors for patients with BMBC and suggested that primary surgery followed by neoadjuvant chemotherapy might increase survival in a selected subgroup of patients.

Global trends of research on depression in breast cancer A bibliometric study based on VOSviewer.

Depression is common psychiatric morbidity in breast cancer survivors, seriously affecting patients quality of life and mental health. A growing body of research has investigated depression in breast cancer. However, no visual bibliometric analysis was conducted in this field. This study aimed to visualize the literature to identify hotspots and frontiers in research on breast cancer and depression. The publications related to depression in breast cancer were retrieved in the Web of Science Core Collection between 1 January 2002 and 17 March 2022. VOSviewer was used to identify co-occurrences and collaborations among countries, institutions, and keywords. CiteSpace was used to detect keyword bursts. A total of 7,350 articles and reviews related to depression in breast cancer were identified. From 2002 to 2022, the United States and the Peoples Republic of China were the most productive countries in this field. The University of California, Los Angeles, and the University of Toronto were the most productive institutions in this field. The Journal of Psycho-oncology, followed by Supportive Care in Cancer and the Journal of Clinical Oncology, had the most publications on depression in breast cancer. Of the top 10 journals, seven were from the United States, two were from England, and one was from Germany. Five research hotspots of depression in breast cancer were identified by co-word analysis. Research on post-traumatic growth, spiritual interventions, cognitive-behavioral therapy, physical activity, and symptom cluster management of depression in breast cancer was relatively mature in the core hotspots. Burst detection of keywords on depression in breast cancer showed the latest hotspots, such as mental health, cancer survivor mortality, and activity. The research on depression in breast cancer is growing. Attention should be paid to the latest hotspots, such as mental health, cancer survivor, mortality, exercise, and physical activity.

Nanobiotherapeutic strategies to target immune microenvironment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the subtype with the least favourable outcomes in breast cancer. Besides chemotherapy, there is a chronic lack of other effective treatments. Advances in omic technologies have liberated us from the ambiguity of TNBC heterogeneity in terms of cancer cell and immune microenvironment in recent years. This new understanding of TNBC pathology has already led to the exploitation of novel nanoparticulate systems, including tumor vaccines, oncolytic viruses, and antibody derivatives. The revolutionary ideas in the therapeutic landscape provide new opportunities for TNBC patients. Translating these experimental medicines into clinical benefit is both appreciated and challenging. In this review, we describe the prospective nanobiotherapy of TNBC that has been developed to overcome clinical obstacles, and provide our vision for this booming field at the overlap of cancer biotherapy and nanomaterial design.

Biological heterogeneity of primary cancer-associated fibroblasts determines the breast cancer microenvironment.

Cancer-associated fibroblasts are a highly heterogeneous group of cells whose phenotypes and gene alterations are still under deep investigation. As a part of tumor microenvironment, they are the focus of a growing number of studies. Cancer-associated fibroblasts might become a new target of breast cancer therapy, but still more tests and analyses are needed to understand mechanisms and interactions between them and breast cancer cells. The study aimed to isolate cancer associated fibroblasts from breast cancer tissue and to phenotype the isolated cell lines. We focused on various cancer-associated fibroblast characteristic biomarkers and those that might differentiate various cancer-associated fibroblasts subtypes. Patients with a histological diagnosis of invasive breast cancer (diameter ≤15 mm) and qualified for primary surgical treatment were enrolled in the study. Cell lines were isolated from breast cancer biopsy. For the phenotyping, we used flow cytometry, immunofluorescence and RT-qPCR analysis. Based on our study, there was no indication of a clear pattern in the cancer-associated fibroblasts classification. Results of cancer-associated fibroblasts expression were highly heterogeneous, and specific subtypes were not defined. Moreover, comparing cancer-associated fibroblasts divided into groups based on BC subtypes from which they were isolated also did not allow to notice of any clear pattern of expressions. In the future, a higher number of analyzed cancer-associated fibroblast cell lines should be investigated to find expression schemes.

Comprehensive pan-cancer analysis identifies cellular senescence as a new therapeutic target for cancer multi-omics analysis and single-cell sequencing validation.

Although cellular senescence has long been recognized as an anti-tumor mechanism, mounting evidence suggests that in some circumstances, senescent cells promote tumor growth and malignancy spread. Therefore, research into the exact relationship between cellular senescence and tumor immunity is ongoing. We analyzed changes in the expression, copy number variation, single-nucleotide variation, methylation, and drug sensitivity of cellular senescence-related genes in 33 tumor types. The cellular senescence score was calculated using the single-sample gene-set enrichment analysis. The correlations between cellular senescence score and prognosis, tumor immune microenvironment (TIME), and expression of tumor immune-related genes were comprehensively analyzed. Single-cell transcriptome sequencing data were used to assess the activation state of cellular senescence in the tumor microenvironment (TME). The expression of cellular senescence-associated hub genes varied significantly across cancer types. In these genes, missense mutation was the major type of single nucleotide polymorphism, and heterozygous deletion and heterozygous amplification were the major types of copy number variation. Moreover, the cellular senescence pathway in tumors was sensitive to drugs such as XMD13-2, TPCA-1, methotrexate, and KIN001-102. Furthermore, the cellular senescence score was significantly higher in most cancer types, related to poor prognosis. The expression of immune checkpoint molecules such as NRP1, CD276, and CD44 was significantly correlated with the cellular senescence score. Monocyte cellular senescence was significantly higher in the TME of kidney renal clear cell carcinoma cells than in normal tissues. The findings of this study provide insights into the important role of cellular senescence in the TIME of human cancers and the effect of immunotherapy.

ICOSL expressed in triple-negative breast cancer can induce Foxp3 Treg cell differentiation and reverse p38 pathway activation.

Inducible costimulator ligand (ICOSL) expressed on cancer cells has immunoregulatory functions in various malignancies. However, the role of ICOSL in triple-negative breast cancer (TNBC) remains unclear. In this study, the role and expression of ICOSL in TNBC were analyzed using the cBioPortal and GEPIA databases. Then the role of ICOSL in Foxp3 Treg cell differentiation, reversal of p38 pathway activation and cell proliferation, migration and apoptosis was determined in vitro. Finally, the effect of ICOSL expression on TNBC progression was verified in a nude mouse model of TNBC. We here observed that ICOSL expression in TNBC was found to be related to relapse-free survival, and Treg abundance was positively correlated with ICOSL expression, as demonstrated by database analyses. In vitro experiments showed that ICOSL overexpression (OE) in MDA-MB-231 cells induced cocultured T cells to differentiate into Foxp3 Treg cells and promoted secretion of the tumor-promoting factors IL-10 and IL-4. Furthermore, in vitro experiments showed that ICOSL reversed p38 phosphorylation and promoted the proliferation, invasion, and metastasis of MDA-MB-231 ICOSL-OE cells. Finally, tumor progression was found to be promoted by ICOSL expression in a TNBC nude mouse model. Together, ICOSL expression can enhance tumor cell growth by inducing Foxp3 Treg cell differentiation and reversing p38 pathway activation in TNBC.

Investigation of the effects of downregulation of jumping translocation breakpoint (JTB) protein expression in MCF7 cells for potential use as a biomarker in breast cancer.

MCF7 is a commonly used luminal type A non-invasivepoor-invasive human breast cancer cell line that does not usually migrate or invade compared with MDA-MB-231 highly metastatic cells, which emphasize an invasive and migratory behavior. Under special conditions, MCF7 cells might acquire invasive features. The aberration in expression and biological functions of the jumping translocation breackpoint (JTB) protein is associated with malignant transformation of cells, based on mitochondrial dysfunction, inhibition of tumor suppressive function of TGF-β, and involvement in cancer cell cycle. To investigate new putative functions of JTB by cellular proteomics, we analyzed the biological processes and pathways that are associated with the JTB protein downregulation. The results demonstrated that MCF7 cell line developed a more aggressive phenotype and behavior. Most of the proteins that were overexpressed in this experiment promoted the actin cytoskeleton reorganization that is involved in growth and metastatic dissemination of cancer cells. Some of these proteins are involved in the epithelial-mesenchymal transition (EMT) process (ACTBL2, TUBA4A, MYH14, CSPG5, PKM, UGDH, HSP90AA2, and MIF), in correlation with the energy metabolism reprogramming (PKM, UGDH), stress-response (HSP10, HSP70A1A, HSP90AA2), and immune and inflammatory response (MIF and ERp57-TAPBP). Almost all upregulated proteins in JTB downregulated condition promote viability, motility, proliferation, invasion, survival into a hostile microenvironment, metabolic reprogramming, and escaping of tumor cells from host immune control, leading to a more invasive phenotype for MCF7 cell line. Due to their downregulated condition, four proteins, such as CREBZF, KMT2B, SELENOS and CACNA1I are also involved in maintenance of the invasive phenotype of cancer cells, promoting cell proliferation, migration, invasion and tumorigenesis. Other downregulated proteins, such as MAZ, PLEKHG2, ENO1, TPI2, TOR2A, and CNNM1, may promote suppression of cancer cell growth, invasion, EMT, tumorigenic abilities, interacting with glucose and lipid metabolism, disrupting nuclear envelope stability, or suppressing apoptosis and developing anti-angiogenetic activities. Therefore, the main biological processes and pathways that may increase the tumorigenic potential of the MCF7 cells in JTB downregulated condition are related to the actin cytoskeleton organization, EMT, mitotic cell cycle, glycolysis and fatty acid metabolism, inflammatory response and macrophage activation, chemotaxis and migration, cellular response to stress condition (oxidative stress and hypoxia), transcription control, histone modification and ion transport.

Involvement of 27-hydroxycholesterol on the progression of non-small cell lung cancer via the estrogen receptor.

The oxysterol 27-hydroxycholesterol (27HC) promotes the proliferation of breast cancer cells as a selective estrogen receptor modulator (SERM), but it is mostly produced by alveolar macrophages

Systematic evaluation of tumor microenvironment and construction of a machine learning model to predict prognosis and immunotherapy efficacy in triple-negative breast cancer based on data mining and sequencing validation.

Patient Experience Ratings What Do Breast Surgery Patients Care About

Introduction Patient experience is essential in the overall care physicians often receive patient reviews evaluating their consultation encounters. Patient experience surveys can be a helpful tool to identify areas to target for improvement. We sought to evaluate what factors influenced breast surgery patients reviews of their clinic visits. Methods Prospective surveys from 2018-2020 were reviewed from a single institution. Surveys were sent to all patients within 48 hours after visiting one of our breast surgery clinics, and patients were asked their preferred mode of contact for the survey. Patients responded to surveys with scores of 0-10, with 0 as not likely and 10 extremely likely to recommend the providers office. Scores 0-6 were considered negative, 7-8 neutral, and 9-10 positive. PositiveNegative comments from patients were reviewed and classified according to mention of surgeon, clinic staffteam, clinic processing, and facility amenities. Results 744 out of 2205 patients contacted responded to the survey, resulting in a 33.7% response rate. Of this cohort, 47.6% (354744) were new patients, and 52.4% (390744) were established patients. Interactive voice response (IVR) and email, per patient indicated preferred mode of survey communication, had the highest responses. The average patient score was 9.5. Most ratings were positive (91.3%, 679744), followed by neutral comments (5.2%, 39744). There were 3.5% (26744) which were negative ratings. Of those who responded, 47.7% (355744) left a comment with their score. Surgeon-specific remarks were often noted in positive comments, followed by clinic staffteam comments. Negative comments most commonly referenced clinic processes. Conclusion Patient satisfaction surveys provide a window into creating the best patient experience. Further efforts to address these factors affecting patient experiences should be made to continue improving patient care.

Traction Radiculopathy After Surgery for Lumbar Spinal Metastasis A Case Report.

Treatment of spinal metastasis has attracted much attention globally, especially in Japan, with the advancement of cancer therapy. Among the metastases, those from breast and prostate cancers may be more important than others considering the high incidence of bone metastasis and the long-term prognosis. This condition often results in surgical procedures of spinal metastases to improve cancer patients quality of life (QOL). In the present case, a patient with lumbar metastasis of breast cancer presented with right L5 nerve palsy after palliative laminectomy surgery with posterior fusion. The nerve palsy had improved after additional bone resection around the right L5 root. The mechanism of this postoperative leg paralysis was subclinical nerve root damage due to the narrowing of the intervertebral foramen caused by the tumor protrusion like lumber disc hernia and the stretching of the nerve roots caused by the posterior shift of the dural tube. When performing decompression and fixation of a metastatic spine showing a herniated tumor formed by a tumor protruding posteriorly into the intervertebral foraminal space, sufficient tumor mass debulking should be considered to avoid postoperative intervertebral foraminal stenosis.

Breast Self-Examination Knowledge, Practice, and Beliefs Among Females in Jordan.

Worldwide, breast cancer is one of the most common types of cancer. It is the leading cause of cancer-related deaths among females in Jordan. The current study aimed to evaluate breast cancer knowledge levels and practice and assess health beliefs regarding the model supporting self-breast examination (BSE) in a group of females aged between 20 and 60 in Jordan. Descriptive, cross-sectional, correlational design was used Two hundred females participated in the study, employing convenient sampling. The adjusted version of the Champions Health Belief Model Scale (CHBMS) was utilized to collect the data. Most participants were married (F 128, 64%), and the mean of the participants age was (36.18, Implications for practice include identifying culturally specific barriers and improving health education programs to trigger breast self-examination utilization.

Association between Oxidative Stress Parameters and Hematological Indices in Breast Cancer Patients.

Breast cancer is one of the leading causes of death in women worldwide. This causes an increase in free radicals, resulting in oxidative stress. The aim of this study was to determine the effect of breast cancer on oxidative stress and its relationship with hematological indices. This case-control study included 43 women with breast cancer and 37 age-matched healthy controls. Oxidative stress and its correlation with hematological profiles over seven months were evaluated. Finally, the data were compared between the two groups using the The results revealed that patients with breast cancer had significantly increased hemoglobin (HB), hematocrit (HCT), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) levels compared with healthy subjects ( Women with breast cancer showed a deranged complete blood count (CBC) pattern compared to healthy individuals.

Olaparib outcomes in metastatic castration-resistant prostate cancer First real-world experience in safety and efficacy from the Chinese mainland.

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been approved for use in breast cancer susceptibility gene (BRCA)-mutated metastatic castration-resistant prostate cancer (mCPRC) patients. Our aim was to evaluate the adverse events (AEs) and efficacy of Olaparib in the treatment of mCRPC patients from the Chinese mainland. We retrospectively included mCPRC patients treated with Olaparib more than for 28 days. Patients with alterations in 15 homologous recombination repair (HRR) genes were defined as the HRRmt group, and the rest were defined as the HRRwt group. The efficacy was analyzed by prostate-specific antigen (PSA) decreased rate and PSA progression-free survival (PFS). The partial response, good response, and high response of PSA were defined as a reduction of between 0% and 50%, greater than 50%, and greater than 90% from baseline. A total of 43 patients were enrolled in this study, including 26 HRRmt group patients and 17 HRRwt group patients. Two HRRwt patients received additional abiraterone therapy. A partial response, good response, and high response were achieved in 89% (2326), 59% (1526), and 15% (426) of HRRmt group patients, respectively. In HRRwt group, 59% (1017), 35% (617), and 12% (217) of patients met the criteria of partial response, good response, and high response, respectively. Median PFS was 8.0 months in the HRRmt group and 3.0s months in the HRRwt group (HR, 0.61 95% CI, 0.24-1.14 Most of the AEs were tolerated, and Olaparib was effective in mCRPC patients with HRR deficiency. In addition, the underlying mechanism of the efficacy of Olaparib observed in HRRwt group patients remained explored.

Moving HER2-low breast cancer predictive and prognostic data from clinical trials into the real world.

Mammographic and Ultrasonographic Imaging Analysis for Neoadjuvant Chemotherapy Evaluation Volume Reduction Indexes That Correlate With Pathological Complete Response.

We aimed to evaluate volume reduction in digital mammography (DM) and ultrasound (US) for neoadjuvant chemotherapy (NAC) evaluation, with breast cancer-specific survival and pathological complete response (pCR) associations. This is a retrospective observational cohort study analyzing recorded images in 122 selected subjects out of which 569 patients presented with advanced breast cancers. Spearmans correlation and generalized estimating equations (GEE) compared volume reduction on DM and US between pCR and non-pCR after NAC with post-surgical anatomopathology. Cox regression and Kaplan-Meier curves analyzed associations between cancer-specific survival, pCR, and volume reductions. A total of 34.4% (N42) obtained pCR and 65.6% (N80) did not. Minimum percentage indexes needed to correlate with pCR over time were, at least, 28.9% for DM (p0.006) and 10.36% for US (p0.046), with high specificity (US98%, DM93%) but low sensitivity (US7%, DM18%). Positive predictive values were 82% (DM) and 86% (US) and negative predictive values were 37% (DM) and 36% (US). Cox regression and Kaplan-Meier curves demonstrated associations of breast cancer-specific survival with pCR (Cox regression coefficient B0.209, CI 95%0.048-0.914, p0.038). At least 28.9% of volume reduction on DM and 10.36% of volume reduction on US are correlated with pCR. Furthermore, pCR was associated with breast cancer-specific survival after NAC in volumetric morphological imaging analysis.

Clinicopathological Significance of STAT3 and p-STAT3 among 91 Patients with Adenocarcinoma of the Esophagogastric Junction.

Adenocarcinoma of the esophagogastric junction (AEG) has increased rapidly worldwide during the last few decades. The purpose of this study is to investigate the clinical and prognostic characteristics of signal transduction and activator of transcription factor 3(STAT3) and phosphorylated STAT3 (p-STAT3) expression in AEG patients. We retrospectively analyzed the immunohistochemical results of 61 AEG patients and followed up for 5 years, while Western blot was performed on tissues from another 30 AEG patients. The results showed that STAT3 and p-STAT3 were overexpressed in AEG tissues (

Identification of Oxidative Stress-Associated Molecular Subtypes and Signature for Predicting Survival Outcome of Cervical Squamous Cell Carcinoma.

Cervical squamous cell carcinoma (CESC) is the gynecologic malignancy with high incidence rate and high mortality rate. Oxidative stress participates in gene regulation and malignant tumor progression, including CESC. RNA-seq, clinical information, and genomic mutation were from The Cancer Genome Atlas- (TCGA-) CESC and GSE44001 datasets. Oxidative stress-related genes were obtained from the gene set enrichment analysis (GSEA) website. ConsensusClusterPlus was used for clustering, which was assessed by the Kaplan-Meier (KM) survival curve analysis, mutation analysis, immunocharacteristic analysis, and therapy. Prognostic signatures were built by combining weighted correlation network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) algorithm, and stepAIC. The prognostic power of this model was evaluated using the KM survival curve analysis, receiver operating characteristic (ROC) curve analysis, nomogram, and decision curve analysis (DCA). 218 of the 291 CESC cases (74.91%) presented oxidative stress-related gene mutation, especially FBXW7. Three clusters were determined based on oxidative stress-related genes, among which cluster 3 (C3) presented low-frequency mutation and hyperimmune state and was sensitive to immunotherapy. This research developed a 5-gene oxidative stress-related prognostic signature and a RiskScore model. As shown by ROC analysis, in the TCGA and GSE44001 datasets, the RiskScore model showed a high prediction accuracy for 1-, 3-, and 5-year CESC overall survival. High RiskScore was associated with enhanced immune status. The nomogram model was greatly predictive of the overall survival of CESC patients. Our prognostic model was based on oxidative stress-related genes in CESC, potentially aids in CESC prognosis, and provides potential targets against CESC.

Immunotheranostic microbubbles (iMBs) - a modular platform for dendritic cell vaccine delivery applied to breast cancer immunotherapy.

Therapeutic strategies engaging the immune system against malignant cells have revolutionized the field of oncology. Proficiency of dendritic cells (DCs) for antigen presentation and immune response has spurred interest on DC-based vaccines for anti-cancer therapy. However, despite favorable safety profiles in patients, current DC-vaccines have not yet presented significant outcome due to technical barriers in active DC delivery, tumor progression, and immune dysfunction. To maximize the therapeutic response, we present here a unique cell-free DC-based vaccine capable of lymphoid organ targeting and eliciting T-cell-mediated anti-tumor effect. We developed this novel immunotheranostic platform using plasma membranes derived from activated DCs incorporated into ultrasound contrast microbubbles (MBs), thereby offering real-time visualization of MBs trafficking and homing in vivo. Human PBMC-derived DCs were cultured ex vivo for controlled maturation and activation using cell membrane antigens from breast cancer cells. Following DC membrane isolation, immunotheranostic microbubbles, called DC-iMBs, were formed for triple negative breast cancer treatment in a mouse model harboring a human reconstituted immune system. Our results demonstrated that DC-iMBs can accumulate in lymphoid organs and induce anti-tumor immune response, which significantly reduced tumor growth via apoptosis while increasing survival length of the treated animals. The phenotypic changes in immune cell populations upon DC-iMBs delivery further confirmed the T-cell-mediated anti-tumor effect. These early findings strongly support the potential of DC-iMBs as a novel immunotherapeutic cell-free vaccine for anti-cancer therapy.

NSMCE2, a novel super-enhancer-regulated gene, is linked to poor prognosis and therapy resistance in breast cancer.

Despite todays advances in the treatment of cancer, breast cancer-related mortality remains high, in part due to the lack of effective targeted therapies against breast tumor types that do not respond to standard treatments. Therefore, identifying additional breast cancer molecular targets is urgently needed. Super-enhancers are large regions of open chromatin involved in the overactivation of oncogenes. Thus, inhibition of super-enhancers has become a focus in clinical trials for its therapeutic potential. Here, we aimed to identify novel super-enhancer dysregulated genes highly associated with breast cancer patients poor prognosis and negative response to treatment. Using existing datasets containing super-enhancer-associated genes identified in breast tumors and public databases comprising genomic and clinical information for breast cancer patients, we investigated whether highly expressed super-enhancer-associated genes correlate to breast cancer patients poor prognosis and to patients poor response to therapy. Our computational findings were experimentally confirmed in breast cancer cells by pharmacological SE disruption and gene silencing techniques. We bioinformatically identified two novel super-enhancer-associated genes - NSMCE2 and MAL2 - highly upregulated in breast tumors, for which high RNA levels significantly and specifically correlate with breast cancer patients poor prognosis. Through in-vitro pharmacological super-enhancer disruption assays, we confirmed that super-enhancers upregulate NSMCE2 and MAL2 transcriptionally, and, through bioinformatics, we found that high levels of NSMCE2 strongly associate with patients poor response to chemotherapy, especially for patients diagnosed with aggressive triple negative and HER2 positive tumor types. Finally, we showed that decreasing NSMCE2 gene expression increases breast cancer cells sensitivity to chemotherapy treatment. Our results indicate that moderating the transcript levels of NSMCE2 could improve patients response to standard chemotherapy consequently improving disease outcome. Our approach offers a new avenue to identify a signature of tumor specific genes that are not frequently mutated but dysregulated by super-enhancers. As a result, this strategy can lead to the discovery of potential and novel pharmacological targets for improving targeted therapy and the treatment of breast cancer.

The FUScircEZH2KLF5 feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition.

Metastasis of breast cancer have caused the majority of cancer-related death worldwide. The circRNAs are associated with tumorigenesis and metastasis in breast cancer according to recent research. However, the biological mechanism of circRNAs in liver metastatic breast cancer remains ambiguous yet. Microarray analysis of three pairs of primary BC tissues and matched hepatic metastatic specimens identified circEZH2. We used RT-qPCR and FISH assays to confirm circEZH2 existence, characteristics, and expression. Both in vivo and in vitro, circEZH2 played an oncogenic role which promoted metastasis as well. A range of bioinformatic analysis, Western blot, RNA pull-down, RIP, ChIP, and animal experiments were used to define the feedback loop involving FUS, circEZH2, miR-217-5p, KLF5, FUS, CXCR4 as well as epithelial and mesenchymal transition. In our research, circEZH2 was proved to be upregulated in liver metastases in BC and predicted the worse prognosis in breast cancer patients. Overexpression of circEZH2 notably accentuated the vitality and invasion of BC cells, whereas knockdown of circEZH2 elicited the literally opposite effects. Besides, overexpressed circEZH2 promoted tumorigenesis and liver metastasis in vivo. Moreover, circEZH2 could adsorb miR-217-5p to upregulate KLF5 thus leading to activate FUS transcription which would facilitate the back-splicing program of circEZH2. Meanwhile, KLF5 could upregulated CXCR4 transcriptionally to accelerate epithelial and mesenchymal transition of breast cancer. Consequently, a novel feedback loop FUScircEZH2KLF5CXCR4 was established while circEZH2 could be novel biomarker and potential target for BC patients therapy.

Development and validation of an extended Cox prognostic model for patients with ERPR and HER2- breast cancer a retrospective cohort study.

The purpose of this study was to explore a new estrogen receptor (ER) andor progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)- breast cancer prognostic model, called the extended Cox prognostic model, for determining the cutoff values for multiple continuous prognostic factors and their interaction via the new model concept and variable selection method. A total of 335 patients with ERPR and HER2- breast cancer were enrolled for the final analysis. The primary endpoint was breast cancer-specific mortality (BCSM). Prognostic factors (histological grade, histological type, stage, T, N, lymphovascular invasion (LVI), P53, Ki67, ER, PR, and age) were included in this study. The four continuous variables (Ki67, ER, PR, and age) were partitioned into a series of binary variables that were fitted in the multivariate Cox analysis. A smoothly clipped absolute deviation (SCAD) variable selection method was used. Model performance was expressed in discrimination and calibration. We developed an extended Cox model with a time threshold of 164-week (more than 3 years) postoperation and developed a user-friendly nomogram based on our extended Cox model to facilitate clinical application. We found that the cutoff values for PR, Ki67, and age were 20%, 60%, and 41-55 years, respectively. There was an interaction between age and PR for patients aged ≥ 41 years and PR ≥ 20% at 164-week postoperation the older the patients with ERPR, HER2-, and PR ≥ 20% were, the lower the survival and more likely to recur and metastasize exceeding 164 weeks (more than 3 years) after surgery. Our study offers guidance on the prognosis of patients with ERPR and HER2- breast cancer in China. The new concept can inform modeling and the determination of cutoff values of prognostic factors in the future.

Healthcare professionals views following implementation of risk stratification into a national breast cancer screening programme.

It is crucial to determine feasibility of risk-stratified screening to facilitate successful implementation. We introduced risk-stratification (BC-Predict) into the NHS Breast Screening Programme (NHSBSP) at three screening sites in north-west England from 2019 to 2021. The present study investigated the views of healthcare professionals (HCPs) on acceptability, barriers, and facilitators of the BC-Predict intervention and on the wider implementation of risk-based screening after BC-Predict was implemented in their screening site. Fourteen semi-structured interviews were conducted with HCPs working across the breast screening pathway at three NHSBSP sites that implemented BC-Predict. Thematic analysis interpreted the data. Three pre-decided themes were produced. (1) Acceptability of risk-based screening risk-stratification was perceived as a beneficial step for both services and women. HCPs across the pathway reported low burden of running the BC-Predict trial on routine tasks, but with some residual concerns (2) Barriers to implementation comprised capacity constraints of services including the inadequacy of current IT systems to manage women with different risk profiles and, (3) Facilitators to implementation included the continuation of stakeholder consultation across the pathway to inform implementation and need for dedicated risk screening admin staff, a push for mammography staff recruitment and guidance for screening services. Telephone helplines, integrating primary care, and supporting access for all language needs was emphasised. Risk-stratified breast screening was viewed as a progressive step providing it does not worsen inequalities for women. Implementation of risk-stratified breast screening requires staff to be reassured that there will be systems in place to support implementation and that it will not further burden their workload. Next steps require a comprehensive assessment of the resource needed for risk-stratification versus current resource availability, upgrades to screening IT and building screening infrastructure. The role of primary care needs to be determined. Simplification and clarification of risk-based screening pathways is needed to support HCPs agency and facilitate implementation. Forthcoming evidence from ongoing randomised controlled trials assessing effectiveness of breast cancer risk-stratification will also determine implementation.

Therapeutic landscape of advanced HER2-positive breast cancer in 2022.

HER2-positive breast cancer is an aggressive subtype of breast cancer with five-year survival rates of 30% for the advanced stage. The development of anti-HER2 treatments has led to a paradigm shift in the management and clinical outcomes of advanced HER2-positive breast cancer patients. The standard first-line treatment consists of taxane-based chemotherapy plus dual anti-HER2 therapies with trastuzumab and pertuzumab. The antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) has been a second-line therapeutic standard, but the second-line treatment approach is rapidly evolving. Given a substantial advantage of another ADC, Fam-trastuzumab deruxtecan (T-DXd), compared to T-DM1 in a recent randomized trial in the second-line setting, T-DXd is currently the preferred second-line option. Optimal third-line treatment strategies are still not established, and multiple approaches have been used including combinations based on capecitabine, trastuzumab, or both with oral anti-HER2 tyrosine kinase inhibitors. Tucatinib plus capecitabine and trastuzumab, lapatinib plus trastuzumab, neratinib or lapatinib plus capecitabine are some of the FDA approved combinations. Another newer agent approved for third- or later-line therapy in the metastatic setting is margetuximab, an Fc-engineered anti-HER2 monoclonal antibody, in combination with chemotherapy. Other novel agents currently under clinical trials are the drugs that indirectly target HER2, including immune cell cycle inhibitors, PI3KmTOR inhibitors, and immunotherapy agents.

5-FU and the dietary flavonoid carvacrol a synergistic combination that induces apoptosis in MCF-7 breast cancer cells.

Along with the benefits of chemotherapy in the treatment of breast cancer, the side effects of these drugs along with drug resistance make their use complicated. One of the solutions to overcome this problem is the use of herbal products and combination therapy. In this research, we try to investigate the effects of carvacrol, a monoterpene flavonoid, in combination with the chemotherapy drug 5-FU. Combination index method was used for the drug-drug interactions analysis based on the Chou and Talalay method and the data from MTT assays. Apoptosis was assessed by the ELISA cell death method. P-glycoprotein expression was evaluated at the gene level by Real-time PCR. Here, we described the first experimental evidence for the existence of synergism between carvacrol and 5-FU in the in vitro model of breast cancer. MTT assay results showed combination treatment of the cells with carvacrol and 5-FU decreased 5-FU concentrations significantly. Incubation of the cells with carvacrol neutralized P-glycoprotein overexpression in qPCR assay (P ≤ 0.05). Compared with adding verapamil (a P-glycoprotein inhibitor) to 5-FU, the combination of carvacrol and 5-FU caused a further increase in the percentage of apoptotic cells when the cells were treated with both agents. Our results suggest that carvacrol can downregulate P-gp expression and combination therapy with carvacrol and 5-FU is considered a novel approach to improve the efficacy of chemotherapeutics in cancer patients with high P-glycoprotein expression.

NDR1 activates CD47 transcription by increasing protein stability and nuclear location of ASCL1 to enhance cancer stem cell properties and evasion of phagocytosis in small cell lung cancer.

Small cell lung cancer (SCLC) is one of the most malignant types of lung cancer. Cancer stem cell (CSC) and tumor immune evasion are critical for the development of SCLC. We previously reported that NDR1 enhances breast CSC properties. NDR1 might also have a role in the regulation of immune responses. In the current study, we explore the function of NDR1 in the control of CSC properties and evasion of phagocytosis in SCLC. We find that NDR1 enhances the enrichment of the ALDEFLUOR

Breast cancer risk among thyroid cancer survivors and the role of I-131 treatment.

Female thyroid cancer survivors are more likely to have a higher risk of breast cancer compared to the general population, and the underlying causes are yet to be understood. The potential role of I-131 treatment on this association remains controversial. We pooled individual data of women who were treated for differentiated thyroid cancer from 1934 to 2005 in France, Italy and Sweden. Standardized incidence ratios (SIRs) for breast cancer were estimated by comparison with age, sex and calendar-year expected values of the general population in each country. We estimated breast cancer risk in relation to I-131 treatment using time-dependent Poisson models. Of 8475 women (mean age at diagnosis 45 years, range 2-90 years), 335 were diagnosed with breast cancer SIR 1.52, 95% confidence interval (CI) 1.36-1.69 during a median follow-up time of 12.7 years since diagnosis. Overall, breast cancer risk did not differ between women treated or not with I-131 (relative risk1.07, 95% CI 0.84-1.35). However, breast cancer risk increased with increasing cumulative I-131 activity, without significant departure from linearity (excess relative risk per 100 mCi17%, 95% CI 2% to 38%). The higher risk associated with a cumulative I-131 activity of ≥100 mCi and ≥400 mCi was translated into 4 (95% CI -4 to 13) and 42 (95% CI -8 to 93) excess breast cancer cases per 10,000 person-years, respectively. An elevated risk was observed for the highest cumulative administered activity (>400 mCi), and a significant dose-dependent association was observed among thyroid cancer survivors who were treated with I-131. However, overall, I-131 treatment might only explain partly the increase in breast cancer risk among female thyroid cancer survivors.

The presentation, management and outcome of patients with ductal carcinoma in situ (DCIS) with microinvasion (invasion ≤1 mm in size)-results from the UK Sloane Project.

The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial. We analysed the outcomes of patients with DCIS with and without microinvasion diagnosed between 2003 and 2012 within the Sloane project. Microinvasion was recorded in 521 of 11,285 patients (4.6%), with considerable variation in reported incidence among screening units (0-25%). Microinvasion was associated with high-grade DCIS, larger DCIS size, comedo necrosis and solid, cribriform architecture (all P < 0.001). Microinvasion was more frequent in patients who underwent mastectomy compared with breast-conserving surgery (BCS) (6.9% vs 3.6%, P < 0.001), and in those undergoing axillary nodal surgery (60.4% vs 30.3%, P < 0.001) including the subset undergoing BCS (43.4% vs 8.5%, P < 0.001). Nodal metastasis rate was low and not statistically significant difference from the DCIS only group (P 0.68). Following median follow-up of 110 months, 3% of patients had recurrent ipsilateral high-grade DCIS, and 4.2% developed invasive carcinoma. The subsequent ipsilateral invasion was of Grade 3 in 71.4% of patients with microinvasion vs 30.4% in DCIS without microinvasion (P 0.02). Distant metastasis and breast cancer mortality were higher with microinvasion compared with DCIS only (1.2% vs 0.3%, P 0.01 and 2.1% vs 0.8% P 0.005). The higher breast cancer mortality with microinvasion indicates a more aggressive disease.

Identification and analysis of dysregulated fatty acid metabolism genes in breast cancer subtypes.

Breast cancer is one of the most aggressive and lethal types of transformation among women. An anomaly of normal fatty acid metabolism is acknowledged as a critical trigger for malignant transformations including breast cancer, but the prospect of targeting fatty acid metabolism for the treatment of malignancy has remained unrecognized so far. It has been observed that specific fatty acid metabolism genes are involved in the commencement and development of breast cancer. These specific genes have also been observed to be related to different isotypesmolecular subtypes of breast cancer. The main purpose of this study was to scrutinize the prognostic significance, functional role, and expression pattern of fatty acid metabolism genes. In-Silico tools like TCGA BrCA, Gepia2, Ualcan Analysis, UCSC Xena, Kaplan-Meier plotter, Bc-gene EXminer, String, gene ontology, and KEGG databases, were used to assess the expression pattern of the fatty acid metabolism genes in breast cancer patients and also among the different molecular sub-types of breast cancer. Differential gene expression analysis revealed dysregulation of FABP4, FABP5, PLIN1, PLIN2, PLIN4, PLIN5, LPIN1, MGLL, PNPLA2, PNPLA7, ACSL1, and ACOX2 showing a fold change > ± 1.5. Also, most of these genes show downregulation in Ualcan analysis of different isotypesmolecular subtypes of breast cancer. The study reveals that the screened genes i.e., FABP4, FABP5, PLIN1, PLIN2, PLIN4, PLIN5, LPIN1, MGLL, PNPLA2, PNPLA7, ACSL1, and ACOX2 can be used as biomarkers that reveal poor prognosis and may serve as therapeutic targets for the treatment of breast cancer.

Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain.

Brain metastasis in breast cancer remains difficult to treat and its incidence is increasing. Therefore, the development of new therapies is of utmost clinical relevance. Recently, toll-like receptor (TLR) 4 was correlated with IL6 expression and poor prognosis in 1 215 breast cancer primaries. In contrast, we demonstrated that TLR4 stimulation reduces microglia-assisted breast cancer cell invasion. However, the expression, prognostic value, or therapeutic potential of TLR signaling in breast cancer brain metastasis have not been investigated. We thus tested the prognostic value of various TLRs in two brain-metastasis gene sets. Furthermore, we investigated different TLR agonists, as well as MyD88 and TRIF-deficient microenvironments in organotypic brain-slice ex vivo co-cultures and in vivo colonization experiments. These experiments underline the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Moreover, analysis of the gene expression datasets of breast cancer brain metastasis patients revealed associations of TLR1 and IL6 with poor overall survival. Finally, our finding that a single LPS application at the onset of colonization shapes the later microgliamacrophage reaction at the macro-metastasis brain-parenchyma interface (MMPI) and reduces metastatic infiltration into the brain parenchyma may prove useful in immunotherapeutic considerations.

Zn (II)-porphyrin-based photochemically green synthesis of novel ZnTPPCu nanocomposites with antibacterial activities and cytotoxic features against breast cancer cells.

This study focuses on synthesizing novel nanocomposites, zinc(II)tetrakis(4-phenyl)porphyrinCu nanoparticles (ZnTPPCu-NPs),with antibacterial activity, fabricated through a single-step green procedure. In this regard, the self-assembly of ZnTPP was carried out through an acid-base neutralization method to prepare ZnTPP nanoparticles. Then, the copper nanoparticles (Cu-NPs) were grown on ZnTPP nanoparticles through a visible-light irradiated photochemical procedure in the absence and presence of polyacrylic acid (PAA) as a modulator. The effect of PAA on the morphological properties of the prepared nanocomposites was evaluated. Eventually, the antibacterial activity of nanocomposites with different morphologies was investigated. In this way, the average zone of inhibition growth of diameter, minimum inhibitory concentration, and minimum bactericidal concentration values was determined. Besides, the cytotoxicity of the nanocomposites was evaluated by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay MCF-7and (HEK-293) cell lines. The specific features of the synthesized nanocomposites identified them as antibacterial compounds which have therapeutic effects on breast cancer.

Design, synthesis and computational study of new benzofuran hybrids as dual PI3KVEGFR2 inhibitors targeting cancer.

Design and synthesis of a new series of benzofuran derivatives has been performed.

Network analysis to identify symptoms clusters and temporal interconnections in oncology patients.

Oncology patients experience numerous co-occurring symptoms during their treatment. The identification of sentinelcore symptoms is a vital prerequisite for therapeutic interventions. In this study, using Network Analysis, we investigated the inter-relationships among 38 common symptoms over time (i.e., a total of six time points over two cycles of chemotherapy) in 987 oncology patients with four different types of cancer (i.e., breast, gastrointestinal, gynaecological, and lung). In addition, we evaluated the associations between and among symptoms and symptoms clusters and examined the strength of these interactions over time. Eight unique symptom clusters were identified within the networks. Findings from this research suggest that changes occur in the relationships and interconnections between and among co-occurring symptoms and symptoms clusters that depend on the time point in the chemotherapy cycle and the type of cancer. The evaluation of the centrality measures provides new insights into the relative importance of individual symptoms within various networks that can be considered as potential targets for symptom management interventions.

CNS Tumors - clinical and radiological aspects.

Tumors of the central nervous system (CNS) include primary tumors - itraaxial, growing from brain and spinal cord cells (neuroepithelial tumors) or extraaxial, growing from surrounding structures (brain and spinal cord, nerve sheaths, vascular structures, lymphatic tissue, germ cells, malformations, pituitary glands). Much more often they are located in the intracranial space a solitary or multiple metastatic spread of malignancy originating from another organ (eg lung, breast, malignant melanoma, Grawitzs tumor). The occurrence of metastases of solid tumors is then in the intraaxial or extraaxial region, leptomeningeal or dural. Even morphologically benign tumors with their occurrence in a closed CNS compartment can have malignant behaviour and cause severe slowly developing to acute neurological symptoms, including intracranial hypertension. Primary tumors of the central nervous system present 1-2% of all cancers, with a higher incidence in adults after the age of 60, with a slight predominance in men, with higher mortality in men than in women. About 5% of CNS tumors are hereditary (e.g., Li-Fraumeni syndrome, neurofibromatosis type I, II). The causes of most brain and spinal cord tumors are unclear, the effect of radiation has been definitely demonstrated, there is an increased risk in transplant patients and AIDS (Acquired Immune Deficiency Syndrome) patients, and the potentiating effects of some chemicals and viruses on the development of CNS neoplasms are uncertain. The effectiveness of treatment of brain and spinal cord tumors is influenced by the existence of the so-called hematoencephalic barrier, which protects the brain from the penetration of toxic substances, but at the same time prevents the penetration of most cytostatics to the tumor target. Another obstacle may be the localization of the tumor in areas difficult to access for histological verification (brain stem, optical chiasma) due to the high risk of complications even after stereotactic biopsy. In some cases, in an effort not to cause an irreversible neurological deficit by inconsiderate tissue collection, the sample of histological material can then become inconclusive to tumor cells, i.e., tumor cells are not captured. Last but not least, the radiosensitivity of some brain structures is also limiting, which makes it impossible to apply a higher dose of ionizing radiation to a tumor affecting sensitive tissues or located near of these sensitive tissues. The rapid development of immunohistochemical (IHC) and molecular genetic analysis methods has significantly refined diagnostics and thus theoretically facilitates the choice of the optimal treatment procedure for the individual patient. While advances in modern conformal photon and particle (currently the most frequently proton) radiotherapy, stereotactic radiosurgery has enabled accurately targeted irradiation of the CNS tumor site and at the same time spare the high-risk brain structures, thereby significantly reduce the risk of acute and late neurotoxicity, pharmacotherapy options are still limited. Just molecular-genetic knowledge already provides us with predictive and prognostic information. They should increasingly stratify patients for targeted therapy.

Metastatic triple negative breast cancer with NTRK gene fusion on tissue but not on ctDNA molecular profile.

A woman presented to medical oncology with almost 4 years of untreated, slowly progressing, triple negative metastatic breast cancer to the lung. About 15 years prior, she was diagnosed with invasive ductal carcinoma of the right breast with ipsilateral chest wall recurrence 6 years later. Comprehensive molecular profiling of a metastatic lesion detected a hotspot

PARP-inhibition reprograms macrophages toward an anti-tumor phenotype.

Poly(ADP)ribosylation inhibitors (PARPis) are toxic to cancer cells with homologous recombination (HR) deficiency but not to HR-proficient cells in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs). As TAMs can promote or inhibit tumor growth, we set out to examine the effects of PARP inhibition on TAMs in BRCA1-related breast cancer (BC). The PARPi olaparib causes reprogramming of TAMs toward higher cytotoxicity and phagocytosis. A PARPi-related surge in NAD increases glycolysis, blunts oxidative phosphorylation, and induces reverse mitochondrial electron transport (RET) with an increase in reactive oxygen species (ROS) and transcriptional reprogramming. This reprogramming occurs in the absence or presence of PARP1 or PARP2 and is partially recapitulated by addition of NAD derivative methyl-nicotinamide (MNA). In vivo and ex vivo, the effect of olaparib on TAMs contributes to the anti-tumor efficacy of the PARPi. In vivo blockade of the dont-eat-me signal with CD47 antibodies in combination with olaparib improves outcomes in a BRCA1-related BC model.

Cytokines drive prostate cancer lineage plasticity.

Lineage plasticity is a critical mechanism of therapeutic resistance in cancer. In a recent issue of Science, Chan and colleagues demonstrate that early lineage plasticity in prostate cancer is driven by JAK-STAT inflammatory cytokine signaling.

Subcutaneous injection of trastuzumab into the thigh versus abdominal wall in patients with HER2-positive early breast cancer Pharmacokinetic, safety and patients preference - Substudy of the randomised phase III GAIN-2 study.

Trastuzumab given intravenously in combination with chemotherapy is standard of care for patients with early HER2-positive breast cancer (BC). Different randomised studies have shown equivalent efficacy of a subcutaneous injection into the thigh compared to the intravenous formulation. Other body regions for injection have not been investigated but might be more convenient for patients. After surgery, patients were randomised to receive either subcutaneous trastuzumab into the thigh or into the abdominal wall (AW). Patient preferences were evaluated using validated questionnaires (PINT). Primary objectives of this multicentre, non-blinded, randomised substudy of the GAIN-2 study were to investigate pharmacokinetics of the injection into the thigh versus AW and to determine patients preferences of either administration site versus the previously received intravenous application. 226 patients were randomised and 219 patients (thigh N 110 AW N 109) formed the modified intent-to-treat (mITT). Overall, 83.5% (out of N 182 with information about patients preference) preferred subcutaneous over previous intravenous application or had no preference. Preference was similar between both administration sites (thigh 80.6% AW 86.5 p 0.322). Pharmacokinetic analysis included 30 patients. Geometric means of C Subcutaneous trastuzumab into the thigh showed an approximately 30% higher bioavailability. Injections were well tolerated and preferred over intravenous administration. The subcutaneous injection into the thigh should remain the standard of care.

iSegMSI An Interactive Strategy to Improve Spatial Segmentation of Mass Spectrometry Imaging Data.

Spatial segmentation is a critical procedure in mass spectrometry imaging (MSI)-based biochemical analysis. However, the commonly used unsupervised MSI segmentation methods may lead to inappropriate segmentation results as the MSI data is characterized by high dimensionality and low signal-to-noise ratio. This process can be improved by the incorporation of precise prior knowledge, which is hard to obtain in most cases. In this study, we show that the incorporation of partial or coarse prior knowledge from different sources such as reference images or biological knowledge may also help to improve MSI segmentation results. Here, we propose a novel interactive segmentation strategy for MSI data called iSegMSI, which incorporates prior information in the form of scribble-regularization of the unsupervised model to fine-tune the segmentation results. By using two typical MSI data sets (including a whole-body mouse fetus and human thyroid cancer), the present results demonstrate the effectiveness of the iSegMSI strategy in improving the MSI segmentations. Specifically, the method can be used to subdivide a region into several subregions specified by the user-defined scribbles or to merge several subregions into a single region. Additionally, these fine-tuned results are highly tolerant to the imprecision of the scribbles. Our results suggest that the proposed iSegMSI method may be an effective preprocessing strategy to facilitate the analysis of MSI data.

Differences in Cancer Screening Responses to State Medicaid Expansions by Race and Ethnicity, 2011‒2019.

IMPACT the Brain A Team-Based Approach to Management of Metastatic Breast Cancer With CNS Metastases.

CNS metastases are associated with decreased survival and quality of life for patients with metastatic breast cancer (MBC). Team-based care can optimize outcomes. IMPACT the Brain is a care coordination program that aims to improve access to team-based care for patients with MBC and CNS metastases. Patients with MBC and CNS metastases were eligible for enrollment in this care coordination program. A team of specialists supported a dedicated program coordinator who provided navigation, education, specialty referral, and clinical trial screening. A unique intake form developed for the program created personalized, coordinated, and expedited specialty referrals. Patient-reported outcomes and caregiver burden assessments were collected on a voluntary basis throughout enrollment. Data were analyzed using descriptive statistics. Sixty patients were referred, and 53 were enrolled (88%). The median time to program enrollment was 1 day (range, 0-11) and to first visit was 5 days (range, 0-25). On the basis of the program intake form, 47 referrals were made across six specialties, most commonly physical medicine and rehabilitation (n 10), radiation oncology (n 10), and neuropsychology (n 10). Nineteen patients (36%) consented to enroll in clinical trials. A tailored team-based care coordination program for patients with MBC and CNS metastases is feasible. Use of a unique intake screening form by a dedicated program coordinator resulted in faster time to first patient visit, enabled access to subspecialist care, and supported enrollment in clinical trials. Future research should focus on intervention development using PRO data collected in this care coordination program.

Tinengotinib (TT-00420), a Novel Spectrum-Selective Small-Molecule Kinase Inhibitor, Is Highly Active Against Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous cancer lacking actionable targets. Using a phenotypic screen of TNBC cells, we discovered a novel multiple kinase inhibitor tinengotinib (TT-00420) that strongly inhibited Aurora AB, FGFR123, VEGFRs, JAK12, and CSF1R in biochemical assays. Exposure to tinengotinib specifically inhibited proliferation across all subtypes of TNBC in vitro and in vivo, while leaving luminal breast cancer cells intact. Incubation of HCC1806 with tinengotinib led to dose-dependent downregulation of genes essential for TNBC cell growth and proliferation. Studies revealed that the potential mechanism of action of tinengotinib involved, predominantly, inhibition of Aurora A or B kinase activity, while inhibition of other pathways contributed to suppression of potency and activity. In vitro treatment of TNBC cell lines or in vivo administration in a syngeneic model with tinengotinib resulted in up-regulation of CXCL10 and 11 or diminished tumor-associated macrophage (TAM) infiltration. Tinengotinib represents a novel combinatorial inhibitory mechanism to treat TNBC. The phase I trial of tinengotinib was completed (ClinicalTrials.gov identifier NCT03654547).

Pro-inflammatory megakaryocyte gene expression in murine models of breast cancer.

Despite abundant research demonstrating that platelets can promote tumor cell metastasis, whether primary tumors affect platelet-producing megakaryocytes remains understudied. In this study, we used a spontaneous murine model of breast cancer to show that tumor burden reduced megakaryocyte number and size and disrupted polyploidization. Single-cell RNA sequencing demonstrated that megakaryocytes from tumor-bearing mice exhibit a pro-inflammatory phenotype, epitomized by increased

Engineering human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia, and solid tumor metastasis.

The bone marrow microenvironment provides indispensable factors to sustain blood production throughout life. It is also a hotspot for the progression of hematologic disorders and the most frequent site of solid tumor metastasis. Preclinical research relies on xenograft mouse models, but these models preclude the human-specific functional interactions of stem cells with their bone marrow microenvironment. Instead, human mesenchymal cells can be exploited for the in vivo engineering of humanized niches, which confer robust engraftment of human healthy and malignant blood samples. However, mesenchymal cells are associated with major reproducibility issues in tissue formation. Here, we report the fast and standardized generation of human mini-bones by a custom-designed human mesenchymal cell line. These resulting humanized ossicles (hOss) consist of fully mature bone and bone marrow structures hosting a human mesenchymal niche with retained stem cell properties. As compared to mouse bones, we demonstrate superior engraftment of human cord blood hematopoietic cells and primary acute myeloid leukemia samples and also validate hOss as a metastatic site for breast cancer cells. We further report the engraftment of neuroblastoma patient-derived xenograft cells in a humanized model, recapitulating clinically described osteolytic lesions. Collectively, our human mini-bones constitute a powerful preclinical platform to model bone-developing tumors using patient-derived materials.

Exercise Leg Blood Flow Is Preserved in Long-term Breast Cancer Survivors Previously Treated With Anthracycline Chemotherapy.

The objective of this investigation was to compare the acute hemodynamic responses during single-leg knee extension (SLKE) exercise between female breast cancer (BC) survivors previously treated with anthracycline chemotherapy and age- and sex-matched control (CON) subjects. Fourteen BC survivors (age 61 ± 7 yr time post-anthracycline therapy 12 ± 6 yr) and nine CON subjects (age 59 ± 7 yr) performed SLKE exercise at 25%, 50%, and 75% of peak power output during which heart rate, blood pressure (BP), leg blood flow (Doppler ultrasonography), and vascular conductance (leg blood flowmean BP) were measured. Quadriceps mass was estimated from thigh volume and skinfold measures. Breast cancer survivors had lower quadriceps mass compared with CON subjects (1803 ± 607 vs 2601 ± 1102 g, P .04). No difference was found between groups for maximal SLKE power output (28 ± 11 vs 34 ± 17 W, P .35), heart rate (109 ± 14 vs 103 ± 13 bpm, P .36), or mean arterial BP (122 ± 18 vs 119 ± 26 mm Hg, P .33). Rest and submaximal exercise mean arterial BP, leg blood flow (indexed to quadriceps muscle mass), and leg vascular conductance were not significantly different between BC survivors and CON subjects. Leg blood flow during submaximal SLKE exercise is preserved in long-term BC survivors previously treated with anthracycline chemotherapy.

Myoglobin regulates fatty acid trafficking and lipid metabolism in mammary epithelial cells.

Myoglobin (MB) is known to bind and deliver oxygen in striated muscles at high expression levels. MB is also expressed at much reduced levels in mammary epithelial cells, where the protein´s function is unclear. In this study, we aim to determine whether MB impacts fatty acid trafficking and facilitates aerobic fatty acid ß-oxidation in mammary epithelial cells. We utilized MB-wildtype versus MB-knockout mice and human breast cancer cells to examine the impact of MB and its oxygenation status on fatty acid metabolism in mouse milk and mammary epithelia. MB deficient cells were generated through CRISPRCas9 and TALEN approaches and exposed to various oxygen tensions. Fatty acid profiling of milk and cell extracts were performed along with cell labelling and immunocytochemistry. Our findings show that MB expression in mammary epithelial cells promoted fatty acid oxidation while reducing stearyl-CoA desaturase activity for lipogenesis. In cells and milk product, presence of oxygenated MB significantly elevated indices of limited fatty acid ß-oxidation, i.e., the organelle-bound removal of a C2 moiety from long-chain saturated or monounsaturated fatty acids, thus shifting the composition toward more saturated and shorter fatty acid species. Presence of the globin also increased cytoplasmic fatty acid solubility under normoxia and fatty acid deposition to lipid droplets under severe hypoxia. We conclude that MB can function in mammary epithelia as intracellular O2-dependent shuttle of oxidizable fatty acid substrates. MBs impact on limited oxidation of fatty acids could generate inflammatory mediator lipokines, such as 7-hexadecenoate. Thus, the novel functions of MB in breast epithelia described herein range from controlling fatty acid turnover and homeostasis to influencing inflammatory signalling cascade. Future work is needed to analyse to what extent these novel roles of MB also apply to myocytic cell physiology and malignant cell behaviour, respectively.

Burden of lymphedema in long-term breast cancer survivors by race and age.

Risk assessment for breast cancer-related lymphedema has emphasized upper-limb symptoms and treatment-related risk factors. This article examined breast cancer-related lymphedema after surgery, overall and in association with broader demographic and clinical features. The Carolina Breast Cancer Study phase 3 followed participants for breast cancer-related lymphedema from baseline (on average, 5 months after breast cancer diagnosis) to 7 years after diagnosis. Among 2645 participants, 552 self-reported lymphedema cases were identified. Time-to-lymphedema curves and inverse probability weighted conditional Cox proportional hazards model were used to evaluate whether demographics and clinical features were associated with breast cancer-related lymphedema. Point prevalence of breast cancer-related lymphedema was 6.8% at baseline, and 19.9% and 23.8% at 2 and 7 years after diagnosis, respectively. Most cases had lymphedema in the arm (88%-93%), whereas 14% to 27% presented in the trunk andor breast. Beginning approximately 10 months after diagnosis, younger Black women had the highest risk of breast cancer-related lymphedema and older non-Black women had the lowest risk. Positive lymph node status, larger tumor size (>5 cm), and estrogen receptor-negative breast cancer, as well as established risk factors such as higher body mass index, removal of more than five lymph nodes, mastectomy, chemotherapy, and radiation therapy, were significantly associated with increased hazard (1.5- to 3.5-fold) of lymphedema. Findings highlight that hazard of breast cancer-related lymphedema differs by demographic characteristics and clinical features. These factors could be used to identify those at greatest need of lymphedema prevention and early intervention. In this study, the aim was to investigate breast cancer-related lymphedema (BCRL) burden. This study found that risk of BCRL differs by race, age, and other characteristics.

Exogenous growth hormone promotes an epithelial-mesenchymal hybrid phenotype in cancerous HeLa cells but not in non-cancerous HEK293 cells.

In cancer, the Epithelial to Mesenchymal Transition (EMT) is the process in which epithelial cells acquire mesenchymal features that allow metastasis, and chemotherapy resistance. Growth hormone (GH) has been associated with melanoma, breast, and endometrial cancer progression through an autocrine regulation of EMT. Since exogenous and autocrine expression of GH is known to have different molecular effects, we investigated whether exogenous GH is capable of regulating the EMT of cancer cells. Furthermore, we investigated whether exogenous GH could promote EMT in non-cancerous cells. To study the effect of GH (100 ngml) on cancer and non-cancer cells, we used HeLa and HEK293 cell lines, respectively. We evaluated the loss of cell-cell contacts, by cell scattering assay and migration by wound-healing assay. Additionally, we evaluated the morphological changes by phalloidin-staining. Finally, we evaluated the molecular markers E-cadherin and vimentin by flow cytometry. GH enhances cell scattering and the migratory rate and promotes morphological changes such as cell area increase and actin cytoskeleton filaments formation on HeLa cell line. Moreover, we found that GH favors the expression of the mesenchymal protein vimentin, followed by an increase in E-cadherins epithelial protein expression, characteristics of an epithelial-mesenchymal hybrid phenotype that is associated with metastasis. On HEK293cells, GH promotes morphological changes, including cell area increment and filopodia formation, but not affects scattering, migration, nor EMT markers expression. Our results suggest that exogenous GH might participate in cervical cancer progression favoring a hybrid EMT phenotype but not on non-cancerous HEK293 cells.

Health-related quality of life among breast cancer patients in India.

This study evaluated the health-related quality of life (HRQoL) among breast cancer patients during various phases of treatment and with different treatment modalities, which helps in monitoring treatment outcomes, assessing the well-being of patients, and conducting health technology assessments. A total of 534 interviews were conducted among the patients of breast cancer recruited at different stages of disease and with different treatment modalities. HRQoL was determined using EuroQoL five dimensions questionnaire with five levels (EQ-5D-5L), EuroQoL Visual Analogue Scale (EQ VAS), and the EORTC QLQ-BR23 instrument. The utility values were determined based on the Indian EQ-5D-5L value set. The socio-demographic and clinico-therapeutic determinants of HRQoL were evaluated using multiple linear regression. The mean utility value of breast cancer patients was 0.602 (SD 0.311) and mean EQ VAS score was 75 (SD 12.3). The mean utility value at diagnosis was 0.628, whereas utility value was 0.55, 0.595, and 0.64 for post-surgery, post-chemotherapy, and post-radiotherapy treatment groups, respectively. The most frequently reported problem was paindiscomfort (in 84.3% patients), followed by anxietydepression (83.5%). On EORTC QLQ-BR23, the maximum symptom scale scores for systemic therapy side effects were reported in the post chemotherapy group. The body image score and future perspective score were better in patients undergoing breast conservative surgery (BCS) compared to patients undergoing modified radical mastectomy. Age, education, and employment status of the patient, type of treatment modality, and use of taxanes are the determinants of HRQoL in breast cancer patients. Clinical interventions should focus upon management of pain and anxiety. BCS should be offered to all eligible patients as it is associated with better HRQoL. Addressing the factors that independently affect the HRQoL will help in improving the treatment compliance and outcomes.

The prevalence of depression and anxiety in patients with cancer in Iran a systematic review and meta-analysis.

Cancer is one of the most prevalent diseases and is recognized as a global problem that is currently showing a growing trend. Cancer is one of the most stressful circumstances that a person may experience. Given how the mental state of patients with depression and anxiety may have a negative impact on their experience with cancer, this study was conducted with the aim to investigate the prevalence of anxiety and depression in cancer patients in Iran. This study was conducted using a systematic review method and based on the guideline Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020). The studies used were searched for via databases, Scopus, Web of Science (WOS), Google Scholar, SID, Magiran, and using keywords related to anxiety, depression, and cancer. After extracting the required data, statistical analysis was performed based on the random model and using the second version of Comprehensive Meta-Analysis Software. In a review of 24 studies with a sample size of 3225 people, the overall prevalence of depression in cancer patients in Iran was reported to be 50.1% (95% CI 40.6-59.6). Additionally, in a review of 15 studies with a sample size of 2009, the overall prevalence of anxiety in cancer patients in Iran was reported to be 40.9% (95% CI 30.9-51.6). The highest reported prevalence of depression in cancer patients in Iran according to the Beck questionnaire is 64.6 (95% CI 48.2-78.1). Specifically, the highest prevalence of depression was reported in patients with breast cancer with a prevalence of 66 (95% CI 50.9-78.4). The highest prevalence of anxiety in patients with cancer in Iran according to the Depression, Anxiety, and Stress Scale was 49.2 (95% CI 18.9-80.1). Comparatively, the highest prevalence of anxiety in patients with breast cancer was reported to be 53.2 (95% CI 25.8-78.7). The prevalence of depression and anxiety among cancer patients in Iran, in particular patients with breast cancer, is significantly higher than in other parts of the world. The prevalence found in our study was even higher than the reported number by studies that have examined the disorder globally. Therefore, it is of great urgency for health system policymakers to work to improve the current situation.

Spatial Attention-Based Deep Learning System for Breast Cancer Pathological Complete Response Prediction with Serial Histopathology Images in Multiple Stains.

In triple negative breast cancer (TNBC) treatment, early prediction of pathological complete response (PCR) from chemotherapy before surgical operations is crucial for optimal treatment planning. We propose a novel deep learning-based system to predict PCR to neoadjuvant chemotherapy for TNBC patients with multi-stained histopathology images of serial tissue sections. By first performing tumor cell detection and recognition in a cell detection module, we produce a set of feature maps that capture cell type, shape, and location information. Next, a newly designed spatial attention module integrates such feature maps with original pathology images in multiple stains for enhanced PCR prediction in a dedicated prediction module. We compare it with baseline models that either use a single-stained slide or have no spatial attention module in place. Our proposed system yields 78.3% and 87.5% of accuracy for patch-, and patient-level PCR prediction, respectively, outperforming all other baseline models. Additionally, the heatmaps generated from the spatial attention module can help pathologists in targeting tissue regions important for disease assessment. Our system presents high efficiency and effectiveness and improves interpretability, making it highly promising for immediate clinical and translational impact.

Predicting Effective Adaptation to Breast Cancer to Help Women BOUNCE Back Protocol for a Multicenter Clinical Pilot Study.

Despite the continued progress of medicine, dealing with breast cancer is becoming a major socioeconomic challenge, particularly due to its increasing incidence. The ability to better manage and adapt to the entire care process depends not only on the type of cancer but also on the patients sociodemographic and psychological characteristics as well as on the social environment in which a person lives and interacts. Therefore, it is important to understand which factors may contribute to successful adaptation to breast cancer. To our knowledge, no studies have been performed on the combination effect of multiple psychological, biological, and functional variables in predicting the patients ability to bounce back from a stressful life event, such as a breast cancer diagnosis. Here we describe the study protocol of a multicenter clinical study entitled Predicting Effective Adaptation to Breast Cancer to Help Women to BOUNCE Back or, in short, BOUNCE. The aim of the study is to build a quantitative mathematical model of factors associated with the capacity for optimal adjustment to cancer and to study resilience through the cancer continuum in a population of patients with breast cancer. A total of 660 women with breast cancer will be recruited from five European cancer centers in Italy, Finland, Israel, and Portugal. Biomedical and psychosocial variables will be collected using the Noona Healthcare platform. Psychosocial, sociodemographic, lifestyle, and clinical variables will be measured every 3 months, starting from presurgery assessment (ie, baseline) to 18 months after surgery. Temporal data mining, time-series prediction, sequence classification methods, clustering time-series data, and temporal association rules will be used to develop the predictive model. The recruitment process stared in January 2019 and ended in November 2021. Preliminary results have been published in a scientific journal and are available for consultation on the BOUNCE project website. Data analysis and dissemination of the study results will be performed in 2022. This study will develop a predictive model that is able to describe individual resilience and identify different resilience trajectories along the care process. The results will allow the implementation of tailored interventions according to patients needs, supported by eHealth technologies. ClinicalTrials.gov NCT05095675 httpsclinicaltrials.govct2showNCT05095675. DERR1-10.219634564.

Therapy-Induced Senescence Enhances the Efficacy of HER2-Targeted Antibody-Drug Conjugates in Breast Cancer.

Antibody-drug conjugates (ADC) are antineoplastic agents recently introduced into the antitumor arsenal. T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer. Next-generation ADCs targeting HER2, such as vic-trastuzumab duocarmazine (SYD985), bear linkers cleavable by lysosomal proteases and membrane-permeable drugs, mediating a bystander effect by which neighboring antigen-negative cells are eliminated. Many antitumor therapies, like DNA-damaging agents or CDK46 inhibitors, can induce senescence, a cellular state characterized by stable cell-cycle arrest. Another hallmark of cellular senescence is the enlargement of the lysosomal compartment. Given the relevance of the lysosome to the mechanism of action of ADCs, we hypothesized that therapies that induce senescence would potentiate the efficacy of HER2-targeting ADCs. Treatment with the DNA-damaging agent doxorubicin and CDK46 inhibitor induced lysosomal enlargement and senescence in several breast cancer cell lines. While senescence-inducing drugs did not increase the cytotoxic effect of ADCs on target cells, the bystander effect was enhanced when HER2-negative cells were cocultured with HER2-low cells. Knockdown experiments demonstrated the importance of cathepsin B in the enhanced bystander effect, suggesting that cathepsin B mediates linker cleavage. In breast cancer patient-derived xenografts, a combination treatment of CDK46 inhibitor and SYD985 showed improved antitumor effects over either treatment alone. These data support the strategy of combining next-generation ADCs targeting HER2 with senescence-inducing therapies for tumors with heterogenous and low HER2 expression. Combining ADCs against HER2-positive breast cancers with therapies that induce cellular senescence may improve their therapeutic efficacy by facilitating a bystander effect against antigen-negative tumor cells.

PRC2-Mediated Epigenetic Suppression of Type I IFN-STAT2 Signaling Impairs Antitumor Immunity in Luminal Breast Cancer.

The immunosuppressive tumor microenvironment in some cancer types, such as luminal breast cancer, supports tumor growth and limits therapeutic efficacy. Identifying approaches to induce an immunostimulatory environment could help improve cancer treatment. Here, we demonstrate that inhibition of cancer-intrinsic EZH2 promotes antitumor immunity in estrogen receptor α-positive (ERα) breast cancer. EZH2 is a component of the polycomb-repressive complex 2 (PRC2) complex, which catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3). A 53-gene PRC2 activity signature was closely associated with the immune responses of ERα breast cancer cells. The stimulatory effects of EZH2 inhibition on immune surveillance required specific activation of type I IFN signaling. Integrative analysis of PRC2-repressed genes and genome-wide H3K27me3 landscape revealed that type I IFN ligands are epigenetically silenced by H3K27me3. Notably, the transcription factor STAT2, but not STAT1, mediated the immunostimulatory functions of type I IFN signaling. Following EZH2 inhibition, STAT2 was recruited to the promoters of IFN-stimulated genes even in the absence of the cytokines, suggesting the formation of an autocrine IFN-STAT2 axis. In patients with luminal breast cancer, high levels of EZH2 and low levels of STAT2 were associated with the worst antitumor immune responses. Collectively, this work paves the way for the development of an effective therapeutic strategy that may reverse immunosuppression in cancer. Inhibition of EZH2 activates a type I IFN-STAT2 signaling axis and provides a therapeutic strategy to stimulate antitumor immunity and therapy responsiveness in immunologically cold luminal breast cancer.

Intraindividual Reliability of Opportunistic Computed Tomography-Assessed Adiposity and Skeletal Muscle Among Breast Cancer Patients.

Adiposity and skeletal muscle levels assessed on computed tomography (CT) scans are prognostic indicators for patients with breast cancer. However, the intraindividual reliability of temporal changes in body composition assessed on opportunistic CT scans is unclear. This retrospective study included 50 patients newly diagnosed with breast cancer who had archived CT scans pre- and postsurgery for breast cancer. The third lumbar CT image was segmented for areas of 3 types of adipose tissues and 5 different densities of skeletal muscles. Mean and percent changes in areas pre- vs postsurgery were compared using Wilcoxon signed rank tests. Intraclass correlation coefficients (ICCs) with 95% confidence intervals were assessed. A 2-sided P less than .05 was considered statistically significant. Mean (SD) age at diagnosis was 58.3 (12.5) years, and the interval between CT scans was 590.6 (536.8) days. Areas for body composition components were unchanged except for intermuscular adipose tissue (mean change 1.45 cm2, 6.74% increase, P .008) and very high-density muscle (mean change -0.37 cm2, 11.08% decrease, P .01) during the interval. There was strong intraindividual reliability in adipose tissue and skeletal muscle areas on pre- vs postsurgery scans overall (ICC 0.763-0.998) and for scans collected 3 or less years apart (ICC 0.802-0.999 42 patients). Although some body composition components may change after breast cancer surgery, CT scan assessments of body composition were reliable for a 3-year interval including the surgery. These findings inform measurement characteristics of body composition on opportunistic CT scans of patients undergoing surgery for breast cancer.

Evaluation of Immunoexpression of AJUBA Protein in Normal Oral Mucosa and Oral Squamous Cell Carcinoma.

AJUBA is multifunctional scaffold protein which belongs to Zyxin family of proteins. It is known to have dual role in cancer as a tumor promoter and tumor suppressor. AJUBA has a key role in systemic malignancies like esophageal squamous cell carcinoma, colorectal cancer, cervical, breast, prostate cancer, etc. But there is very sparse literature available regarding its expression profile in oral squamous cell carcinoma (OSCC) and moreover its expression has not been observed in normal oral mucosa (NOM). Thus, the aim of this research is to explore the expression profile of AJUBA by immunohistochemical method in NOM and OSCC. Furthermore, we also evaluated the association of AJUBA expression with clinicopathologic parameters. A total of 84 samples of formalin fixed paraffin embedded tissue blocks comprising of 42 cases each of NOM and OSCC were subjected to detect immunoexpression of AJUBA. We found enhanced intense immune-expression of AJUBA in OSCC cases than compared with NOM and found to be statistically significant. The parameters specific to histologic tumor grade and inflammatory response in OSCC also found to have statistically significant with AJUBA expression. Our study is first of its kind to reveal AJUBA expression in basal and suprabasal layer of NOM suggestive of its definitive role in differentiation and stratification process. We also observed its intense expression in peripheral cell of tumor islands of OSCC cases, which can suggest its possible role in tumor growth and progression.

The Diagnostic Utility of IDH2 R172 Immunohistochemistry in Tall Cell Carcinoma With Reversed Polarity of the Breast.

Tall cell carcinoma with reversed polarity (TCCRP) is a rare histologic type of low-grade breast cancer, consisting of tall columnar cells with reversed nuclear polarity and characterized by frequent IDH2 mutations. We herein report 3 cases of TCCRP with sequencing analyses of the IDH2 gene and immunohistochemical examination using monoclonal antibodies (11C8B1) against IDH2 R172. IDH2 R172 mutations were detected in all 3 resected tumors (R172S in 2 tumors and R172T in 1 tumor), and the presence of these mutations was confirmed by IDH2 R172 immunohistochemistry. Tumor cells of TCCRP showed strong and diffuse staining for the antibody against IDH2 R172. In 1 case, tumor tissue from 2 core needle biopsy samples collected on different days were also immunohistochemically positive for IDH2 R172. These results indicate that IDH2 R172 immunohistochemistry is suitable for the detection of TCCRP in both resection and biopsy samples. In addition, a literature review revealed that R172S and R172T account for 76% of IDH2 mutations in TCCRP, suggesting that 11C8B1, which reacts with R172S and R172T, was likely most sensitive for IDH2 -mutated TCCRP among many available antibodies for IDH2 R172. Furthermore, the combination of 2 or more antibodies against IDH2 R172 could be more effective for detecting TCCRP mutation. However, it is important to note that IDH2 R172 immunohistochemistry is not absolute, because IDH2 wild type is found in a small proportion (10%) of cases, and a few cases of IDH2 -mutated TCCRP may harbor rare subtypes of R172 that are not covered by available antibodies.

Occult recurrent breast cancer masquerading as thrombotic thrombocytopenic purpura.

GATA3 immunohistochemistry stain of the bone marrow biopsy required to diagnose recurrent metastatic breast cancer.

Morphological signatures of actin organization in single cells accurately classify genetic perturbations using CNNs with transfer learning.

The actin cytoskeleton plays essential roles in countless cell processes, from cell division to migration to signaling. In cancer cells, cytoskeletal dynamics, cytoskeletal filament organization, and overall cell morphology are known to be altered substantially. We hypothesize that actin fiber organization and cell shape may carry specific signatures of genetic or signaling perturbations. We used convolutional neural networks (CNNs) on a small fluorescence microscopy image dataset of retinal pigment epithelial (RPE) cells and triple-negative breast cancer (TNBC) cells for identifying morphological signatures in cancer cells. Using a transfer learning approach, CNNs could be trained to accurately distinguish between normal and oncogenically transformed RPE cells with an accuracy of about 95% or better at the single cell level. Furthermore, CNNs could distinguish transformed cell lines differing by an oncogenic mutation from each other and could also detect knockdown of cofilin in TNBC cells, indicating that each single oncogenic mutation or cytoskeletal perturbation produces a unique signature in actin morphology. Application of the Local Interpretable Model-Agnostic Explanations (LIME) method for visually interpreting the CNN results revealed features of the global actin structure relevant for some cells and classification tasks. Interestingly, many of these features were supported by previous biological observation. Actin fiber organization is thus a sensitive marker for cell identity, and identification of its perturbations could be very useful for assaying cell phenotypes, including disease states.

A novel ferroptosis‑related gene signature for overall survival prediction and immune infiltration in patients with breast cancer.

Breast cancer is the most prevalent type of cancer among women worldwide. The heterogeneous nature of breast cancer poses a serious challenge for prognostic prediction and individualized therapies. Recently, ferroptosis, an iron‑dependent form of programmed cell death, has been reported to serve a significant role in the regulation of the biological behavior of tumors. Several studies have revealed the prognostic significance of the ferroptosis‑related gene (FRG) model however, additional efforts are required to elucidate the details. Moreover, genes that modulate ferroptosis may be promising candidate bioindicators in cancer therapy. The present study systematically assessed the expression profiles of FRGs to reveal the relationship between FRGs and the prognostic features of patients with breast cancer based on data obtained from the Gene Expression Omnibus and Molecular Taxonomy of Breast Cancer International Consortium. Using a non‑negative matrix factorization clustering method, patients with breast cancer were classified into two sub‑groups (cluster 1 and cluster 2) based on the expression of FRGs. Furthermore, Cox regression, and least absolute shrinkage and selection operator methods were used to construct a risk score formula comprised of nine genes, which stratified patients with breast cancer into two risk groups. Patients belonging to the high‑risk group exhibited significantly shorter overall survival (OS) time compared with patients in the low‑risk group. The prognostic value of this signature was further verified in the training and validation cohorts. The results for univariate and multivariate Cox regression analyses indicated that risk score acted as an independent predictor for OS. Subsequently, a nomogram was constructed. Receiver operating characteristic analysis further confirmed that the resulting nomogram exhibited powerful discriminatory ability. Functional analysis revealed that the immune environment differed notably between the two groups and indicated an association between ferroptosis and breast cancer proliferation, migration and drug resistance. Taken together, the present study demonstrated that FRGs were significantly associated with breast cancer progression, and thus could be used as novel biomarkers for prognostic prediction and individualized treatment of patients with breast cancer.

Porphyrin Centered Paclitaxel Tetrameric Prodrug Nanoassemblies as Tumor-Selective Theranostics for Synergized Breast Cancer Therapy.

Although having undergone decades of development, nanoparticulate drug delivery vehicles for efficient cancer therapy remain a challenge, confined by low drug loading, instability, and poor cancer tissue selectivity. A self-assembled prodrug, the combination of prodrug strategy and the self-assembly merits, represents a special chemical entity which spontaneously organizes into supramolecular composites with defined architecture, therefore also providing a strategy to develop new medications. Paclitaxel (PTX) is still among the most generally prescribed chemotherapeutics in oncology but is restricted by poor solubility. Although photodynamic therapy, with its noninvasive features and barely developed drug resistance, signifies an alternative tool to suppress life-threatening cancer, sole use hardly fulfills its potential. To this end, a reduction-activatable heterotetrameric prodrug with the photosensitizer is synthesized, then formulated into self-assembled nanoparticles (NPs) for tumor imaging and combined chemo- and photodynamic therapy. Coating the NPs with amphiphilic polymer distearylphosphatidylethanolamine-polyethylene glycol-arginine-glycine-aspartate (DSPE-PEG-RGD) offers high stability and enables cancer tissue targeting. The as-prepared NPs enlighten disease cells and reveal more potent cytotoxicity comparing to PTX and the photosensitizer alone. Furthermore, the NPs selectively accumulates into tumors and synergistically inhibits tumor proliferation with reduced side effects in mice.

Cutaneous metastases of non-cutaneous neuroendocrine neoplasms A histopathologic review of 15 cases.

Cutaneous metastases from non-cutaneous neuroendocrine neoplasms are rare however, distinction from primary neuroendocrine carcinomas of the skin (Merkel cell carcinoma) guides clinical management. We performed a retrospective review from September 1, 2010 to September 30, 2020 of the histopathologic, immunohistochemical, and clinical characteristics of metastatic neuroendocrine neoplasms to the skin from non-cutaneous primaries. Fourteen patients were identified for the study (nine males and five females mean age of 59.5 years). Fifteen skin specimens from 14 patients were available for review. At the time of skin biopsy, a known non-cutaneous neuroendocrine neoplasm was present in 50% of patients. Primary sites of neuroendocrine carcinoma included lung (n 5), terminal ileum (n 2), and one each from prostate, breast, rectum, uterus, esophagus, and sinus, with one unknown (suspected bladder malignancy). Eleven of fourteen patients are dead of disease one was lost to follow-up. All 15 specimens showed subcutaneousdeep dermal involvement with six involving the papillary dermis and one involving the epidermis. The tumors ranged from well to poorly differentiated. Two of fifteen specimens showed focal CK20 positivity (one metastatic uterine small cell carcinoma and one metastatic ileal carcinoid). TTF-1 was performed in 13 specimens and was positive in six, of which two were of non-pulmonary origin. While immunohistochemical stains, in particular CK20, CK7, and TTF-1, are integral in the workup of confirming the origin of neuroendocrine tumors found in the skin, results vary and are often non-specific for a single primary site. Therefore, complete radiologic imaging as well as clinical correlation should be recommended to further aid in the identification of a non-cutaneous primary neoplasm.

Biomolecular docking interactions, cytotoxicity and antioxidant property evaluations with novel Mn(II), Ni(II), Cd(II) and Pb(II) Schiff base ligand complexes Synthesis and characterization.

The development of Schiff base-centered medical chemistry in conjunction with the use of less-expensive transition metals with high pharmacological activity has currently triggered enormous interest in the development of novel Schiff base ligands. In this context, four different metal complexes comprising Mn(II), Ni(II), Cd(II) and Pb(II) (labeled as complexes 1-4) were synthesized using a novel tetra-dentate ligand (L) obtained by condensation of 3,5-dichlorosalicylaldehyde and trans-1,2-diaminocyclohexane, as demonstrated herein. The physico-chemical properties of the complexes were evaluated through UV-Vis, FT-IR, NMR, TGA, powder XRD and ESI-MS analyses. The crystalline states of the metal complexes were analysed by powder XRD. The existence of the lattice as well as coordinated water molecules in the complexes were demonstrated by the thermal characteristics of the complexes. The thermal stability of all the compounds is due to their high melting points. Studies on the free radical scavenging and antibacterial properties performed with the ligand L and the synthesized metal complexes 1-4 revealed that the Ni(II) complex had higher efficiency. Also, their bactericidal properties were tested with gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) bacteria. Using Ni(II) as a model, anticancer studies for MCF-7 breast cancer cell lines were performed. By using molecular docking studies, the interactions between drugs and biomolecules were identified. The Ni(II) complex showed synergistic activity, exemplifying its stronger anticancer action, establishing its higher inhibiting efficiency of 68.26% at 320 gmL. The present investigation, therefore, acknowledges the viability of these newly synthesized Schiff base-derived complexes as clinical-trial prodrugs.

The Role of Exercise Self-Efficacy in Exercise Participation Among Women With Persistent Fatigue After Breast Cancer A Mixed-Methods Study.

Survivors of breast cancer with persistent cancer-related fatigue (CRF) report less exercise participation compared to survivors of breast cancer without CRF. Although CRF predicts other domains of self-efficacy among survivors, the effect of CRF on exercise self-efficacy (ESE)-an important predictor of exercise participation-has not been quantified. This study examined the relationship between CRF, ESE, and exercise participation and explored the lived experience of engaging in exercise among survivors of breast cancer with persistent CRF. Fifty-eight survivors of breast cancer (3.7 SD 2.4 years after primary treatment) self-reported CRF, ESE, and exercise participation (hours of moderate-intensity exercise per week). Regression and mediation analyses were conducted. Survivors who reported clinically significant CRF and weekly exercise were purposively sampled for 1-on-1 interviews (N 11). Thematic analysis was performed across participants and within higher versus lower ESE subsets. Greater CRF predicted lower ESE (β -0.32) and less exercise participation (β -0.08). ESE mediated the relationship between CRF and exercise participation (β -0.05 95% CI -0.09 to -0.02). Qualitative data showed that survivors of breast cancer with higher ESE perceived exercise as a strategy to manage fatigue, described self-motivation and commitment to exercise, and had multiple sources of support. In contrast, survivors with lower ESE described less initiative to manage fatigue through exercise, greater difficulty staying committed to exercise, and less support. Survivors of breast cancer with persistent CRF may experience decreased ESE which negatively influences exercise participation. Clinicians should screen for or discuss confidence as it relates to exercise and consider tailoring standardized exercise recommendations for this population to optimize ESE. This may facilitate more sustainable exercise participation and improve outcomes. This study highlights the behavioral underpinnings of CRF as a barrier to exercise. Individualized exercise tailored to optimize ESE may facilitate sustainable exercise participation among survivors of breast cancer with CRF. Strategies for clinicians to address ESE are described and future research is suggested.

A pH-responsive cascade nanoplatform with circulating oxygen supply for collaborative breast cancer treatment.

A pH-responsive cascade nanoplatform based on ZIF-8 disintegrates in the weakly acidic tumor microenvironment to release MnO

Patient-oncologist working alliance and its relation to locus of control.

In this study, we assessed the patient-oncologist relationship, conceptualized as the working alliance from a dyadic perspective, and its relation to locus of control. One hundred and three oncologist-patient dyads were recruited. Measures included a sociodemographic and medical questionnaire the internal, powerful others, and chance locus of control scale and the working alliance inventory. Application of the actor-partner interdependence model yielded 2 actor effects a positive association between oncologist internal locus of control and oncologist working alliance, and a negative association between oncologist chance locus of control and oncologist working alliance. It also yielded one partner effect a positive association between oncologist internal locus of control and patient working alliance. The actor-partner effect suggests that oncologists locus of control has a role in the establishment of the patient-oncologist working alliance oncologists internal locus of control is a dominant factor affecting not only their own perceived alliance but patients perceived alliance as well.

Cancer-associated Fibroblasts Communicate with Breast Tumor Cells Through Extracellular Vesicles in Tumor Development.

Breast cancer is the leading cause of cancer death among women worldwide. In solid tumors, the microenvironment plays a critical role in tumor development, and it has been described a communication between the different cell types that conform the stroma, including fibroblasts, pericytes, adipocytes, immune cells and cancer-associated fibroblasts. Intercellular communication is bidirectional, complex, multifactorial and is mediated by the secretion of molecules and extracellular vesicles. The extracellular vesicles are vesicles limited by two membranes that are secreted by normal and cancer cells into the extracellular space. Extracellular vesicle cargo is complex and includes proteins, miRNAs, DNA and lipids, and their composition is specific to their parent cells. Extracellular vesicles are taken up for neighboring or distant cells. Particularly, extracellular vesicles from breast cancer cells are taken up for fibroblasts and it induces the activation of fibroblasts into cancer-associated fibroblasts. Interestingly, cancer associated fibroblasts release extracellular vesicles that are taken up for breast cancer cells and promote migration, invasion, proliferation, epithelial-mesenchymal transition, changes in metabolism, chemoresistance, evasion of immune system and remodeling of extracellular matrix. In addition, the enrichment of specific cargos in extracellular vesicles of breast cancer patients has been suggested to be used as biomarkers of the disease. Here we review the current literature about the intercommunication between tumor cells and cancer associated fibroblasts through extracellular vesicles in breast cancer.

Cerium oxide nanoparticles exert antitumor effects and enhance paclitaxel toxicity and activity against breast cancer cells.

Cerium oxide nanoparticles (CeONPs) displayed cytotoxic properties against some cancer cells. However, there is very limited data about the possible antitumoral potential of them in breast cancer cells when used alone andor together with a chemotherapeutic drug. We investigated the effects of CeONPs alone or in combination with paclitaxel (PAC) on healthy or carcinoma breast cells. After human breast cancer cells (MCF-7) treated with CeONPs alone or together with PAC for 24, 48, and 72 h, the effects of CeONPs on cell viability, apoptosis, migration, and adhesion were investigated. All cell viability and IC50 values of CeONPs and PAC treatments in healthy breast cells (HTERT-HME1) were higher than MCF-7 cells. They showed higher cytotoxicity against MCF-7 cells. CeONPs (10, 20, and 30 mM) andor abraxane (AB) (2 μM) significantly decreased cell viability values in MCF-7 cells. All CeONPs concentrations increased the number of apoptotic MCF-7 cells. CeONPs (20 and 30 mM) alone or in combination with AB for 72 h treatment also significantly increased the apoptosis in compared to AB alone. CeONPs andor AB can significantly inhibit the migratory ability of breast cancer cells. The migration rates in co-treated groups with CeONPs and AB were lower than CeONPs treatments. Higher concentrations of CeONPs alone or together with AB inhibited cell adhesion. Our results showed CeONPs can increase cytotoxicity and apoptosis and decrease cell migration and cell adhesion when used alone or together with AB. Therefore, combination of chemotherapeutics with CeONPs may provide a good strategy against cancer.

Development of PI3Kα inhibitors for tumor therapy.

The PI3KAKTmTOR signaling pathway is well known to be involved in cell growth, proliferation, metabolism and other cellular physiological processes. Abnormal activation of this pathway is closely related to tumorigenesis and metastasis. As the starting node of the pathway, PI3K is known to contain 4 isoforms, including PI3Kα, a heterodimer composed of the catalytic subunit p110α and the regulatory subunit p85. PIK3CA, which encodes p110α, is frequently mutated in cancer, especially breast cancer. Abnormal activation of PI3Kα promotes cancer cell proliferation, migration, invasion, and angiogenesis therefore, PI3Kα has become a key target for the development of anticancer drugs. The hinge region and the region of the mutation site in the PI3Kα protein are important for designing PI3Kα-specific inhibitors. As the group shared by the most PI3Kα-specific inhibitors reported thus far, carboxamide can produce hydrogen bonds with Gln859 and Ser854. Gln859 is specific to the p110α protein in producing hydrogen bond interactions with PI3Kα-specific inhibitors and this is a key point for designing PI3Kα inhibitors. To date, alpelisib is the only PI3Kα inhibitor approved for the treatment of breast cancer. Several other PI3Kα inhibitors are under evaluation in clinical trials. In this review, we briefly describe PI3Kα and its role in tumorigenesis, summarize the clinical trial results of some PI3Kα inhibitors as well as the synthetic routes of alpelisib, and finally give our proposal for the development of novel PI3Kα inhibitors for tumor therapy. HighlightsWe summarize the progress of PI3Kα and PI3Kα inhibitors in cancer from the second half of the 20th century to the present.We describe the clinical trial results of PI3Kα inhibitors as well as the synthetic routes of the only approved PI3Kα inhibitor alpelisib.Crystal structure of alpelisib bound to the PI3Kα receptor binding domain.This review gives proposal for the development of novel PI3Kα inhibitors and will serve as a complementary summary to other reviews in the research field of PI3K inhibitors.

Stabilization of estrogen receptor α by USP37 contributes to the progression of breast cancer.

Breast cancer is a major cause of cancer-related morbidity and mortality in women. Estrogen receptor-positive breast cancer accounts for roughly 70-80% of breast tumors, and estrogen receptor alpha (ERα) has been considered as a key driver in promoting breast cancer progression. In the present study, we identified USP37 as a novel modulator in modulating ERα ubiquitination and stability. The expression of USP37 was upregulated in ERα-positive breast cancer and correlated with ERα protein level. High expression of USP37 was associated with unfavorable prognosis. USP37 depletion resulted in significantly decreased ERα protein level, ERα target genes expression as well as the estrogen response element activity in breast cancer cells. Further mechanistic study revealed the interaction between USP37 and ERα USP37 regulated ERα signaling through modulating protein stability instead of gene expression, in which it stabilized ERα protein via inhibiting the K48-specific poly-ubiquitination process. Additionally, USP37 depletion led to growth inhibition and cell cycle arrest of ERα-positive breast cancer cells, which could be further rescued by ERα overexpression. Overall, our study proposed a novel post-translational mechanism of ERα in promoting breast cancer progression. Targeting USP37 may be proved to be a promising strategy for patients with ERα-positive breast cancer.

Vimentin and tumor-stroma ratio for neoadjuvant chemoradiotherapy response prediction in locally advanced rectal cancer.

Vimentin expression in tumor tissues and the tumor-stroma ratio (TSR) have been demonstrated as strong prognostic factors for cancer patients, but whether they are predictive markers of neoadjuvant chemoradiotherapy (nCRT) outcome in locally advanced rectal cancer (LARC) patients is poorly understood. This study aimed to explore the predictive significance of vimentin and TSR combined for nCRT response in LARC patients. Imaging mass cytometry (IMC) was performed to determine the association of vimentin and TSR with nCRT response in six LARC patients three achieved pathological complete response (pCR), three did not. Immunohistochemistry (IHC) for vimentin and TSR on biopsy tissues before nCRT and logistic regression analysis were performed to further evaluate their predictive value for treatment responses in a larger patient cohort. A trend of decreased vimentin expression and increased TSR in the pCR group was revealed by IMC. In the validation group, vimentin odds ratio (OR) 0.260, 95% confidence interval (CI) 0.102-0.602, p 0.002 and TSR (OR 4.971, 95% CI 1.933-15.431, p 0.002) were associated with pCR by univariate analysis. Patients in the vimentin-lowTSR-low or vimentin-highTSR-high (OR 5.211, 95% CI 1.248-35.582, p 0.042) and vimentin-lowTSR-high groups (OR 11.846, 95% CI 3.197-77.079, p 0.001) had significantly higher odds of pCR. By multivariate analysis, only the combination of vimentin and TSR was an independent predictor for nCRT response (OR 9.324, 95% CI 2.290-63.623, p 0.006). Our study suggested that the combined assessment of vimentin and TSR can provide additive significance and may be a promising indicator of nCRT response in LARC patients.

Flexible terahertz metamaterial biosensor for label-free sensing of serum tumor marker modified on a non-metal area.

Terahertz (THz) metamaterials for rapid label-free sensing show application potential for the detection of cancer biomarkers. A novel flexible THz metamaterial biosensor based on a low refraction index parylene-C substrate is proposed. The biomarkers are modified on non-metal areas by a three-step modification method that simplifies the modification steps and improves the modified effectivity. Simulation results for non-metal modification illustrate that a bulk refractive index sensitivity of 325 GHzRIU is achieved, which is larger than that obtained for the traditional metal modification (147 GHzRIU). Meanwhile, several fluorescence experiments proved the uniform modification effect and selective adsorption capacity of the non-metal modification method. The concentration of the carcinoembryonic antigen (CEA) biomarkers for breast cancer patients tested using this THz biosensor is found to be consistent with results obtained from traditional clinical tests. The limit of detection reaches 2.97 ngmL. These findings demonstrate that the flexible THz metamaterial biosensor can be extensively used for the rapid detection of cancer biomarkers in the future.

Prognostic nomogram for female patients suffering from non-metastatic Her2 positive breast cancer A SEER-based study.

This paper aimed at constructing and validating a novel prognostic nomogram, so that physicians forecast the overall survival (OS) rates of female patients suffering from non-metastatic human epidermal growth element receptor-2 (HER2) positive breast. Information of primary female her2 positive breast cancer patients without metastasis was obtained from the Surveillance, Epidemiology, and End Results (SEER) database with given inclusion and exclusion standards. Independent variables were obtained greatly by performing univariable and multivariate analyses. Based on those independent predictors, a novel prognostic nomogram was constructed for predicting the survival of those with 3- and 5-year OS. Then, concordance index (C-index), receiver operating characteristic curve (ROC), and calibration plot were adopted for the assessment of the predictive power of the nomogram. A total of 36,083 eligible patients were classified into a training cohort (n 25,259) and a verification cohort (n 10,824) randomly. According to the identification of multivariate analysis, survival was predicted by age at diagnosis, marital status, race, site, T stage, N stage, progesterone receptor (PR) status, estrogen receptor (ER) status, surgery, radiation, and chemotherapy independently. A nomogram was established by applying the training cohort. The nomogram displayed excellent discrimination and performance as indicated by the C-index (0.764, 95% confidence interval 0.756-0.772), and the 3- and 5-year area under the curve of ROC (AUC) values (0.760 and 0.692 respectively). The calibration plots for forecasting the 3- and 5-year OS were in great agreement. The OS for female her2 positive breast cancer patients without metastasis was predicted by constructing a nomogram on basis of the SEER database. A precise survival prediction could be offered for each patient.

Bioinformatics analysis of the clinical significance of HLA class II in breast cancer.

Human leukocyte antigen (HLA) class II plays critical roles in antigen presentation and the initiation of immune responses. However, the correlation between the HLA class II gene expression level and the survival of patients with breast cancer is still under investigation. We analyzed microarray and RNA-Seq data of breast cancer from the cancer genome atlas (TCGA), genotype-tissue expression (GTEx) and Oncomine databases by using bioinformatics tools. The expression of the HLA-DQA1, HLA-DQA2, and HLA-DQB2 genes was significantly upregulated in breast cancer. Higher expression levels of HLA class II genes in breast cancer, especially HLA-DOB and HLA-DQB2, were significantly associated with better overall survival. Furthermore, the expression of HLA class II genes was more closely associated with survival in breast cancer than in other cancer types. CD48 coexpressed with both HLA-DOB and HLA-DQB2 was also positively associated with the overall survival of breast cancer patients. The results indicated that HLA class II and CD48 may enhance antitumor immunity, and their expression patterns may serve as potential prognostic biomarkers and therapeutic targets in breast cancer.

Survival of women with pregnancy-associated breast cancer according to clinical characteristics A propensity score matching study.

In recent years, postponing childbearing has increased the prevalence of pregnancy-associated breast cancer (PABC). PABC has a poorer prognosis than breast cancer not associated with pregnancy (non-PABC) due to delayed diagnosis and aggressive subtype. Additionally, pregnancy itself predicts a poor prognosis but, this is a subject of debate. Thus, we analyzed the effects of known prognostic factors and pregnancy on the prognosis of PABC. We retrospectively analyzed women aged 20 to 49 years who were diagnosed with breast cancer (BC) between 1989 and 2014. Patients were distributed into PABC and non-PABC groups, and 14 propensity score matching was performed to adjust for baseline characteristics. Primary endpoints were overall survival (OS) and BC-specific survival (BCSS). Secondary endpoint was the difference in prognosis according to BC subtype. Of the 34,970 recruited patients with BC, 410 (1.2%) had PABC. Patients with PABC were younger and tended to have triple-negative BC (TNBC) subtype than non-PABC patients. The 1640 matched non-PABC patients showed a significantly worse mean survival rate than the unmatched non-PABC patients. Patients with PABC had a significantly worse OS and BCSS than those with non-PABC. In multivariate analyses, patients with PABC of luminal B (Ki-67 ≥14.0%) and TNBC subtypes had worse OS and BCSS than patients with non-PABC. Patients with PABC had poorer prognosis than non-PABC patients after adjusting for several prognostic factors. This difference was particularly significant in patients with the luminal B and TNBC subtypes.

Real-world study of trastuzumab and pertuzumab combined with chemotherapy in neoadjuvant treatment for patients with HER2-positive breast cancer.

Clinical trials have shown that trastuzumab (H) and pertuzumab (P) combined with chemotherapy as neoadjuvant therapy increased pathological complete response (pCR) rate of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, date in China in the real world are currently limited. Clinical data from patients with HER2-positive breast cancer who received HP combined with chemotherapy as neoadjuvant therapy at 2 institutions from March 2019 to February 2022 were retrospectively analyzed. Adverse reactions were evaluated using CTCAE version 5.0. The primary endpoint was total pathologic complete response (tpCR ypT0isypN0), and the secondary endpoints were breast pathologic complete response (bpCR ypT0is) and axillary pathologic complete response (apCR ypN0). Factors influencing tpCR were also analyzed. A total of 302 patients were included in the analysis, of which 145 were treated with H P taxane carboplatin (TcbHP), 94 with H P taxane (THP) and 63 with sequential anthracycline and cyclophosphamide, followed by H P taxane (AC-THP). The overall tpCR rate was 64.9%, and those of TcbHP, THP, and AC-THP were 73.1%, 52.1%, and 65.1%, respectively. The tpCR rate of the hormone receptor (HR) negative group (80.3%) was higher than that of the HR positive group (52.1%). The overall bpCR rate was 73.5% and the apCR rate was 75.8%. In the univariate analysis, HR, HER2 status and treatment regimen were related factors that affected tpCR. In the multivariate analysis, HR, HER2 status and treatment regimen were independent predictors of tpCR (P < .001, P < .001 and P .009). The levels 3 and 4 toxicities rates of TcbHP were slightly higher than those of THP and AC-THP. HP combined with chemotherapy has achieved a high pCR rate. The TcbHP regimen had the highest pCR. HR-negative tumors demonstrated a higher pCR. HR, HER2 status and treatment regimen were independent predictors of tpCR. The adverse reactions are controllable.

A web-based survey of SARS-CoV-2 vaccination and its adverse effects in Chinese postoperative patients with breast cancer a cross-sectional study.

Vaccination against SARS-CoV-2 has been the most important strategy for preventing infection and controlling pandemics of coronavirus disease 2019 (COVID-19). Cancer patients have a significantly higher risk of infection with COVID-19 because of their impaired immunity. Breast cancer is the most common female malignant tumor in the world. However, studies on COVID-19 vaccination in breast cancer patients are scarce, so that more information is needed to guide vaccination in these. We conducted a web-based questionnaire survey on SARS-CoV-2 vaccination in breast cancer patient. Questionnaires completed by non-postoperative patients will be considered invalid. The main variables in the questionnaire including vaccination status, willingness to get the vaccines, candidate factors, and measures of adverse events in vaccinated individuals were used for analysis. Univariate and multivariate logistic regression was used to estimate the associations. Among 947 valid online questionnaires, 341 (36.0%) accepted SARS-CoV-2 vaccination, while 606 (64.0%) did not. There were significant differences in age, current treatment, time since surgery, and symptoms of anxiety and depression between the two groups. Compared to vaccinated patients, we identified current treatment odds ratio (OR) 0.51 for endocrine therapy 95% confidence interval (CI) 0.29-0.89, time since surgery (OR 22.49 for 1-2 years 95% CI 12.31-41.10 OR 8.49 for 2-5 years 95% CI 4.98-14.46 OR 1.79 for >5 years 95% CI 1.11-2.89), and symptoms of depression (OR 2.48 95% CI 1.19-5.15) as significant factors for being unvaccinated. The overall incidence of adverse reactions was 43.1%, and the most common local and systemic adverse reactions were pain (28.4%) and fatigue (8.8%). However, about 76.6% of the unvaccinated participants were willing to be vaccinated. Compared to the general population, postoperative patients with breast cancer had a lower rate of vaccination for SARS-CoV-2. Receiving treatment, a shorter time since surgery, and symptoms of depression were associated with being unvaccinated. However, about 76.6% of the unvaccinated participants were willing to be vaccinated. Although our study showed that there were adverse effects of SARS-CoV-2 vaccines, such as pain, fatigue, they are common adverse effects of routine vaccination. We believe that vaccination against COVID-19 is safe in postoperative patients with breast cancer.

Comprehensive analysis reveals potential hub genes and therapeutic drugs in an acquired lymphedema model.

Acquired lymphedema is a common and often severe complication of breast cancer surgery and radiology that seriously affects patients quality of life. Nevertheless, the pathogenesis for acquired lymphedema is complex and remains unclear. The aim of this study is to find out possible genetic markers and potential drugs for acquired lymphedema. First, the GSE4333 datasets, which include expression data for six female humanized hairless immunocompetent SKH-1 mice (the condition of whom mimics acquired lymphedema), were reanalyzed. According to the criteria of a fold change (FC) ≥1.4 and an adjusted P value <0.05, we identified the differentially expressed genes (DEGs) between a normal group and the lymphedema group. Next, we analyzed the Gene Ontology (GO) terms and enriched signaling pathways associated with these DEGs with an online tool DAVID. We also constructed protein-protein interaction (PPI) networks and selected meaningful gene modules for additional gene-drug interaction research. Finally, the extant drugs targeting these module genes were identified for further study of their therapeutic effects against acquired lymphedema. A total of 481 DEGs were identified that were closely associated with the immune system, inflammatory response, and extracellular matrix (ECM) structural constituent terms, among others. Moreover, we identified the top 10 significant genes in the PPI networks and identified one extant drug, fiboflapon, that targets the We ultimately identified 10 hub genes, molecular mechanisms, and one extant drug related to acquired lymphedema. The findings identified targets and a potential drug for further research on acquired lymphedema.

Identification of biomarkers related to tumorigenesis and prognosis in breast cancer.

The aim of the present study was to identify the central genes and prognostic index of breast cancer, and to determine the relationship between prognostic index and immune infiltration levels to provide useful information for the diagnosis and treatment of breast cancer. The Cancer Genome Atlas breast cancer dataset and 2 microarray datasets were applied to screen overlapping differentially expressed genes (DEGs) between breast cancer tissue and normal breast tissue samples. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted through the Database for Annotation, Visualization, and Integrated Discovery. Protein-protein interaction (PPI) networks were used to screen hub genes of the overlapping DEGs. Gene Expression Profiling Interactive Analysis (GEPIA), The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), and The Human Protein Atlas (HPA) databases were used to validate their expression. The correlation of hub genes with immune infiltration was analyzed using TISIDB software. Kaplan-Meier Plotter was used to analyze the prognosis of hub genes. Ten hub genes cyclin A2 ( The findings indicated that the 10 hub genes could be potential biomarkers for progression in breast cancer.

Evaluation of indocyanine green combined with methylene blue staining in sentinel lymph node biopsy of breast cancer.

Methylene blue as tracer used in sentinel lymph node biopsy (SLNB) have low detection rate and high false negative rate. Indocyanine green (ICG) can detect the flow of subcutaneous lymphatic vessels and the position of lymph nodes dynamically. This study sought to evaluate the efficacy of ICG combined with methylene blue staining in SLNB of breast cancer. One hundred and fifty-six early breast cancer patients treated at our hospital from July 2020 to May 2022 were enrolled in this study. SLNB was performed by ICG combined with methylene blue staining under the guidance of the fluorescent tracer navigation system FLI-10B. Standard axillary lymph node dissection (ALND) was performed in patients with sentinel lymph node (SLN) metastasis confirmed by intraoperative frozen pathology, while low ALND was performed in patients with negative SLNs. According to the staining condition, the SLNs were divided into (I) the combined group (SLNs with methylene blue staining andor ICG luminescence) (II) the methylene blue group (SLNs with methylene blue staining alone) and (III) the ICG group (SLNs with ICG luminescence alone). The detection rate, accuracy, sensitivity, and false negative rate of SLNB were compared among the 3 groups. A total of 592 SLNs were detected in the combined group (average 3.8 SLNs), yielding a detection rate of 97.4% the accuracy, sensitivity, and false negative rates were 97.4%, 92.7%, and 7.3%. In the methylene blue group, 390 SLNs were detected (average 2.5 SLNs), yielding a detection rate of 84.6% the accuracy, sensitivity, and false negative rates were 83.3%, 89.1%, and 10.9%. A total of 483 SLNs were detected in the ICG group (average 3.1 SLNs), the detection rate was 92.9% the accuracy, sensitivity and false negative rates were 91.7%, 90.9%, and 9.1%. The average number of detected SLNs, detection rate and accuracy rate in the combined group were higher than those in the methylene blue group (P<0.05), and the accuracy rate of the combined group was higher than that of the ICG group (P<0.05). ICG combined with methylene blue staining is a promising and effective tracing strategy in the SLNB of breast cancer with high detection and accuracy rates.

A deep learning-based diagnostic pattern for ultrasound breast imaging can it reduce unnecessary biopsy

Early studies have demonstrated the potential of deep learning in bringing revolutionary changes in medical analysis. However, it is unknown which deep learning based diagnostic pattern is more effective for differentiating malignant and benign breast lesions (BLs) and can assist radiologists to reduce unnecessary biopsies. A total of 506 malignant BLs and 557 benign BLs were enrolled in this study after excluding incomplete ultrasound images. 396 malignant BLs and 447 benign BLs were included in the training cohort while 110 malignant and 110 benign BLs were included in the validation cohort. All BLs in the training and validation cohort were biopsy-proven. The most common convolutional neural networks (VGG-16 and VGG-19) were applied to identify malignant and benign BLs using grey-scale ultrasound images. Two radiologists determined the malignant (suggestion for biopsy) and benign (suggestion for follow-up) BLs with a 2-step reading session. The first step was based on conventional ultrasound (US) images alone to make a biopsy or follow-up decision. The second step was to take deep learning results into account for the decision adjustment. If a deep learning result of a first-classified benign BL was above the cut-off value, then it was re-classified as malignant. In terms of area under the curve (AUC), the VGG-19 model yielded the best diagnostic performance in both training 0.939, 95% confidence interval (CI) 0.924-0.954 and testing dataset (0.959, 95% CI 0.937-0.982). With the aid of deep learning models, the AUC of radiologists improved from 0.805 (95% CI 0.744-0.865) to 0.827 (95% CI 0.771-0.875, VGG-16) and 0.914 (95% CI 0.871-0.957, VGG-19). The unnecessary biopsies decreased from 10.0% (11110) to 8.2% (9110) (assisted by VGG-16) and 0.9% (1110) (assisted by VGG-19). The application of deep learning patterns in breast US may improve the diagnostic performance of radiologists by offering a second opinion. And thus, the assist of deep learning algorithm can considerably reduce the unnecessary biopsy rate in the clinical management of breast lesions.

Assessment of Tissue Oxidative Stress, Antioxidant Parameters, and Zinc and Copper Levels in Patients with Breast Cancer.

Breast cancer is a multifactorial disease, and among the many factors which are involved in the onset, progression, and invasion of the disease, oxidative stress plays a significant role. The concentration and activity of enzymatic antioxidants are proportional to the concentration of trace elements, and the concentration of trace elements is often deficient in malignancies. Therefore, in the present study, we studied the tissue levels of oxidative stress, antioxidant status, zinc (Zn), and copper (Cu) in breast cancer patients. Tissue samples were collected from 40 patients with breast cancer and 40 tumor margin tissue as a control group. All subjects gave their informed consent. The tissue samples were measured for superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), total antioxidants capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), malondialdehyde (MDA), Zn, and Cu. Data of all biochemical parameters of two groups were statistically analyzed by SPSS software, t test, and GraphPad Prism. Concentrations of MDA, TOS, and OSI in tumor tissue were significantly higher than tumor margin tissue, but the level of TAC and CAT, SOD, and GPX activities was significantly reduced in tumor tissue (p<0.05). It was found that the concentrations of Zn and Cu in breast cancer patients were higher than tumor margin tissue. Patients with breast cancer have a rise in oxidative stress indicators and a decrease in antioxidant stress markers. Since oxidative stress is a significant contributor to the development and progression of breast cancer, more research might lead to a more effective method of breast cancer treatment. Considering the dual role of oxidative stress in cancer, which can both cause survival and adaptation, and the death of cancer cells, and with more information, it can be used to manage the treatment and destruction of cancer cells.

Integrin alpha9 emerges as a key therapeutic target to reduce metastasis in rhabdomyosarcoma and neuroblastoma.

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.

Breast cancer knowledge and understanding treatment rationales among diverse breast cancer survivors.

The degree to which breast cancer survivors know about their tumors and understand treatment rationales is not well understood. We sought to identify information gaps within a diverse sample and explore whether knowledge about breast cancer and treatment may impact care. We conducted a one-time, interviewer-administered survey of women who were diagnosed with breast cancer during 2013-2017 and received care at one of three centers in Boston, MA, and New York, NY. We examined knowledge of breast cancer and treatment rationales, information preferences, and treatment receipt. During 2018-2020, we interviewed 313 women (American Association for Public Opinion Research Cooperation Rates 58.4-76.5% across centers) who were 56.9% White, 23.6% Black, 14.1% Hispanic, and 5.4% other. Among the 296 included in analyses, we observed high variability in knowledge of breast cancer and treatment rationales, with a substantial number demonstrating limited knowledge despite feeling highly informed > 25% actively avoided information. Black and Hispanic (vs. White) women consistently knew less about their cancers. Lack of understanding of treatment rationales for chemotherapy, radiation, and hormonal therapy was common but not consistently different by race and ethnicity. Understanding treatment rationale (but not cancer knowledge) was associated with treatment initiation, but small sample sizes limited in-depth examination. Our study highlights the need for enhanced informational support for breast cancer survivors, who are challenged with complex information during the decision-making process and beyond. More research is needed to understand how to further educate and empower diverse populations of patients with breast cancer.

Mitochondrial transporter expression patterns distinguish tumor from normal tissue and identify cancer subtypes with different survival and metabolism.

Transporters of the inner mitochondrial membrane are essential to metabolism. We demonstrate that metabolism as represented by expression of genes encoding SLC25 transporters differentiates human cancers. Tumor to normal tissue expression ratios for clear cell renal cell carcinoma, colon adenocarcinoma, lung adenocarcinoma and breast invasive carcinoma were found to be highly significant. Affinity propagation trained on SLC25 gene expression patterns from 19 human cancer types (6825 TCGA samples) and normal tissues (2322 GTEx samples) was used to generate clusters. They differentiate cancers from normal tissues. They also indicate cancer subtypes with survivals distinct from the total patient population of the cancer type. Probing the kidney, colon, lung, and breast cancer clusters, subtype pairs of cancers were identified with distinct prognoses and differing in expression of protein coding genes from among 2080 metabolic enzymes assayed. We demonstrate that SLC25 expression clusters facilitate the identification of the tissue-of-origin, essential to efficacy of most cancer therapies, of CUPs (cancer-unknown-primary) known to have poor prognoses. Different cancer types within a single cluster have similar metabolic patterns and this raises the possibility that such cancers may respond similarly to existing and new anti-cancer therapies.

Real-world study of overall survival with palbociclib plus aromatase inhibitor in HRHER2- metastatic breast cancer.

Data on real-world effectiveness of cyclin-dependent kinase 46 inhibitor combination therapy versus endocrine therapy alone are limited. The Flatiron Health Analytic Database was used to assess overall survival (OS) in patients with hormone receptor-positivehuman epidermal growth factor receptor 2-negative (HRHER2-) metastatic breast cancer (MBC) treated with first-line palbociclib plus an aromatase inhibitor (AI) versus an AI alone in routine US clinical practice. In total, 2888 patients initiated treatment during February 3, 2015-March 31, 2020, with a potential ≥6-month follow-up (cutoff date, September 30, 2020). After stabilized inverse probability treatment weighting, median OS (95% CI) is significantly longer among palbociclib versus AI recipients (49.1 45.2-57.7 versus 43.2 37.6-48.0 months hazard ratio, 0.76 95% CI, 0.65-0.87 P < 0.0001). Progression-free survival (95% CI) is 19.3 (17.5-20.7) versus 13.9 (12.5-15.2) months, respectively (hazard ratio, 0.70 95% CI, 0.62-0.78 P < 0.0001). These data support first-line palbociclib plus an AI treatment for HRHER2- MBC.(Trial number NCT05361655).