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Hyperparameter Optimizer with Deep Learning-Based Decision-Support Systems for Histopathological Breast Cancer Diagnosis.

Histopathological images are commonly used imaging modalities for breast cancer. As manual analysis of histopathological images is difficult, automated tools utilizing artificial intelligence (AI) and deep learning (DL) methods should be modelled. The recent advancements in DL approaches will be helpful in establishing maximal image classification performance in numerous application zones. This study develops an arithmetic optimization algorithm with deep-learning-based histopathological breast cancer classification (AOADL-HBCC) technique for healthcare decision making. The AOADL-HBCC technique employs noise removal based on median filtering (MF) and a contrast enhancement process. In addition, the presented AOADL-HBCC technique applies an AOA with a SqueezeNet model to derive feature vectors. Finally, a deep belief network (DBN) classifier with an Adamax hyperparameter optimizer is applied for the breast cancer classification process. In order to exhibit the enhanced breast cancer classification results of the AOADL-HBCC methodology, this comparative study states that the AOADL-HBCC technique displays better performance than other recent methodologies, with a maximum accuracy of 96.77%.

Facilitating Factors and Barriers in the Return to Work of Working Women Survivors of Breast Cancer A Qualitative Study.

Several studies have identified the main barriers and facilitators that breast cancer survivors experience in the return to work (RTW). The authors conducted a qualitative study using focus group discussions with a group of female non-metastatic breast cancer survivors (n 6), a group of health professionals from different medical specialties (n 8), and a third group of company managers mainly composed of human resources managers (n 7). The study was carried out between March and December 2021 in Zaragoza (Spain). Transcripts were analyzed using inductive content analysis to identify work-related barriers and facilitators and coded by the research team. Barriers identified included physical and cognitive symptoms, psychosocial problems, lack of knowledge and coordination (health professional, patients, and managers), legal vacuum, physical change, time constraints, work characteristics (lower skilled jobs), unsupportive supervisors and coworkers, family problems and self-demand. Facilitators included family and work support, physical activity and rehabilitation, personalized attention, interdisciplinary collaboration, legal advice for workers, knowledge about breast cancer in companies, positive aspects of work, elaboration of protocols for RTW in women with breast cancer. RTW in working women with breast cancer requires a personalized and holistic view that includes the perspectives of patients, healthcare professionals and company managers.

Deep Learning with Transformer or Convolutional Neural Network in the Assessment of Tumor-Infiltrating Lymphocytes (TILs) in Breast Cancer Based on US Images A Dual-Center Retrospective Study.

This study aimed to explore the feasibility of using a deep-learning (DL) approach to predict TIL levels in breast cancer (BC) from ultrasound (US) images. A total of 494 breast cancer patients with pathologically confirmed invasive BC from two hospitals were retrospectively enrolled. Of these, 396 patients from hospital 1 were divided into the training cohort (

Factors Influencing Residual Glandular Breast Tissue after Risk-Reducing Mastectomy in Genetically Predisposed Individuals Detected by MRI Mammography.

This study seeks to evaluate MR imaging morphological factors and other covariates that influence the presence of residual glandular tissue after risk-reducing mastectomy in patients with a familial predisposition. We analyzed women of a high-risk collective with pathogenic mutation (BRCA1 (n 49), BRCA2 (n 24), or further mutation (n 9)). A total of 117 breasts were analyzed, 63 left and 54 right, from a cohort of 81 patients, who were on average 40 years old. The mean follow-up was 63 months (range 12-180 months, SD 39.67). Retrospective analysis of MR imaging data from 2006-2022 of patients of a high-risk collective (all carriers of a pathogenic mutation) with contralateral (RRCM) or bilateral risk-reducing mastectomy (RRBM) was performed. In the image data the remaining skin flap thickness by distance measurements at eight equally distributed, clockwise points and the retromamillary area, as well as by volumetry of each breast, was elected. Residual glandular tissue was also volumetrized. In addition, patient-related covariates were recorded and their influence on postoperative residual glandular tissue and skin flap thickness was analyzed by uni- and multivariate regressions. A significant association with postoperative residual glandular tissue was shown in multivariate analysis for the independent variables breast density, skin flap mean, and surgical method (all Postoperative residual glandular tissue is an important tool for quantifying the risk of developing breast cancer after risk-reducing mastectomy. Different effects on residual glandular tissue were shown for the independent variables breast density, skin flap, surgical method, preoperative breast volume, and surgeon experience, so these should be considered in future surgical procedures preoperatively as well as postoperatively. Breast MRI has proven to be a suitable method to analyze the skin flap as well as the RGT.

MicroRNAs with Multiple Targets of Immune Checkpoints, as a Potential Sensitizer for Immune Checkpoint Inhibitors in Breast Cancer Treatment.

Breast cancer is the most common cancer type and the leading cause of cancer-associated mortality in women worldwide. In recent years, immune checkpoint inhibitors (ICIs) have made significant progress in the treatment of breast cancer, yet there are still a considerable number of patients who are unable to gain lasting and ideal clinical benefits by immunotherapy alone, which leads to the development of a combination regimen as a novel research hotspot. Furthermore, one miRNA can target several checkpoint molecules, mimicking the therapeutic effect of a combined immune checkpoint blockade (ICB), which means that the miRNA therapy has been considered to increase the efficiency of ICIs. In this review, we summarized potential miRNA therapeutics candidates which can affect multiple targets of immune checkpoints in breast cancer with more therapeutic potential, and the obstacles to applying miRNA therapeutically through the analyses of the resources available from a drug target perspective. We also included the content of too many targets for miRNA effect (TMTME), combined with applying TargetScan database, to discuss adverse events. This review aims to ignite enthusiasm to explore the application of miRNAs with multiple targets of immune checkpoint molecules, in combination with ICIs for treating breast cancer.

The Omega-3 Docosahexaenoyl Ethanolamide Reduces CCL5 Secretion in Triple Negative Breast Cancer Cells Affecting Tumor Progression and Macrophage Recruitment.

Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype lacking effective targeted therapies, is considered to feature a unique cellular microenvironment with high infiltration of tumor-associated macrophages (TAM), which contribute to worsening breast cancer patient outcomes. Previous studies have shown the antitumoral actions of the dietary omega-3 docosahexaenoic acid (DHA) in both tumor epithelial and stromal components of the breast cancer microenvironment. Particularly in breast cancer cells, DHA can be converted into its conjugate with ethanolamine, DHEA, leading to a more effective anti-oncogenic activity of the parent compound in estrogen receptor-positive breast cancer cells. Here, we investigated the ability of DHEA to attenuate the malignant phenotype of MDA-MB-231 and MDA-MB-436 TNBC cell lines, which in turn influenced TAM behaviors. Our findings revealed that DHEA reduced the viability of TNBC cells in a concentration-dependent manner and compromised cell migration and invasion. Interestingly, DHEA inhibited oxygen consumption and extracellular acidification rates, reducing respiration and the glycolytic reserve in both cell lines. In a co-culture system, TNBC cells exposed to DHEA suppressed recruitment of human THP-1 cells, reduced their viability, and the expression of genes associated with TAM phenotype. Interestingly, we unraveled that the effects of DHEA in TNCB cells were mediated by reduced C-C motif chemokine ligand 5 (CCL5) expression and secretion affecting macrophage recruitment. Overall, our data, shedding new light on the antitumoral effects of DHA ethanolamine-conjugated, address this compound as a promising option in the treatment of TNBC patients.

Implementing HRD Testing in Routine Clinical Practice on Patients with Primary High-Grade Advanced Ovarian Cancer.

The chemotherapy backbone for patients with high-grade advanced epithelial ovarian cancer (HG-AOC) is carboplatin and paclitaxel followed by a maintenance therapy either with bevacizumab, with a PARP inhibitor, or with a combination of both, which is defined by the presence of a homologous recombination deficiency (HRD) and by the

The Evolution of Ki-67 and Breast Carcinoma Past Observations, Present Directions, and Future Considerations.

The 1983 discovery of a mouse monoclonal antibody-the Ki-67 antibody-that recognized a nuclear antigen present only in proliferating cells represented a seminal discovery for the pathologic assessment of cellular proliferation in breast cancer and other solid tumors. Cellular proliferation is a central determinant of prognosis and response to cytotoxic chemotherapy in patients with breast cancer, and since the discovery of the Ki-67 antibody, Ki-67 has evolved as an important biomarker with both prognostic and predictive potential in breast cancer. Although there is universal recognition among the international guideline recommendations of the value of Ki-67 in breast cancer, recommendations for the actual use of Ki-67 assays in the prognostic and predictive evaluation of breast cancer remain mixed, primarily due to the lack of assay standardization and inconsistent inter-observer and inter-laboratory reproducibility. The treatment of high-risk ER-positivehuman epidermal growth factor receptor-2 (HER2) negative breast cancer with the recently FDA-approved drug abemaciclib relies on a quantitative assessment of Ki-67 expression in the treatment decision algorithm. This further reinforces the urgent need for standardization of Ki-67 antibody selection and staining interpretation, which will hopefully lead to multidisciplinary consensus on the use of Ki-67 as a prognostic and predictive marker in breast cancer. The goals of this review are to highlight the historical evolution of Ki-67 in breast cancer, summarize the present literature on Ki-67 in breast cancer, and discuss the evolving literature on the use of Ki-67 as a companion diagnostic biomarker in breast cancer, with consideration for the necessary changes required across pathology practices to help increase the reliability and widespread adoption of Ki-67 as a prognostic and predictive marker for breast cancer in clinical practice.

Tumor Infiltrating Lymphocytes across Breast Cancer Subtypes Current Issues for Biomarker Assessment.

Tumor-infiltrating lymphocytes (TILs) represent a surrogate biomarker of anti-tumor, lymphocyte-mediated immunity. In early, triple-negative breast cancer, TILs have level 1B of evidence to predict clinical outcomes. TILs represent a promising biomarker to select patients who can experience a better prognosis with de-intensified cancer treatments and derive larger benefits from immune checkpoint inhibitors. However, the assessment and the validation of TILs as a biomarker require a prospective and rigorous demonstration of its clinical validity and utility, provided reproducible analytical performance. With pending data about the prospective validation of TILs clinical validity to modulate treatments in early breast cancer, this review summarizes the most important current issues and future challenges related to the implementation of TILs assessments across all breast cancer subtypes and their potential integration into clinical practice.

The addition to chemotherapy of anti-HER2 drugs such as trastuzumab or pertuzumab has improved outcomes in HER2-positive breast cancer patients. However, resistance to these drugs in some patients remains a major concern. This study examines the possible association between the response to neoadjuvant anti-HER2 treatment in breast cancer patients and the presence of 28 SNPs in 17 genes involved in different cell processes (

Potent Inhibition of Macropinocytosis by Niclosamide in Cancer Cells A Novel Mechanism for the Anticancer Efficacy for the Antihelminthic.

Niclosamide, a drug used to treat tapeworm infection, possesses anticancer effects by interfering with multiple signaling pathways. Niclosamide also causes intracellular acidification. We have recently discovered that the amino acid transporter SLC38A5, an amino acid-dependent Na

Innate Immune Program in Formation of Tumor-Initiating Cells from Cells-of-Origin of Breast, Prostate, and Ovarian Cancers.

Tumor-initiating cells (TICs), also known as cancer stem cells (CSCs), are cancer cells that can initiate a tumor, possess self-renewal capacity, and can contribute to tumor heterogeneity. TICsCSCs are developed from their cells-of-origin. In breast, prostate, and ovarian cancers, progenitor cells for mammary alveolar cells, prostate luminal (secretory) cells, and fallopian tube secretory cells are the preferred cellular origins for their corresponding cancer types. These luminal progenitors (LPs) express common innate immune program (e.g., Toll-like receptor (TLR) signaling)-related genes. Microbes such as bacteria are now found in breast, prostate, and fallopian tube tissues and their corresponding cancer types, raising the possibility that their LPs may sense the presence of microbes and trigger their innate immuneTLR pathways, leading to an inflammatory microenvironment. Crosstalk between immune cells (e.g., macrophages) and affected epithelial cells (e.g., LPs) may eventually contribute to formation of TICsCSCs from their corresponding LPs, in part via STAT3 andor NFκB pathways. As such, TICsCSCs can inherit expression of innate-immunityTLR-pathway-related genes from their cells-of-origin the innate immune program may also represent their unique vulnerability, which can be explored therapeutically (e.g., by enhancing immunotherapy via augmenting TLR signaling).

CANTO-RT One of the Largest Prospective Multicenter Cohort of Early Breast Cancer Patients Treated with Radiotherapy including Full DICOM RT Data.

This article describes the methodology used and provides a characterization of the study population in CANTO-RT (CANcer TOxicities RadioTherapy). CANTO (NCT01993498) is a prospective clinical cohort study including patients with stage I-III BC from 26 French cancer centers. Patients matching all CANTO inclusion and exclusion criteria who received RT in one of the 10 top recruiting CANTO centers were selected. Individual full DICOM RT files were collected, pseudo-anonymized, structured and analyzed on the CANTO-RTUNITRAD web platform. CANTO-RT included 3875 BC patients with a median follow-up of 64 months. Among the 3797 patients with unilateral RT, 3065 (80.4%) had breast-conserving surgery, and 2712 (71.5%) had sentinel node surgery. Tumor bed boost was delivered in 2658 patients (68.5%) and lymph node RT in 1356 patients (35%), including internal mammary chain in 844 patients (21.8%). Most patients (3691 (95.3%)) were treated with 3D conformal RT. Target volumes, organs at risk contours and dosevolume histograms were extracted after quality-control procedures. CANTO-RT is one of the largest early BC prospective cohorts with full individual clinical, biological, imaging and DICOM RT data available. It is a valuable resource for the identification and validation of clinical and dosimetric predictive factors of RT and multimodal treatment-related toxicities.

Combined Hyperthermia and Re-Irradiation in Non-Breast Cancer Patients A Systematic Review.

This systematic literature review summarizes clinical studies and trials involving combined non-ablative hyperthermia and re-irradiation in locoregionally recurrent cancer except breast cancer. One database and one registry, MEDLINE and clinicaltrials.gov, respectively, were searched for studies on combined non-ablative hyperthermia and re-irradiation in non-breast cancer patients. Extracted study characteristics included treatment modalities and re-irradiation dose concepts. Outcomes of interest were tumor response, survival measures, toxicity data and palliation. Within-study bias assessment included the identification of conflict of interest (COI). The final search was performed on 29 August 2022. Twenty-three articles were included in the final analysis, reporting on 603 patients with eight major tumor types. Twelve articles (52%) were retrospective studies. Only one randomized trial was identified. No COI statement was declared in 11 studies. Four of the remaining twelve studies exhibited significant COI. Low study and patient numbers, high heterogeneity in treatment modalities and endpoints, as well as significant within- and across-study bias impeded the synthesis of results. Outside of locoregionally recurrent breast cancer, the role of combined moderate hyperthermia and re-irradiation can so far not be established. This review underscores the necessity for more clinical trials to generate higher levels of clinical evidence for combined re-irradiation and hyperthermia.

Sialyl Lewis

Triple-negative breast cancer (TNBC) encompasses multiple entities and is generally highly aggressive and metastatic. We aimed to determine the clinical and biological relevance of Sialyl-Lewis X and A (sLe

Cancer-Associated Adipocytes and Breast Cancer Intertwining in the Tumor Microenvironment and Challenges for Cancer Therapy.

Adipocytes are the main components in breast tissue, and cancer-associated adipocytes (CAAs) are one of the most important components in the tumor microenvironment of breast cancer (BC). Bidirectional regulation was found between CAAs and BC cells. BC facilitates the dedifferentiation of adjacent adipocytes to form CAAs with morphological and biological changes. CAAs increase the secretion of multiple cytokines and adipokines to promote the tumorigenesis, progression, and metastasis of BC by remodeling the extracellular matrix, changing aromatase expression, and metabolic reprogramming, and shaping the tumor immune microenvironment. CAAs are also associated with the therapeutic response of BC and provide potential targets in BC therapy. The present review provides a comprehensive description of the crosstalk between CAAs and BC and discusses the potential strategies to target CAAs to overcome BC treatment resistance.

A Suggested Modification to FIGO Stage IV Epithelial Ovarian Cancer.

International Federation of Gynecology and Obstetrics (FIGO) staging classification for stage IV epithelial ovarian cancer (EOC) separates stages IVA (pleural effusion) and IVB (parenchymal andor extra-abdominal lymph node metastases). We aimed to evaluate its prognostic impact and to compare survival according to the initial metastatic location. We conducted a multicenter study between 2000 and 2020, including patients with a FIGO stage IV EOC. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS) and recurrence rates. We included 307 patients 98 (32%) had FIGO stage IVA and 209 (68%) had FIGO stage IVB. The median OS and PFS of stage IVA patients were significantly lower than those of stage IVB patients (31 versus 45 months (

Long-Term Non-Cancer Risks in People with

Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is the gold standard preventative option for

Insights of Platinum Drug Interaction with Spinel Magnetic Nanocomposites for Targeted Anti-Cancer Effect.

In nanotherapeutics, gaining insight about the drug interaction with the pore architecture and surface functional groups of nanocarriers is crucial to aid in the development of targeted drug delivery. Manganese ferrite impregnated graphene oxide (MnFe

Quantitative Assessment of Treatment Response in Metastatic Breast Cancer Patients by SPECT-CT Bone Imaging-Getting Closer to PET-CT.

Cancer represents the major cause of death mainly through its ability to spread to other organs, highlighting the importance of metastatic disease diagnosis and accurate follow up for treatment management purposes. Although until recently the main method for imaging interpretation was represented by qualitative methods, quantitative analysis of SPECT-CT data represents a viable, objective option. Seventy-five breast cancer patients presenting metastatic bone disease underwent at least two Bone SPECT-CT studies using Our findings show a good positive relationship between the qualitative methods of imaging interpretation and quantitative analysis, with a correlation coefficient of 0.608 between qualitative whole body scintigraphy and quantitative SPECT-CT, and a correlation coefficient of 0.711 between the qualitative and quantitative interpretation of SPECT-CT data nevertheless, there is a need for accurate, objective and reproducible methods for imaging interpretation, especially for research purposes. Quantitative evaluation of the SPECT-CT data has the potential to be the first choice of imaging interpretation for patient follow up and treatment response evaluation, especially for research purposes, because of its objectivity and expression of uptake changes in absolute units.

Use of Nonsteroidal Anti-Inflammatory Drugs and Risk of Breast Cancer Evidence from a General Female Population and a Mammographic Screening Cohort in Sweden.

A link has been proposed between the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of breast cancer. There is, however, insufficient data regarding the subtype and stage of breast cancer, and few studies have assessed the interaction between the use of NSAIDs and breast density or previous breast disorders. There is also a lack of data from population-based studies. We first conducted a nested case-control study within the general female population of Sweden, including 56,480 women with newly diagnosed breast cancer during 2006-2015 and five breast cancer-free women per case as controls, to assess the association of NSAID use with the risk of incident breast cancer, focusing on subtype and stage of breast cancer as well as the interaction between NSAID use and previous breast disorders. We then used the Karolinska Mammography Project for Risk Prediction of Breast Cancer (Karma) cohort to assess the interaction between NSAID use and breast density in relation to the risk of breast cancer. Conditional logistic regression was used to estimate the hazard ratio (HR) and a 95% confidence interval (CI) was used for breast cancer in relation to the use of aspirin and non-aspirin NSAIDs. In the nested case-control study of the general population, exclusive use of aspirin was not associated with the risk of breast cancer, whereas exclusive use of non-aspirin NSAIDs was associated with a modestly higher risk of stage 0-2 breast cancer (HR 1.05 95% CI 1.02-1.08) but a lower risk of stage 3-4 breast cancer (HR 0.80 95% CI 0.73-0.88). There was also a statistically significant interaction between the exclusive use of NSAIDs and previous breast disorders (

Safety and Feasibility of Radiation Therapy Combined with CDK 46 Inhibitors in the Management of Advanced Breast Cancer.

The addition of CDK46 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK46i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK46i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK46i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%) however, CDK46i dose reduction rates were similar. In patients treated with CDK46i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK46i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK46i cycles, and more than one concurrent RT a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK46i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK46i and RT combination without a significantly increased toxicity compared with CDK46i alone. However, one might delay RT for the first two CDK46i cycles, when myelotoxic AE are most common.

Breast Cancer Prediction Using Fine Needle Aspiration Features and Upsampling with Supervised Machine Learning.

Breast cancer is one of the most common invasive cancers in women and it continues to be a worldwide medical problem since the number of cases has significantly increased over the past decade. Breast cancer is the second leading cause of death from cancer in women. The early detection of breast cancer can save human life but the traditional approach for detecting breast cancer disease needs various laboratory tests involving medical experts. To reduce human error and speed up breast cancer detection, an automatic system is required that would perform the diagnosis accurately and timely. Despite the research efforts for automated systems for cancer detection, a wide gap exists between the desired and provided accuracy of current approaches. To overcome this issue, this research proposes an approach for breast cancer prediction by selecting the best fine needle aspiration features. To enhance the prediction accuracy, several feature selection techniques are applied to analyze their efficacy, such as principal component analysis, singular vector decomposition, and chi-square (Chi2). Extensive experiments are performed with different features and different set sizes of features to investigate the optimal feature set. Additionally, the influence of imbalanced and balanced data using the SMOTE approach is investigated. Six classifiers including random forest, support vector machine, gradient boosting machine, logistic regression, multilayer perceptron, and K-nearest neighbors (KNN) are tuned to achieve increased classification accuracy. Results indicate that KNN outperforms all other classifiers on the used dataset with 20 features using SVD and with the 15 most important features using a PCA with a 100% accuracy score.

Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes.

Breast cancer (BC) is a nearly ubiquitous malignancy that effects the lives of millions worldwide. Recently, nutritional prevention of BC has received increased attention due to its efficacy and ease of application. Chief among chemopreventive compounds are plant-based substances known as dietary phytochemicals. Sulforaphane (SFN), an epigenetically active phytochemical found in cruciferous vegetables, has shown promise in BC prevention. In addition, observational studies suggest that the life stage of phytochemical consumption may influence its anticancer properties. These life stages, called critical periods (CPs), are associated with rapid development and increased susceptibility to cellular damage. Puberty, a CP in which female breast tissue undergoes proliferation and differentiation, is of particular interest for later-life BC development. However, little is known about the importance of nutritional chemoprevention to CPs. We sought to address this by utilizing two estrogen receptor-negative ER(-) transgenic mouse models fed SFN-containing broccoli sprout extract during the critical period of puberty. We found that this treatment resulted in a significant decrease in tumor incidence and weight, as well as an increase in tumor latency. Further, we found significant alterations in the long-term expression of cancer-associated genes, including

Plasma CytokinesChemokines as Predictive Biomarkers for Lymphedema in Breast Cancer Patients.

Breast cancer-related lymphedema (BCRL) occurs in 40% of patients after axillary lymph node dissection (ALND), radiation therapy (RT), or chemotherapy. First-line palliative treatment utilizes compression garments and specialized massage. Reparative microsurgeries have emerged as a second-line treatment, yet both compression and surgical therapy are most effective at early stages of LE development. Identifying patients at the highest risk for BCRL would allow earlier, more effective treatment. Perometric arm volume measurements, near-infrared fluorescent lymphatic imaging (NIRF-LI) data, and blood were collected between 2016 and 2021 for 40 study subjects undergoing treatment for breast cancer. Plasma samples were evaluated using MILLIPLEX human cytokinechemokine panels at pre-ALND and at 12 months post-RT. A Mann-Whitney

Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats.

The nonsteroidal anti-inflammatory drug (NSAID) sulindac demonstrates attractive anticancer activity, but the toxicity resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins precludes its long-term, high dose use in the clinic for cancer prevention or treatment. While inflammation is a known tumorigenic driver, evidence suggests that sulindacs antineoplastic activity is partially or fully independent of its COX inhibitory activity. One COX-independent target proposed for sulindac is cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) isozymes. Sulindac metabolites, i.e., sulfide and sulfone, inhibit cGMP PDE enzymatic activity at concentrations comparable with those associated with cancer cell growth inhibitory activity. Additionally, the cGMP PDE isozymes PDE5 and PDE10 are overexpressed during the early stages of carcinogenesis and appear essential for cancer cell proliferation and survival based on gene silencing experiments. Here, we describe a novel amide derivative of sulindac, sulindac sulfide amide (SSA), which was rationally designed to eliminate COX-inhibitory activity while enhancing cGMP PDE inhibitory activity. SSA was 68-fold and 10-fold less potent than sulindac sulfide (SS) in inhibiting COX-1 and COX-2, respectively, but 10-fold more potent in inhibiting growth and inducing apoptosis in breast cancer cells. The pro-apoptotic activity of SSA was associated with inhibition of cGMP PDE activity, elevation of intracellular cGMP levels, and activation of cGMP-dependent protein kinase (PKG) signaling, as well as the inhibition of β-cateninTcf transcriptional activity. SSA displayed promising in vivo anticancer activity, resulting in a 57% reduction in the incidence and a 62% reduction in the multiplicity of tumors in the N-methyl-N-nitrosourea (MNU)-induced model of breast carcinogenesis. These findings provide strong evidence for cGMPPKG signaling as a target for breast cancer prevention or treatment and the COX-independent anticancer properties of sulindac. Furthermore, this study validates the approach of optimizing off-target effects by reducing the COX-inhibitory activity of sulindac for future targeted drug discovery efforts to enhance both safety and efficacy.

An Optimized Single Nucleotide Polymorphism-Based Detection Method Suggests That Allelic Variants in the 3 Untranslated Region of

Unlike classical

The Relationship between Cancer and Dementia An Updated Review.

The risk of cancer and dementia increases with age, raising complex questions about whether it is appropriate to continue cancer treatment in older patients. There is emerging research suggesting the association between cancer and dementia. However, the mechanistic underpinnings are still under investigation. Progress has already been made toward understanding the cognitive effects associated with cancer therapy. Such associations raise awareness about the need to establish better prevention methods and early screening in clinical practice. Additionally, recent studies have suggested possible therapeutic strategies for better preserving cognitive function and reducing the risk for dementia before patients start cancer treatment. We review the current literature and summarize the incidence and mechanisms of cognitive impairment in patients with lung cancer, breast cancer, head and neck cancer, gastric cancer, prostate cancer, colorectal cancer, and brain tumorbrain metastasis following different kinds of therapies. Possible risk factors are suggested to identify the early onset of cognitive changes in cancer patients and provide more insight into the pathophysiological process of dementia.

Applying Explainable Machine Learning Models for Detection of Breast Cancer Lymph Node Metastasis in Patients Eligible for Neoadjuvant Treatment.

Due to recent changes in breast cancer treatment strategy, significantly more patients are treated with neoadjuvant systemic therapy (NST). Radiological methods do not precisely determine axillary lymph node status, with up to 30% of patients being misdiagnosed. Hence, supplementary methods for lymph node status assessment are needed. This study aimed to apply and evaluate machine learning models on clinicopathological data, with a focus on patients meeting NST criteria, for lymph node metastasis prediction. From the total breast cancer patient data ( In the NST-criteria group, random forest achieved the highest performance (AUC 0.793 0.713, 0.865), while in the total study population, XGBoost performed the best (AUC 0.762 0.726, 0.795). Shapley values identified tumor size, Ki-67, and patient age as the most important predictors. Tree-based models achieve a good performance in assessing lymph node status. Such models can lead to more accurate disease stage prediction and consecutively better treatment selection, especially for NST patients where radiological and clinical findings are often the only way of lymph node assessment.

Salvage Perioperative Interstitial High-Dose-Rate Interventional Radiotherapy (Brachytherapy) for Local Recurrences of the Chest Wall Following Mastectomy and Previous External Irradiation.

(1) Background To investigate the technical feasibility, safety, and efficacy of interstitial perioperative high-dose-rate interventional radiotherapy (HDR-IRT, brachytherapy) as a local salvage treatment combined with surgery for local chest wall recurrences following mastectomy and subsequent external beam radiation treatment (EBRT). (2) Methods A retrospective analysis of 56 patients treated with interstitial HDR-IRT in combination with local surgery of a chest wall recurrence of breast cancer after previous treatment with mastectomy and EBRT from 2008 to 2020. (3) Results Local recurrence following HDR-IRT was encountered in seven (12.5%) patients. The 1-year local recurrence-free survival (RFS), 3-year RFS, and 5-year RFS were 91%, 82%, and 82%, respectively. The 1-year overall survival (OS), 3-year OS, and 5-year OS was 85.5%, 58%, and 30%, respectively. Acute grade 1-2 radiation dermatitis was observed in 22 (39.3%) patients. Late ≥grade 3 toxicities were encountered in five (8.9%) patients. (4) Conclusions Salvage perioperative interstitial high-dose-rate interventional radiotherapy (brachytherapy) combined with surgery seems to be an effective interdisciplinary management with acceptable treatment-related toxicity for local recurrences of the chest wall following mastectomy and previous external irradiation.

Barriers to Breast Cancer-Screening Adherence in Vulnerable Populations.

Breast cancer screening through periodic mammography has been effective in decreasing mortality and reducing the impact of this disease. However, adherence to screening does not meet the desired expectations from all populations. The main objective of this review is to explore the barriers that affect adherence to breast cancer-screening programs in vulnerable populations according to race andor ethnicity in order to propose measures to reduce the lack of adherence. We conducted a search of publications in the PubMed Central and Scopus databases. The eligible criteria for the articles were as follows original quantitative studies appearing in SJR- andor JCR-indexed journals from 2016 to 2021 in English or Spanish. Most of them present common barriers, such as raceethnicity (47%), low socioeconomic (35.3%) and educational levels (29.4%), no family history of cancer and being single (29.4%), medical mistrust and a health information gap (23.5%), lack of private health insurance (17.6%) and not having annual health checks (17.6%). The target populations with the lowest adherence were Black, Asian, Hispanic and foreign women. Implementing awareness campaigns focused on these populations should be promoted, as well as working on diversity, cultural acceptance and respect with healthcare workers, in order to improve breast cancer-screening adherence worldwide.

Prognostic Implications of the Residual Tumor Microenvironment after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients without Pathological Complete Response.

With a high risk of relapse and death, and a poor or absent response to therapeutics, the triple-negative breast cancer (TNBC) subtype is particularly challenging, especially in patients who cannot achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Although the tumor microenvironment (TME) is known to influence disease progression and the effectiveness of therapeutics, its predictive and prognostic potential remains uncertain. This work aimed to define the residual TME profile after NAC of a retrospective cohort with 96 TNBC patients by immunohistochemical staining (cell markers) and chromogenic in situ hybridization (genetic markers). Kaplan-Meier curves were used to estimate the influence of the selected TME markers on five-year overall survival (OS) and relapse-free survival (RFS) probabilities. The risks of each variable being associated with relapse and death were determined through univariate and multivariate Cox analyses. We describe a unique tumor-infiltrating immune profile with high levels of lymphocytes (CD4, FOXP3) and dendritic cells (CD21, CD1a and CD83) that are valuable prognostic factors in post-NAC TNBC patients. Our study also demonstrates the value of considering not only cellular but also genetic TME markers such as MUC-1 and CXCL13 in routine clinical diagnosis to refine prognosis modelling.

Breast Cancer Survivors and Healthy Women Could Gut Microbiota Make a Difference-BiotaCancerSurvivors A Case-Control Study.

In this first analysis, samples from 23 BC survivors (group 1) and 291 healthy female controls (group 2) were characterised through the V3 and V4 regions that encode the 16S rRNA gene of each bacteria. The samples were sequenced by next-generation sequencing (NGS), and the taxonomy was identified by resorting to Kraken2 and improved with Bracken, using a curated database called GutHealthDB. The α and β-diversity analyses were used to determine the richness and evenness of the gut microbiota. A non-parametric Mann-Whitney

Intraoperative Evaluation of Soft Tissue Sarcoma Surgical Margins with Indocyanine Green Fluorescence Imaging.

Soft tissue sarcomas (STS) are rare malignant tumors often associated with poor outcomes and high local recurrence rates. Current tools for intraoperative and definitive margin assessment include intraoperative frozen section and permanent pathology, respectively. Indocyanine green dye (ICG) is a historically safe fluorophore dye that has demonstrated efficacy for intraoperative margin assessment in the surgical management of both breast and gastrointestinal cancers. The utility of ICG in the surgical management of sarcoma surgery has primarily been studied in pre-clinical mouse models and warrants further investigation as a potential adjunct to achieving negative margins. This study is a prospective, non-randomized clinical study conducted on patients with confirmed or suspected STS. Patients younger than 18 years, with a prior adverse reaction to iodine or fluorescein, or with renal disease were excluded from the study. Intravenous ICG was infused approximately three hours prior to surgery at a dosage of 2.0-2.5 mgkg, and following tumor resection, the excised tumor and tumor bed were imaged for fluorescence intensity. When scanning the tumor bed, a threshold of 77% calibrated to the region of maximum intensity in the resected tumor was defined as a positive ICG margin, according to published protocols from the breast cancer literature. ICG results were then compared with the surgeons clinical impression of margin status and permanent pathology results. Out of 26 subjects recruited for the original study, 18 soft tissue sarcomas (STS) were included for analysis. Three subjects were excluded for having bone sarcomas, and five subjects were excluded due to final pathology, which was ultimately inconsistent with sarcoma. The average age of patients was 64.1 years old (range 28-83), with an average ICG dose of 201.8 mg. In 56% (1018) of patients, ICG margins were consistent with the permanent pathology margins, with 89% specificity. The use of ICG as an intraoperative adjunct to obtaining negative margins in soft tissue sarcoma surgery is promising. However, studies with larger sample sizes are warranted to further delineate the accuracy, optimal dosage, timing, and types of sarcoma in which this diagnostic tool may be most useful.

The Influence of the Normal Mammary Microenvironment on Breast Cancer Cells.

The tumor microenvironment is recognized as performing a critical role in tumor initiation, progression, and metastasis of many cancers, including breast cancer. The breast cancer microenvironment is a complex mixture of cells consisting of tumor cells, immune cells, fibroblasts, and vascular cells, as well as noncellular components, such as extracellular matrix and soluble products. The interactions between the tumor cells and the tumor microenvironment modulate tumor behavior and affect the responses of cancer patients to therapies. The interactions between tumor cells and the surrounding environment can include direct cell-to-cell contact or through intercellular signals over short and long distances. The intricate functions of the tumor microenvironment in breast cancer have led to increased research into the tumor microenvironment as a possible therapeutic target of breast cancer. Though expanded research has shown the clear importance of the tumor microenvironment, there is little focus on how normal mammary epithelial cells can affect breast cancer cells. Previous studies have shown the normal breast microenvironment can manipulate non-mammary stem cells and tumor-derived cancer stem cells to participate in normal mammary gland development. The tumorigenic cells lose their tumor-forming capacity and are redirected to divide into normal, non-tumorigenic cells. This cellular behavior is cancer cell redirection. This review will summarize the current literature on cancer cell redirection and the normal mammary microenvironments influence on breast cancer cells.

Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer.

Doxycycline is often used as a promoter of inducible gene expression in preclinical models however, it can also have direct effects on tumor growth and survival. This is due in part to its ability to inhibit cell invasion and regulate matrix metalloproteinase (MMP) expression. Given that doxycycline is also osteotropic, a clinical study to assess its effects on modulation of tumor progression or prevention of skeletal-related events (SRE) in patients with bone metastases from breast cancer (the Achilles trial) was undertaken. Patients received 100 mg of oral doxycycline twice daily for 12 weeks, with serum obtained at baseline and 4, 8 and 12 weeks post-initiation of doxycycline treatment. Exploratory analysis of the effects of doxycycline on circulating levels of MMP or tissue inhibitor of matrix metalloproteinase 2 (TIMP2) was performed in enrolled patients. Statistically significant associations were observed between MMP2, MMP9 and TIMP2 at baseline with significant associations maintained between absolute levels and changes in levels of MMP2 and TIMP2 at weeks 4-12 post initiation of doxycycline. Treatment with doxycycline generally resulted in decreases in MMP2 and MMP9 levels with concurrent upregulation of TIMP2 at 12 weeks post-initiation of doxycycline treatment. Despite this, we observed no association with the levels of any of these factors with either SRE-free or overall survival in this patient cohort. In summary, despite observing hypothesized effects of doxycycline administration on surrogate markers of its anti-tumor activity, measures of circulating levels of these biomarkers were not prognostic in this patient population.

Multi-Parameter Analysis of Disseminated Tumor Cells (DTCs) in Early Breast Cancer Patients with Hormone-Receptor-Positive Tumors.

Patients with hormone-receptor-positive (HR) breast cancer are at increased risk for late recurrence. One reason might be disseminated tumor cells (DTCs), which split off in the early stages of the disease and metastasize into the bone marrow (BM). We developed a novel multi-parameter immunofluorescence staining protocol using releasable and bleachable antibody-fluorochrome-conjugates. This sequential procedure enabled us to analyze six distinct phenotypical and therapy-related markers on the same DTC. We characterized BM aspirates from 29 patients with a HR tumor and a known positive DTC status-based on the standardized detection of epithelial cells in BM. Using the immunofluorescence staining, a total of 153 DTCs were detected. Luminal A patients revealed a higher DTC count compared with luminal B. The majority of the detected DTCs were CK-positive (128153). However, in 16 of 17 luminal A patients we found HER2-positive DTCs. We detected CK-negative DTCs (25153) in 12 of 29 patients. Of those cells, 76% were Ki67-positive and 68% were HER2-positive. Moreover, we detected DTC clusters consisting of mixed characteristics in 6 of 29 patients. Using sequential multi-parameter imaging made it possible to identify distinct DTC profiles not solely based on epithelial features. Our findings indicate that characterization rather than quantification of DTCs might be relevant for treatment decisions.

Standardising Breast Radiotherapy Structure Naming Conventions A Machine Learning Approach.

In progressing the use of big data in health systems, standardised nomenclature is required to enable data pooling and analyses. In many radiotherapy planning systems and their data archives, target volumes (TV) and organ-at-risk (OAR) structure nomenclature has not been standardised. Machine learning (ML) has been utilised to standardise volumes nomenclature in retrospective datasets. However, only subsets of the structures have been targeted. Within this paper, we proposed a new approach for standardising all the structures nomenclature by using multi-modal artificial neural networks. A cohort consisting of 1613 breast cancer patients treated with radiotherapy was identified from Liverpool Macarthur Cancer Therapy Centres, NSW, Australia. Four types of volume characteristics were generated to represent each target and OAR volume textual features, geometric features, dosimetry features, and imaging data. Five datasets were created from the original cohort, the first four represented different subsets of volumes and the last one represented the whole list of volumes. For each dataset, 15 sets of combinations of features were generated to investigate the effect of using different characteristics on the standardisation performance. The best model reported 99.416% classification accuracy over the hold-out sample when used to standardise all the nomenclatures in a breast cancer radiotherapy plan into 21 classes. Our results showed that ML based automation methods can be used for standardising naming conventions in a radiotherapy plan taking into consideration the inclusion of multiple modalities to better represent each volume.

Immunotherapy Review of the Existing Evidence and Challenges in Breast Cancer.

Breast cancer (BC) is a representative malignant tumor that affects women across the world, and it is the main cause of cancer-related deaths in women. Although a large number of treatment methods have been developed for BC in recent years, the results are sometimes unsatisfying. In recent years, treatments of BC have been expanded with immunotherapy. In our article, we list some tumor markers related to immunotherapy for BC. Moreover, we introduce the existing relatively mature immunotherapy and the markers pathogenesis are involved. The combination of immunotherapy and other therapies for BC are introduced in detail, including the combination of immunotherapy and chemotherapy, the combined use of immunosuppressants and chemotherapy drugs, immunotherapy and molecular targeted therapy. We summarize the clinical effects of these methods. In addition, this paper also makes a preliminary exploration of the combination of immunotherapy, radiotherapy, and nanotechnology for BC.

The Michigan Genetic Hereditary Testing (MiGHT) studys innovative approaches to promote uptake of clinical genetic testing among cancer patients a study protocol for a 3-arm randomized controlled trial.

Although most cancers are sporadic, germline genetic variants are implicated in 5-10% of cancer cases. Clinical genetic testing identifies pathogenic germline genetic variants for hereditary cancers. The Michigan Genetic Hereditary Testing (MiGHT) study is a three-arm randomized clinical trial that aims to test the efficacy of two patient-level behavioral interventions on uptake of cancer genetic testing. The two interventions being tested are (1) a virtual genetics navigator and (2) motivational interviewing by genetic health coaches. Eligible participants are adults with a diagnosis of breast, prostate, endometrial, ovarian, colorectal, or pancreatic cancer who meet the National Comprehensive Cancer Network (NCCN) criteria for genetic testing. Participants are recruited through community oncology practices affiliated with the Michigan Oncology Quality Consortium (MOQC) and have used the Family Health History Tool (FHHT) to determine testing eligibility. The recruitment goal is 759 participants, who will be randomized to usual care or to either the virtual genetics navigator or the motivational interviewing intervention arms. The primary outcome will be the proportion of individuals who complete germline genetic testing within 6 months. This study addresses patient-level factors which are associated with the uptake of genetic testing. The study will test two different intervention approaches, both of which can help address the shortage of genetic counselors and improve access to care. This study has been approved by the Institutional Review Board of the University of Michigan Medical School (HUM00192898) and registered in ClinicalTrials.gov (NCT05162846).

Cellular senescence in the response of HR

Preclinical evidence from us and others demonstrates that the anticancer effects of cyclin-dependent kinase 46 (CDK46) inhibitors can be enhanced with focal radiation therapy (RT), but only when RT is delivered prior to (rather than after) CDK46 inhibition. Depending on tumor model, cellular senescence (an irreversible proliferative arrest that is associated with the secretion of numerous bioactive factors) has been attributed beneficial or detrimental effects on response to treatment. As both RT and CDK46 inhibitors elicit cellular senescence, we hypothesized that a differential accumulation of senescent cells in the tumor microenvironment could explain such an observation, i.e., the inferiority of CDK46 inhibition with palbociclib (P) followed by RT (P→RT) as compared to RT followed by palbociclib (RT→P). The impact of cellular senescence on the interaction between RT and P was assessed by harnessing female INK-ATTAC mice, which express a dimerizable form of caspase 8 (CASP8) under the promoter of cyclin dependent kinase inhibitor 2A (Cdkn2a, coding for p16 In vivo depletion of p16 Pending validation in other experimental systems, these findings suggest that a program of cellular senescence in malignant cells may explain (at least partially) the inferiority of P→RT versus RT→P in preclinical models of HR

The various role of microRNAs in breast cancer angiogenesis, with a special focus on novel miRNA-based delivery strategies.

After skin malignancy, breast cancer is the most widely recognized cancer detected in women in the United States. Breast cancer (BCa) can happen in all kinds of people, but its much more common in women. One in four cases of cancer and one in six deaths due to cancer are related to breast cancer. Angiogenesis is an essential factor in the growth of tumors and metastases in various malignancies. An expanded level of angiogenesis is related to diminished endurance in BCa patients. This function assumes a fundamental part inside the human body, from the beginning phases of life to dangerous malignancy. Various factors, referred to as angiogenic factors, work to make a new capillary. Expanding proof demonstrates that angiogenesis is managed by microRNAs (miRNAs), which are small non-coding RNA with 19-25 nucleotides. MiRNA is a post-transcriptional regulator of gene expression that controls many critical biological processes. Endothelial miRNAs, referred to as angiomiRs, are probably concerned with tumor improvement and angiogenesis via regulation of pro-and anti-angiogenic factors. In this article, we reviewed therapeutic functions of miRNAs in BCa angiogenesis, several novel delivery carriers for miRNA-based therapeutics, as well as CRISPRCas9 as a targeted therapy in breast cancer.

Risks of second non-breast primaries following breast cancer in women a systematic review and meta-analysis.

Second primary cancer incidence is rising among breast cancer survivors. We examined the risks of non-breast second primaries, in combination and at specific cancer sites, through a systematic review and meta-analysis. We conducted a systematic search of PubMed, Embase, and Web of Science, seeking studies published by March 2022. We included studies that reported standardized incidence ratios (SIRs), with associated standard errors, assessing the combined risk of second non-breast primaries following breast cancer. We performed meta-analyses of combined second primary risks, stratifying by age, follow-up duration, and geographic region. We also assessed second primary risks at several specific sites, stratifying by age. The inverse variance method with DerSimonian-Laird estimators was used in all meta-analyses, assuming a random-effects model. Associated biases and study quality were evaluated using the Newcastle-Ottawa scale. One prospective and twenty-seven retrospective cohort studies were identified. SIRs for second non-breast primaries combined ranged from 0.84 to 1.84. The summary SIR estimate was 1.24 (95% CI 1.14-1.36, I Breast cancer survivors are at significantly increased risk of second primaries at many sites. Risks are higher for those diagnosed with breast cancer before age 50 and in Asian breast cancer survivors compared to European breast cancer survivors. This study is limited by a lack of data on potentially confounding variables. The conclusions may inform clinical management decisions following breast cancer, although specific clinical recommendations lie outside the scope of this review.

METTL3 depletion contributes to tumour progression and drug resistance via N6 methyladenosine-dependent mechanism in HRHER2-breast cancer.

Chemotherapy is an important strategy for the treatment of hormone receptor-positivehuman epidermal growth factor receptor 2-negative (HRHER2-) breast cancer (BC), but this subtype has a low response rate to chemotherapy. Growing evidence indicates that N mRNA and protein expression levels were analysed by quantitative real-time polymerase chain reaction and western blotting, respectively. Cell proliferation was detected by CCK-8 and colony formation assays. Cell cycle progression was assessed by flow cytometry. Cell migration and invasion were analysed by wound healing assays and transwell assays, respectively, and apoptosis was analysed by TUNEL assays. Finally, m Chemotherapy-induced downregulation of the m METTL3 depletion promotes the proliferation and migration and decreases the drug sensitivity of HRHER2- BC via regulation of the CDKN1AEMT and m

A large single-center prospective study to investigate the factors influencing the choice of breast-conserving surgery versus mastectomy in Chinese women with early breast cancer.

Compared to mastectomy, breast-conserving surgery (BCS) provides the same survival rate and a higher quality of life for patients with early breast cancer (EBC). However, Chinese women with EBC are known to have a low BCS rate. A large prospective cohort study was conducted to investigate the factors influencing the choice of BCS in this population. In 2017, all women with unilateral EBC and eligible for BCS at our institution were enrolled. Before surgery, the patients trust in the surgeon and her perceived strength of the surgeons recommendation of BCS were measured through an in-person interview and validated ad hoc questionnaire. Multivariate logistic regressions on BCS procedure vs. mastectomy were used to estimate the odds ratio (OR). One thousand one hundred thirty-six patients enrolled at analysis had an average age of 51.8 and tumor size of 2.4 cm. 19.9% of patients had BCS. The strong level of trust in the surgeon was significantly associated with BCS with an OR of 2.944 (p<0.001) when compared to the average or under trust. The strong and moderate strengths in surgeon recommendation for BCS were also found to be significantly associated with the BCS procedure with ORs of 12.376 (p <0.001) and 1.757 (p 0.040), respectively, compared to the neutral or dissuaded strength. Stronger trust in surgeons and BCS recommendation by surgeons are associated with a higher rate of BCS in Chinese women with EBC. Interventional trials are needed to confirm this finding.

Efficacy of subsequent treatments in patients with hormone-positive advanced breast cancer who had disease progression under CDK 46 inhibitor therapy.

There is no standard treatment recommended at category 1 level in international guidelines for subsequent therapy after cyclin-dependent kinase 46 inhibitor (CDK46) based therapy. We aimed to evaluate which subsequent treatment oncologists prefer in patients with disease progression under CDKi. In addition, we aimed to show the effectiveness of systemic treatments after CDKi and whether there is a survival difference between hormonal treatments (monotherapy vs. mTOR-based). A total of 609 patients from 53 centers were included in the study. Progression-free-survivals (PFS) of subsequent treatments (chemotherapy (CT, n434) or endocrine therapy (ET, n175)) after CDKi were calculated. Patients were evaluated in three groups as those who received CDKi in first-line (group A, n202), second-line (group B, n 153) and ≥ 3rd-line (group C, n 254). PFS was compared according to the use of ET and CT. In addition, ET was compared as monotherapy versus everolimus-based combination therapy. The median duration of CDKi in the ET arms of Group A, B, and C was 17.0, 11.0, and 8.5 months in respectively it was 9.0, 7.0, and 5.0 months in the CT arm. Median PFS after CDKi was 9.5 (5.0-14.0) months in the ET arm of group A, and 5.3 (3.9-6.8) months in the CT arm (p 0.073). It was 6.7 (5.8-7.7) months in the ET arm of group B, and 5.7 (4.6-6.7) months in the CT arm (p 0.311). It was 5.3 (2.5-8.0) months in the ET arm of group C and 4.0 (3.5-4.6) months in the CT arm (p 0.434). Patients who received ET after CDKi were compared as those who received everolimus-based combination therapy versus those who received monotherapy ET the median PFS in group A, B, and C was 11.0 vs. 5.9 (p 0.047), 6.7 vs. 5.0 (p 0.164), 6.7 vs. 3.9 (p 0.763) months. Physicians preferred CT rather than ET in patients with early progression under CDKi. It has been shown that subsequent ET after CDKi can be as effective as CT. It was also observed that better PFS could be achieved with the subsequent everolimus-based treatments after first-line CDKi compared to monotherapy ET.

GDNF-RET signaling and EGR1 form a positive feedback loop that promotes tamoxifen resistance via cyclin D1.

Rearranged during transfection (RET) tyrosine kinase signaling has been previously implicated in endocrine resistant breast cancer, however the mechanism by which this signaling cascade promotes resistance is currently not well described. We recently reported that glial cell-derived neurotrophic factor (GDNF)-RET signaling appears to promote a positive feedback loop with the transcription factor early growth response 1 (EGR1). Here we investigate the mechanism behind this feedback loop and test the hypothesis that GDNF-RET signaling forms a regulatory loop with EGR1 to upregulate cyclin D1 (CCND1) transcription, leading to cell cycle progression and tamoxifen resistance. To gain a better understanding of the GDNF-RET-EGR1 resistance mechanism, we studied the GDNF-EGR1 positive feedback loop and the role of GDNF and EGR1 in endocrine resistance by modulating their transcription levels using CRISPR-dCAS9 in tamoxifen sensitive (TamS) and tamoxifen resistant (TamR) MCF-7 cells. Additionally, we performed kinetic studies using recombinant GDNF (rGDNF) treatment of TamS cells. Finally, we performed cell proliferation assays using rGDNF, tamoxifen (TAM), and Palbociclib treatments in TamS cells. Statistical significance for qPCR and chromatin immunoprecipitation (ChIP)-qPCR experiments were determined using a students paired t-test and statistical significance for the cell viability assay was a one-way ANOVA. GDNF-RET signaling formed a positive feedback loop with EGR1 and also downregulated estrogen receptor 1 (ESR1) transcription. Upregulation of GDNF and EGR1 promoted tamoxifen resistance in TamS cells and downregulation of GDNF promoted tamoxifen sensitivity in TamR cells. Additionally, we show that rGDNF treatment activated GDNF-RET signaling in TamS cells, leading to recruitment of phospho-ELK-1 to the EGR1 promoter, upregulation of EGR1 mRNA and protein, binding of EGR1 to the GDNF and CCND1 promoters, increased GDNF protein expression, and subsequent upregulation of CCND1 mRNA levels. We also show that inhibition of cyclin D1 with Palbociclib, in the presence of rGDNF, decreases cell proliferation and resensitizes cells to TAM. Outcomes from these studies support the hypotheses that GDNF-RET signaling forms a positive feedback loop with the transcription factor EGR1, and that GDNF-RET-EGR1 signaling promotes endocrine resistance via signaling to cyclin D1. Inhibition of components of this signaling pathway could lead to therapeutic insights into the treatment of endocrine resistant breast cancer.

Multi-responsive chitosan-based hydrogels for controlled release of vincristine.

As medical research progresses, the derivation and development of biological materials such as hydrogels have steadily gained more interest. The biocompatibility and non-toxicity of chitosan make chitosan hydrogels potential carriers for drug delivery. This work aims to develop two multi-reactive, safe, and highly swellable bio-hydrogels consisting of chitosan-graft-glycerol (CS-g-gly) and carboxymethyl chitosan-graft-glycerol (CMCS-g-gly), for sustained and controlled drug release, improved bioavailability along with entrapment in nanocarriers, which reduces side effects of vincristine sulphate. CS-g-gly and CMCS-g-gly are successfully prepared and fully characterized using analytical techniques. Under various conditions, the prepared hydrogels exhibit a high swelling ratio. Vincristine-loaded CS-g-gly (VCRCS-g-gly), and CMCS-g-gly (VCRCMCS-g-gly) show high encapsulation efficiency between 72.28-89.97%, and 56.97-71.91%, respectively. VCRCS-g-gly show a sustained release behavior, and the maximum release of VCR from hydrogels reached 82% after 120 h of incubation. MCF-7 (breast cancer cell line) and MCF-10 (normal breast cell line) are evaluated for cell viability and apoptosis induction. The in-vitro anti-tumor efficacy is investigated using flow cytometry. The tetrazolium-based MTT assay of hydrogels shows no evidence of significant cytotoxicity in MCF-7 and MCF-10 cells. According to these findings, these hydrogels can effectively deliver drugs to MCF-7 and other breast cancer cells.

Integrative competing endogenous RNA network analyses identify novel lncRNA and genes implicated in metastatic breast cancer.

Competing endogenous RNAs (ceRNAs) have gained attention in cancer research owing to their involvement in microRNA-mediated gene regulation. Previous studies have identified ceRNA networks of individual cancers. Nevertheless, none of these studies has investigated different cancer stages. We identify stage-specific ceRNAs in breast cancer using the cancer genome atlas data. Moreover, we investigate the molecular functions and prognostic ability of ceRNAs involved in stage I-IV networks. We identified differentially expressed candidate ceRNAs using edgeR and limma R packages. A three-step analysis was used to identify statistically significant ceRNAs of each stage. Survival analysis and functional enrichment analysis were conducted to identify molecular functions and prognostic ability. We found five genes and one long non-coding RNA unique to the stage IV ceRNA network. These genes have been described in previous breast cancer studies. Genes acted as ceRNAs are enriched in cancer-associated pathways. Two, three, and three microRNAs from stages I, II, and III were prognostic from the Kaplan-Meier survival analysis. Our results reveal a set of unique ceRNAs in metastatic breast cancer. Further experimental work is required to evaluate their role in metastasis. Moreover, identifying stage-specific ceRNAs will improve the understanding of personalised therapeutics in breast cancer.

Tumour-educated platelets for breast cancer detection biological and technical insights.

Studies have shown that blood platelets contain tumour-specific mRNA profiles tumour-educated platelets (TEPs). Here, we aim to train a TEP-based breast cancer detection classifier. Platelet mRNA was sequenced from 266 women with stage I-IV breast cancer and 212 female controls from 6 hospitals. A particle swarm optimised support vector machine (PSO-SVM) and an elastic net-based classifier (EN) were trained on 71% of the study population. Classifier performance was evaluated in the remainder (29%) of the population, followed by validation in an independent set (37 cases and 36 controls). Potential confounding was assessed in post hoc analyses. Both classifiers reached an area under the curve (AUC) of 0.85 upon internal validation. Reproducibility in the independent validation set was poor with an AUC of 0.55 and 0.54 for the PSO-SVM and EN classifier, respectively. Post hoc analyses indicated that 19% of the variance in gene expression was associated with hospital. Genes related to platelet activity were differentially expressed between hospitals. We could not validate two TEP-based breast cancer classifiers in an independent validation cohort. The TEP protocol is sensitive to within-protocol variation and revision might be necessary before TEPs can be reconsidered for breast cancer detection.

Prevalence and trends of perioperative major adverse cardiovascular and cerebrovascular events during cancer surgeries.

Major adverse cardiovascular and cerebrovascular events (MACCE) is an important cause of morbidity and mortality during perioperative period. In this study, we looked for national trends in perioperative MACCE and its components as well as cancer types associated with high rates of perioperative MACCE during major cancer surgeries. This study was a retrospective analysis of the National Inpatient Sample, 2005-2014. Hospitalizations for surgeries of prostate, bladder, esophagus, pancreas, lung, liver, colorectal, and breast among patients 40 years and greater were included in the analysis. MACCE was defined as a composite measure that included in-hospital all-cause mortality, acute myocardial infarction (AMI), and ischemic stroke. A total of 2,854,810 hospitalizations for major surgeries were included in this study. Of these, 67,316 (2.4%) had perioperative MACCE. Trends of perioperative MACCE showed that it decreased significantly for AMI, death and any MACCE, while stroke did not significantly change during the study period. Logistic regression analysis for perioperative MACCE by cancer types showed that surgeries for esophagus, pancreas, lung, liver, and colorectal cancers had significantly greater odds for perioperative MACCE. The surgeries identified to have greater risks for MACCE in this study could be risk stratified for better informed decision-making and management.

Clinical utility of axillary nodal markers in breast cancer.

De-escalation of axillary surgery for lymph node (LN) positive breast cancer is facilitated by marking involved nodes which, when removed with sentinel nodes constitute risk-adapted targeted axillary dissection (TAD). Whether after chemotherapy or for primary surgery, selected patients with biopsy-proven involvement of nodes may be eligible for axillary conservation. Likewise, impalpable recurrence or stage 4 patients with localised axillary disease may benefit. In these contexts, several devices are used to mark biopsied nodes to facilitate their accurate surgical removal. We report our experience using the paramagnetic MAGSEED (Endomag®, Cambridge, UK). Local approval (BR2021149) was obtained to interrogate a prospective database of all axillary markers. The primary endpoint was successful removal of the marked LN. Of 241 markers (in 221 patients) inserted between October 2018 and July 2022, all were retrieved. Of 74 patients who had Magseeds® inserted after completion of NACT (involved nodes initially marked using an UltraCor™Twirl™ marker), the Magseeds® were found outside the node in neighbouring axillary tissue in 18 (24.3%) patients. When Magseeds® were placed at commencement of NACT in 54 patients, in only 1 (1.8%) was the marker found outside the node - a statistically significantly lower rate (Chi This series supports our axillary nodal marking technique as safe and reliable. For TAD following NACT, placement at the start of treatment led to a significantly higher localisation rate.

Clinical Outcomes of Conservative Treatment for Low-Risk Ductal Carcinoma in Situ A Systematic Review and Pooled Analysis.

The current gold standard of treatment for ductal carcinoma in situ (DCIS) is surgical resection with or without adjuvant radiotherapy. However, the increased detection and radical treatment of DCIS did not result in a declined incidence of invasive breast cancers, leading to the debate if DCIS has been overtreated. While ongoing randomised controlled trials on active surveillance of DCIS are still in progress, this systematic review aims to evaluate the best evidence on conservative treatment for DCIS from the literature. This systematic review was conducted in line with the PRISMA statement. We included all relevant studies published up to June 2022 for analysis. The primary outcomes were overall survival and breast cancer-specific survival (BCSS) of conservative treatment for DCIS. Three studies, with a total of 34 007 women with low-risk DCIS, were included in the analysis. Active and conservative treatments both resulted in excellent 10-year BCSS, with no statistically insignificant difference (98.6% versus 96.0%, 31 478 women). One study comparing 5-year BCSS of active and conservative treatments only in subjects aged over 80 years also reported AQ1an insignificant difference (98.2% versus 96.0%, 2529 women). One study measuring 5- and 10-year overall survival between the treatment groups also reported AQ1an insignificant difference (5-year 96.2% versus 92.4% 10-year 85.6% versus 86.7%, 31 106 women). BCSS between active and conservative treatment for women with low-risk DCIS is both excellent and comparable, suggesting that conservative treatment is a possible alternative without compromising survival.

The Association Between Survival and Receipt of Post-mastectomy Radiotherapy According to Age at Diagnosis Among Women With Early Invasive Breast Cancer A Population-Based Cohort Study.

Clinical trials of post-mastectomy radiotherapy (PMRT) for early invasive breast cancer (EIBC) have included few older women. This study examined whether the association between overall survival or breast cancer-specific survival (BCSS) and receipt of PMRT for EIBC altered with age. The study used patient-level linked cancer registration, routine hospital and radiotherapy data for England and Wales. It included 31 243 women aged ≥50 years diagnosed between 2014 and 2018 with low- (T1-2N0), intermediate- (T3N0T1-2N1) or high-risk (T1-2N2T3N1-2) EIBC who received a mastectomy within 12 months from diagnosis. Patterns of survival were analysed using a landmark approach. Associations between overall survivalBCSS and PMRT in each risk group were analysed with flexible parametric survival models, which included patient and tumour factors whether the association between PMRT and overall survivalBCSS varied by age was assessed using interaction terms. Among 4711 women with high-risk EIBC, 86% had PMRT. Five-year overall survival was 70.5% and BCSS was 79.3%. Receipt of PMRT was associated with improved overall survival adjusted hazard ratio (aHR) 0.75, 95% confidence interval 0.64-0.87 and BCSS (aHR 0.78, 95% confidence interval 0.65-0.95) compared with women who did not have PMRT associations did not vary by age (overall survival, P-value for interaction term 0.141 BCSS, P 0.077). Among 10 814 women with intermediate-risk EIBC, 59% had PMRT 5-year overall survival was 78.4% and BCSS was 88.0%. No association was found between overall survival (aHR 1.01, 95% confidence interval 0.92-1.11) or BCSS (aHR 1.16, 95% confidence interval 1.01-1.32) and PMRT. There was statistical evidence of a small change in the association with age for overall survival (P 0.007), although differences in relative survival were minimal, but not for BCSS (P 0.362). The association between PMRT and overall survivalBCSS does not appear to be modified by age among women with high- or intermediate-risk EIBC and, thus, treatment recommendations should not be modified on the basis of age alone.

Circ0108942 Regulates the Progression of Breast Cancer by Regulating the MiR-1178-3pTMED3 Axis.

Breast cancer (BC) has posed a fatal threat to womens lives and the search for new methods of diagnosis and treatment is an important way to break the bottleneck of high mortality in BC. Circular RNAs (circRNAs) have been confirmed to be aberrantly expressed in several types of cancers, and this study is intended to elucidate the role and mechanism of circ0108942 in BC. The levels of circ0108942, microRNA-1178-3p (miR-1178-3p), and transmembrane p24 trafficking protein 3 (TMED3) were measured using real-time quantitative polymerase chain reaction (RT-qPCR) or western blot. Meanwhile, the cell proliferation, migration, invasion, angiopoiesis, and apoptosis were analyzed using 5-ethynyl-2-deoxyuridine (EdU), transwell, tubule formation, and flow cytometry assays. Protein levels were determined by western blot. In addition, we used dual-luciferase reporter and RNA pull-down assays to identify the interplay between miR-1178-3p and circ0108942 or TMED3. Lastly, the impact of circ0108942 on the growth of BC tumors in vivo was analyzed by xenograft models. Circ0108942 and TMED3 were notably upregulated in BC, and the miR-1178-3p was downregulated. Functionally, silencing circ0108942 suppressed cell proliferation, migration, invasion and promoted apoptosis in BC cells. In mechanism, circ0108942 regulated TMED3 expression by sponging miR-1178-3p. Meanwhile, circ0108942 knockdown also greatly constrained tumor growth in vivo. Circ0108942 boosted BC progression by regulating miR-1178-3p and thus upregulating TMED3.

A universal and sensitive gene mutation detection method based on CRISPR-Cas12a.

Single nucleotide mutations are highly related to the occurrence and development of cancer. The development of simple single nucleotide mutation detection methods with high sensitivity and specificity has great clinical significance for the prevention, diagnosis, treatment and prognosis evaluation of cancer. In recent years, CRISPRCas12a has been developed as a highly sensitive, simple and fast tool for nucleic acid detection. However, the specificity and universality of current detection methods based on it are still insufficient, so their clinical applications are limited. Herein, we developed a simple and rapid single nucleotide mutation detection method based on CRISPRCas12a system. This method not only solves the problem of PAM sequence restriction of CRISPRCas12a, but also significantly improves the specificity of CRISPRCas12a for single nucleotide mutation and greatly improves the sensitivity. We detected three clinically significant mutations, PTEN R130Q, BRAF V600E, and TP53 R248W, with a detection limit of 0.1%. Finally, we further verified the clinical practicability of this method. We selected TP53 R248W mutation site for testing. The accuracy of testing results for 10 clinical samples was as high as 100%. In conclusion, the detection method of specific PCR combined with CRISPRCas12a is simple, rapid, universal and highly sensitive. We believe that this method has promising application prospects in clinical diagnosis of cancer.

M6A-mediated upregulation of FZD10 regulates liver cancer stem cells properties and lenvatinib resistance through WNTβ-catenin and Hippo signaling pathways.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, but there is deficiency of early diagnosis biomarkers and therapeutic targets. Drug-resistance account for most HCC-related deaths, yet the mechanisms underlying drug-resistance remain poorly understood. The expression of Frizzled-10 (FZD10) in liver cancer stem cells (CSCs) was identified by RNA sequencing and validated by real-time PCR and immunohistochemistry. In vitro and in vivo experiments were used to assess the effect of FZD10 on liver CSCs expansion and lenvatinib resistance. RNA sequencing, RNA binding protein immunoprecipitation and luciferase report assays were applied to explore the mechanism underlying FZD10-mediated liver CSCs expansion and lenvatinib resistance. The activation of FZD10 in liver CSCs was mediated by METTL3-dependent m6A methylation of FZD10 mRNA. Functional studies revealed that FZD10 promotes liver CSCs self-renewal, tumorigenicity and metastasis via activating β-catenin and YAP1. The FZD10-β-cateninYAP1 axis is activated in liver CSCs and predicts poor prognosis. Moreover, FZD10-β-catenin-c-Jun axis transcriptionally activates METTL3 expression, forming a positive feedback loop. Importantly, FZD10β-cateninc-JunMEKERK axis determines the responses of hepatoma cells to lenvatinib treatment. Analysis of patient cohort, patient-derived tumor organoids (PDOs) and patient-derived xenografts (PDXs) further suggest that FZD10 might predict lenvatinib clinical benefit in HCC patients. Furthermore, treatment of lenvatinib-resistant HCC with adeno-associated virus (AAV) targeting FZD10 or an β-catenin inhibitor restored lenvatinib response. Elevated FZD10 expression promotes liver CSCs expansion and lenvatinib resistance, indicating that FZD10 expression is a novel prognostic biomarker and therapeutic target for human HCC.

Contemporary Treatment Outcome of Metastases to the Pituitary Gland.

Metastasis to the pituitary gland is uncommon. With life expectancy after cancer diagnosis improving, we sought to understand the impact of treating pituitary metastasis in the modern era of advanced cancer treatment. Patients diagnosed and treated as pituitary metastasis from 2000 to 2021 were retrospectively analyzed. Forty-eight patients were identified. Twenty-three (48%) were women. The common primary cancer origins were the lung (23 patients 48%) and the breast (9 patients). Twenty-nine patients (60%) had hypopituitarism and 12 (25%) had visual field deficits. Twenty-seven patients (56%) had solitary pituitary metastasis (no evidence of other intracranial metastatic lesions). Fourteen patients (29%) had surgery, and 20 (42%) had standalone radiation (biopsy was preceded in three). After surgery andor radiation, visual field deficits improved in six patients, hypopituitarism improved in four patients, and hypopituitarism occurred in three patients. The median overall survival (OS) was 12 months (interquartile range, 3.0-28). Multivariate analysis showed non-solitary pituitary metastasis (hazard ratio HR, 2.8 95% confidence interval CI, 1.5-5.5 P0.0021) and no surgery or radiation (HR, 2.08 95% CI, 1.04-4.15 P0.038) to be associated with OS. For solitary pituitary metastasis, patients who had surgery and radiation had better 1-year OS than patients who had neither (P0.03), whereas, for non-solitary pituitary metastasis, patients who had standalone radiation had better 1-year OS than patients who had neither (P0.03). In the selected population, metastasis-directed therapy was associated with improved OS. Either correct patient selection for additional therapy or surgeryradiation directly benefited the patient in OS.

Development of Thiol-Maleimide hydrogels incorporating graphene-based nanomaterials for cancer chemo-photothermal therapy.

Nano-sized materials have been widely explored in the biomedicine field, especially due to their ability to encapsulate drugs intended to be delivered to cancer cells. However, systemically administered nanomaterials face several barriers that can hinder their tumor-homing capacity. In this way, researchers are now focusing their efforts in developing technologies that can deliver the nanoparticles directly into the tumor tissue. Particularly, hydrogels assembled using Thiol-Maleimide Michael type additions are emerging for this purpose due to their capacity to incorporate high nanoparticles doses in a compact 3D structure as well as good chemical selectivity, biocompatibility, and straightforward preparation. Nevertheless, such hydrogels have been mostly prepared using synthetic polymers, which is not ideal due to their poor biodegradability. In this work, a novel natural polymer-based Thiol-Maleimide hydrogel was produced for application in breast cancer chemo-photothermal therapy. To obtain natural polymers compatible with this crosslinking chemistry, Hyaluronic acid was endowed with Thiol groups and deacetylated Chitosan was grafted with Maleimide groups. Parallelly, Doxorubicin loaded Dopamine-reduced graphene oxide (DOXDOPA-rGO) was prepared for attaining Near Infrared (NIR) light responsive chemo-photothermal nanoagents. By simply mixing Hyaluronic Acid-Thiol, deacetylated Chitosan-Maleimide and DOXDOPA-rGO, Thiol-Maleimide crosslinked hydrogels incorporating this nanomaterial could be assembled (DOXDOPA-rGOTMgel). When breast cancer cells were incubated with DOPA-rGOTMgel and exposed to NIR light (photothermal therapy), their viability was reduced to about 59 %. On the other hand, DOXDOPA-rGOTMgel (chemotherapy) reduced cancer cells viability to 50 %. In stark contrast, the combined action of DOXDOPA-rGOTMgel and NIR light decreased breast cancer cells viability to just 21 %, highlighting its chemo-photothermal potential.

Imidazo1,2-aquinazolines as novel, potent EGFR-TK inhibitors Design, synthesis, bioactivity evaluation, and in silico studies.

Tyrosine protein kinases (TKs) have been proved to play substantial roles on many cellular processes and their overexpression tend to be found in various types of cancers. Therefore, over recent decades, numerous tyrosine protein kinase inhibitors particularly epidermal growth factor receptor (EGFR) inhibitors have been introduced to treat cancer. Present study describes a novel series of imidazo1,2-aquinazolines 18 as potential -inhibitors. These imidazoquinazolines (18a and 18o, in particular) had great anti-proliferative activities with IC

Comparison of tumor-derived total RNA and cell lysate on antitumor immune activity.

Tumor-derived total RNA (TdRNA) and cell lysate (TCL), with almost all the relevant tumor antigens, represent attractive alternative sources of antigens in antitumor immunotherapy. However, the comparison of their capacity to elicit immune responses against breast cancer is still lacking. In this study, the antitumor immune effects of TdRNA and TCL were systematically compared. We isolated TdRNA and TCL from 4T1 mouse breast cancer cells, and found that both sources of antigens could stimulate the maturation of dendritic cells (DCs) at the cellular and in vivo levels, and induce robust cellular immune responses, as evidenced by the increased percentages of both CD4

Graphene-based 3D-Printed nanocomposite bioelectronics for monitoring breast cancer cell adhesion.

This work examines the suitability of graphene-based 3D-printed nanocomposite bioelectronics as innovative systems to in situ monitor and evaluate both breast cancer cell adhesion and the chemosensitivity of anti-cancer drugs. With this aim, 3D-printed nanocomposite graphene electrodes (3D-nGEs) -made of a commercially available graphenepolylactic acid filament- have been covalently biofunctionalized with an extracellular matrix protein (i.e., fibronectin) by exploiting the carbon reactivity of 3D-nGEs. The specificity and selectivity of the developed electrochemical system to monitor breast cancer cell adhesion has been tested via electrochemical impedance spectroscopy (EIS). Importantly, the resulting 3D-printed bioelectronic system displayed excellent accuracy for the rapid screening of anti-cancer drugs, which exactly corresponded with the results achieved by the standard optical method, while having the advantage of employing a label-free approach. In light of the current state-of-the-art in the field, this proof-of-concept connects electronics to biological systems within 3D printing technology, providing the bases for the sustainable and cost-effective manufacturing of graphene-based 3D-printed nanocomposite bioelectronics to simulate in vivo microenvironments using in situ and real time electronic output signals.

Discovery of unglycosylated indolocarbazoles as ROCK2 isoform-selective inhibitors for the treatment of breast cancer metastasis.

Breast cancer metastasis is a major challenge in clinical therapy because of the absence of effective treatments. Rho-associated coiled-coil kinase (ROCK), which is essential for cell invasion and migration, has recently been suggested as a potential target for the treatment of cancer metastasis. Herein, we report the structure-activity relationships (SAR) of indolocarbazoles against ROCK2 and reveal the crucial role of the C-3 hydroxyl for ROCK2 inhibition. The most potent unglycosylated aglycone THK01 was demonstrated to bind to and stabilize ROCK2 with potent anti-metastatic effects in breast cancer in vitro and in vivo with no obvious toxicities. Further mechanistic studies revealed that the anti-metastatic effect of THK01 was closely related to the suppression of STAT3

Targeting HER3 for cancer treatment a new horizon for an old target.

Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptors family, having as its main ligands neuregulins 1 and 2. Although its poor tyrosine kinase activity entails a weak oncogenic power on its own, HER3 can heterodimerize with HER2 andor epidermal growth factor receptor (EGFR), leading to a drastic enhancement of transphosphorylation and activation of downstream signaling pathways, ultimately promoting oncogenesis, metastatic dissemination, and drug resistance. Given its ubiquitous expression across solid tumors, multiple efforts have been done to therapeutically target HER3 by blocking either the ligand binding domain or its dimerization with other receptors. Treatment with anti-HER3 monoclonal antibodies or bispecific antibodies, both as single agents and in combination with other compounds, unfortunately led to unsatisfactory results across several tumor types. The HER3-directed delivery of cytotoxic payloads through antibody-drug conjugates has recently demonstrated encouraging activity in several tumor types, however, suggesting a potential role for the therapeutic targeting of HER3 in cancer treatment.

Pre-operative Radiotherapy And Deep Inferior Epigastric Artery Perforator (DIEP) flAp study (PRADA) Aesthetic outcome and patient satisfaction at one year.

The optimal combination of radiotherapy and breast reconstruction has not yet been defined. Post-mastectomy radiotherapy (PMRT) has deleterious effects on breast reconstruction, leading to caution amongst surgeons. Pre-operative radiotherapy (PRT) is a growing area of interest, is demonstrated to be safe, and spares autologous flaps from radiotherapy. This study evaluates the aesthetic outcome of PRT and deep inferior epigastric artery perforator (DIEP) flap reconstruction within the Pre-operative Radiotherapy And Deep Inferior Epigastric artery Perforator (DIEP) flAp (PRADA) cohort. PRADA was an observational cohort study designed to evaluate the feasibility and safety of PRT for women undergoing neoadjuvant chemotherapy and DIEP reconstruction. Panel evaluation of 3D surface images (3D-SIs) and patient-reported outcome measures (BREAST-Q) for a subset of women in the study were compared with those of a DIEP-PMRT cohort who had undergone DIEP reconstruction and PMRT. Seventeen out of 33 women from the PRADA study participated in this planned substudy. Twenty-eight women formed the DIEP-PMRT cohort (median follow-up 23 months). The median (inter-quartile range IQR) satisfaction with breasts score at 12 months for the PRADA cohort was significantly better than the DIEP-PMRT cohort (77 72-87 versus 64 54-71, respectively), p0.01). Median IQR panel evaluation (5-point scale) was also significantly better for the PRADA cohort than for the DIEP-PMRT cohort (4.3 3.9-4.6 versus 3.6 2.8-4 p0.003). Aesthetic outcome for the PRADA cohort was reported to be good or excellent in 93% of cases using a bespoke panel assessment with robust methodology. Patient satisfaction at one year is encouraging and superior to DIEP-PMRT at 23 months. Switching surgery-radiotherapy sequencing leads to similar breast aesthetic outcomes and warrants further large-scale, multi-centre evaluation in a randomised trial.

The influence of axillary surgery and radiotherapeutic strategy on the risk of lymphedema and upper extremity dysfunction in early breast cancer patients.

To explore the risk factors for breast cancer-related lymphedema (BCRL) and upper extremity dysfunction (UED) in patients with early breast cancer after modern comprehensive treatment and to compare the toxicity of different treatment strategies. From 2017 to 2020, a total of 1369 female patients with pT1-3N0-1M0 breast cancer who underwent adjuvant radiotherapy in our centre were retrospectively reviewed. BCRL and UED were identified by the Norman and QuickDASH questionnaires. The incidence, severity and risk factors for BCRL and UED were evaluated. After a median follow-up of 25 months, a total of 249 patients developed BCRL axillary lymph node dissection (ALND), increased number of dissected nodes, right-sided and hypofractionated radiotherapy containing RNI were found to be significant risk factors (all p values < 0.05). The sentinel lymph node biopsy (SLNB) regional nodal irradiation (RNI) group had a significantly lower BCRL risk than the ALND RNI group (10.8% vs. 32.5%, HR 0.426, p 0.020), while there was no significant difference between ALND vs. ALND RNI or SLNB vs. SLNB RNI. A total of 193 patients developed UED, and ALND (p 0.02) was the only significant risk factor. The SLNB RNI group had a significantly decreased risk of UED compared with the ALND RNI group (7.5% vs. 23.9%, HR 0.260, p 0.001), and there was no significant difference between SLNB vs. SLNB RNI or ALND vs. ALND RNI. Aggressive ALND remains the primary risk factor for BCRL and UED while RNI does not. Thus, replacing ALND with tailored radiotherapy would be an effective preventive strategy in early breast cancer patients.

Attitude sustains longer than subjective norm and perceived behavioral control Results of breast cancer screening educational intervention.

Breast malignancy is the most frequent carcinoma among females across the world and third-most in Nepal. Early diagnosis of breast cancer through breast health awareness and self-examination, in addition to mammography screening, is a highly feasible and useful technique in poorly resourced settings. However, their intentions, whether to modify behaviors or actions, remain debatable and less explained in the literature. So, we aimed to assess how long an educational intervention affects womens intention to do a breast self-examination (BSE) and mammography screening. After assessing feasibility, one ward was assigned to the intervention (IG ward number 30) and control group (CG ward number 33), and then with inclusion criteria, a total of 360 females (180 each in IG and CG) aged 40-75 years enrolled in the study. After the baseline assessment, participants in the IG were delivered an hour-long breast cancer screening-related lecture-discussion- demonstration session that included BSE and mammography, aided with a silicone dummy. The session was carried out by the female trained nurses. Outcome data were obtained at the baseline, 4, 8, and 12 months following the intervention. Attitudes, perceived behavioral controls (PBCs) and behavioral intents (BIs) of both mammography and BSE at baseline were similar in both IG and CG except in case of subjective norms (SNs). Intents of BSE remained effective for 4 months, whereas for mammography, it was effective only at 4 and 12 months. Moreover, attitudes toward both tests remained intact for 4, 8, and 12 months (p < .05) consistently. With regards to PBCs, women having good control remained only for 4 months in both screening tests. Further, regarding SN, significant mean changes were observed at 4 and 12 months in BSE, and only at 4 months in mammography screening. The session was effective in sustaining BSE and mammography intentions for at least 4 months. To retain the effects longer (up to 12 months), additional educational strategies focusing on subjective norms and perceived behavioral controls of both tests are highly warranted.

Neoadjuvant chemotherapy modulates exhaustion of T cells in breast cancer patients.

Breast cancer is the leading cause of cancer deaths in women worldwide. It has been observed that the incidence of breast cancer increases linearly with age after 45, which suggest a link between cancer, aging, and senescence. A growing body of evidence indicates that the immunosuppressive tumor network in breast cancer patients can lead to T-cell exhaustion and senescence. Cytotoxic chemotherapy is a common treatment for many cancers, and it is hypothesized that its efficacy may be related to immune activation. However, the effects of neoadjuvant chemotherapy on T-cell dysfunction in breast cancer patients are not fully understood. This study aimed to evaluate the impact of neoadjuvant chemotherapy on the expression of exhaustion and senescence markers in T cells in women with breast cancer. Our results showed that T cells from breast cancer patients have a reduced ability to respond to stimulation in-vitro and an increased expression of senescence and exhaustion-associated markers, such as TIM-3, LAG3, and CD57. Furthermore, we found that neoadjuvant chemotherapy has an immunomodulatory effect and reduces the expression of exhaustion markers. Our observations of the immune phenotype of T cells during neoadjuvant chemotherapy treatment highlight its ability to stimulate the immune system against cancer. Therefore, monitoring the response of T cells during chemotherapy may enable early prediction of clinical response.

Expression of estrogen and progesterone receptors in vestibular schwannomas.

Stereotactic radiosurgery is one of the main treatments for vestibular schwannomas (VS). Their feature is frequent post-radiation pseudoprogression. This may be due to hormonal status of patients. To analyze expression of progesterone and estrogen receptors in women and men with VS. Immunohistochemical analysis of expression of progesterone (PR) and estrogen receptors (ER) after biopsy was performed in 240 patients with VS between 2018 and 2021. ERPR expression was assessed in men ( ER expression is not typical for VS (men - 1 (0.01%), women - 3 (2.5%)). At the same time, PR expression was found in 29 (24.2%) men and 21 (17.5%) women. We found no significant difference in expression of ER and PR between men and women. However, variability in PR expression was revealed, i.e. predominance of this indicator in young women ( The established incidence of PR expression may be one of the probable causes affecting development and duration of VS pseudoprogression after radiosurgery without clear relationship between sex and age. Further prospective research is needed to predict the risks of pseudoprogression. Стереотаксическая радиохирургия является одним из основных методов лечения вестибулярных шванном (ВШ). Особенностью ВШ является их частая склонность к развитию постлучевой псевдопрогрессии, что может быть обусловлено гормональным статусом пациентов. Анализ экспрессии рецепторов прогестерона (PR) и эстрогена (ER) в ВШ у женщин и мужчин различного возраста. Проведено иммуногистохимическое исследование уровня экспрессии рецепторов ER и PR в биопсийном материале 240 пациентов с ВШ, оперированных в ФГАУ «НМИЦ нейрохирургии им. акад. Н.Н. Бурденко» Минздрава России с 2018 по 2021 г. Экспрессию ER и PR оценили в ВШ у мужчин ( Установлено, что экспрессия ER не характерна для ВШ (мужчины — 1 (0,01%), женщины — 3 (2,5%)). В то же время экспрессия PR была обнаружена у 29 (24,2%) мужчин и 21 (17,5%) женщины. При анализе полученных результатов не обнаружено достоверного различия уровня экспрессии ER и PR между мужчинами и женщинами, однако выявлена вариабельность экспрессии PR преобладание этого показателя в молодом возрасте у женщин ( Установленная частота экспрессии PR может являться одной из вероятных причин, влияющих на развитие и длительность течения псевдопрогрессии ВШ после радиохирургии, но без четкой связи между полом и возрастом. Требуется дальнейшее проспективное исследование прогнозирования рисков развития псевдопрогрессии.

Effect of Fractional Carbon Dioxide vs Sham Laser on Sexual Function in Survivors of Breast Cancer Receiving Aromatase Inhibitors for Genitourinary Syndrome of Menopause The LIGHT Randomized Clinical Trial.

Survivors of breast cancer present more severe symptoms of genitourinary syndrome of menopause (GSM) than patients without history of breast cancer. Recently, new treatments, such as vaginal laser therapy, have appeared, but evidence of their efficacy remains scarce. To assess the safety and efficacy of carbon dioxide (CO2) vs sham vaginal laser therapy after 6 months of follow-up in survivors of breast cancer with GSM receiving aromatase inhibitors. This prospective double-blind sham-controlled randomized clinical trial with two parallel study groups was performed during October 2020 to March 2022 in a tertiary referral hospital. Survivors of breast cancer using aromatase inhibitors were assessed for eligibility, and eligible patients were randomized into the 2 treatment groups. Follow-up was conducted at 6 months. Data were analyzed in July 2022. All patients from both groups were instructed to use the first-line treatment (FLT) based on nonhormonal moisturizers and vaginal vibrator stimulation. Patients for each group were allocated to 5 monthly sessions of fractional CO2 laser therapy (CLT) or sham laser therapy (SLT). The primary outcome was sexual function, evaluated through Female Sexual Function Index (FSFI) score. Other subjective measures of efficacy included a visual analog scale of dyspareunia, vaginal pH, a Vaginal Health Index, quality of life (assessed via Short-Form 12), and body image (assessed with the Spanish Body Image Scale). Objective measures of efficacy included vaginal maturation index, vaginal epithelial elasticity (measured in Pascals) and vaginal epithelial thickness (measured in millimeters). Measures were assessed before and after the intervention. Tolerance (measured on a Likert scale), adverse effects, and estradiol levels were recorded. Among 211 survivors of breast cancer assessed, 84 women were deemed eligible and 72 women (mean SD age, 52.6 8.3 years) were randomized to CLT (35 participants) or SLT (37 participants) and analyzed. There were no statistically significant differences between groups at baseline. At 6 months, both groups showed improvement in FSFI (mean SD score at baseline vs 6 months CLT, 14.8 8.8 points vs 20.0 9.5 points SLT, 15.6 7.0 points vs 23.5 6.5 points), but there was no significant difference between CLT and SLT groups in the improvement of sexual function evaluated through the FSFI test overall (mean SD difference, 5.2 1.5 points vs 7.9 1.2 points P .15) or after excluding women who were not sexually active (mean SD difference, 2.9 1.4 points vs 5.5 1.1 points P .15). There were also no differences between improvement of the 2 groups at 6 months of follow-up in the other assessed subjective outcomes, including dyspareunia (mean SD difference, -4.3 3.4 vs -4.5 2.3 P .73), Vaginal Health Index (mean SD difference, 3.3 4.1 vs 5.0 4.5 P .17), body image (mean SD difference, -3.7 4.5 vs -2.7 4.8 P .35), and quality of life (mean SD difference, -0.3 3.6 vs -0.7 3.2 P .39). Similarly, there were no differences in improvements in objective outcomes, including vaginal pH (mean SD difference, -0.6 0.9 vs -0.8 1.2 P .29), vaginal maturation index (mean SD difference, 10.2 17.4 vs 14.4 17.1 P .15), vaginal epithelial thickness (mean SD difference, 0.021 0.014 mm vs 0.013 0.012 mm P .30), vaginal epithelial elasticity (mean SD difference, -1373 3197 Pascals vs -2103 3771 Pascals P .64). There were significant improvements in the overall analysis regardless of group in many outcomes. The 2 interventions were well tolerated, but tolerance was significantly lower in the CLT group than the SLT group (mean SD Likert scale score, 3.3 1.3 vs 4.1 1.0 P .007). No differences were observed in complications or serum estradiol levels. In this randomized clinical trial, vaginal laser treatment was found to be safe after 6 months of follow-up, but no statistically significant differences in efficacy were observed between CLT and SLT. ClinicalTrials.gov identifier NCT04619485.

Clinical utility of abbreviated breast MRI based on diffusion tensor imaging in patients underwent breast conservative therapy.

To evaluate the added value of the diffusion tensor imaging (DTI) parameters to abbreviated breast MRI protocol in differentiating recurrent breast cancer from post-operative changes in cases of breast conservative surgery (BCS). This prospective study was approved by our institutional review board. Written informed consent was obtained in all patients. 47 female patients (mean age, 49 years range, 32-66 years) that previously underwent breast conservative surgery with a palpable mass were included in this study (62 breast lesions). Two abbreviated MRI protocols were compared using 1.5 Tesla MRI, AB-MRI 1 (axial T1, T2, pre-contrast T1, 1st post-contrast and subtracted images) and AB-MRI 2 (same sequences plus adding DTI). In both protocols, the wash-in rate was calculated. Histopathology was used as the standard of reference. Appropriate statistical tests were used to assess sensitivity, specificity, and diagnostic accuracy for each protocol. The mean total acquisition time was of 6 min for AB-MRI 1 and 10 min for AB-MRI 2 protocols while the mean interpretation time was of 57.5 and 75 s, respectively. Among analyzed DTI parameters, MD (mean diffusivity) showed the highest sensitivity (96.43%) and specificity (91.18%) (P value < 0.001). FA (fractional anisotropy), AD (axial diffusivity) and RD (radial diffusivity) showed sensitivity (78.57%, 82.14% and 85.71%), specificity (88.24, 85.29% and 79.41%), respectively, P value (< 0.001). DTI may be included in abbreviated MRI protocols without a significant increase in acquisition time and with the advantage of increasing specificity and clinical utility in the characterization of post-conservative breast lesions.

Evaluation of optimal monoenergetic images acquired by dual-energy CT in the diagnosis of T staging of thoracic esophageal cancer.

The purpose of our study was to objectively and subjectively assess optimal monoenergetic image (MEI ()) characteristics from dual-energy CT (DECT) and the diagnostic performance for the T staging in patients with thoracic esophageal cancer (EC). In this retrospective study, patients with histopathologically confirmed EC who underwent DECT from September 2019 to December 2020 were enrolled. One standard polyenergetic image (PEI) and five MEI () were reconstructed. Two readers independently assessed the lesion conspicuity subjectively and calculated the contrast-to-noise ratio (CNR) and the signal-to-noise ratio (SNR) of EC. Two readers independently assessed the T stage on the optimal MEI () and PEI subjectively. Multiple quantitative parameters were measured to assess the diagnostic performance to identify T1-2 from T3-4 in EC patients. The study included 68 patients. Subjectively, primary tumor delineation received the highest ratings in MEI () MEI () reconstructions at low keV in the venous phase improved the assessment of lesion conspicuity and also have great potential for preoperative assessment of T staging in patients with EC.

Effect of acupuncture in myelosuppression and quality of life in women with breast cancer undergoing chemotherapy a randomized clinical study.

This study aimed to evaluate the effect of acupuncture on myelosuppression and quality of life in women with breast cancer during treatment with anthracyclines (ANT). Women with indication for ANT chemotherapy were randomized into two groups acupuncture group (AG) and control group (CG). A quality of life questionnaire (FACT-G) and peripheral blood levels of the participants were evaluated before and at the end of treatment. The AG was submitted to an acupuncture intervention, starting before the first chemotherapy infusion, and continuing throughout the treatment. A total of 26 women were randomized into 2 groups AG (10) and CG (16). Of these, 26.9% had a dense dose indication according to the services protocol for the administration of granulocyte-stimulating factor (G-CSF) from the first cycle, not participating in the analysis. The need for secondary prophylaxis with G-CSF occurred in 72.7% in the control group versus 12% in the acupuncture group. Regarding quality of life (QoL), it was observed that the groups did not initially differ from each other. At the end of the treatment, there was a significant difference in the AG for the physical (GP) (p-value0.011), socialfamily (GS) (p-value0.018), and functional (GF) (p-value0.010) domains, regarding the initial and final FACT-G showed a difference between the groups, where the GA average at the end rose from 80.68 to 90.12 (p-value 0.004) and in the CG the average dropped from 81.95 to 70.59 (p-value0.003). Acupuncture was efficient in the secondary prophylaxis of myelosuppression during chemotherapy and the quality of life of women during treatment has increased. Brazilian Registry of Clinical Trials - Rebec on 06282018, registration number U1111-1216-3921, Rebec Trial RBR-7BWJ6R.

Chromosomal radiosensitivity of human breast carcinoma cells and blood lymphocytes following photon and proton exposures.

Breast carcinomas (BC) are among the most frequent cancers in women. Studies on radiosensitivity and ionizing radiation response of BC cells are scarce and mainly focused on intrinsic molecular mechanisms but do not include clinically relevant features as chromosomal rearrangements important for radiotherapy. The main purpose of this study was to compare the ionizing radiation response and efficiency of repair mechanisms of human breast carcinoma cells (Cal 51) and peripheral blood lymphocytes (PBL) for different doses and radiation qualities (

Characterization of Oxygen Nanobubbles and In Vitro Evaluation of Retinal Cells in Hypoxia.

Vein or artery occlusion causes a hypoxic environment by preventing oxygen delivery and diffusion to tissues. Diseases such as retinal vein occlusion, central retinal artery occlusion, or diabetic retinopathy create a stroke-type condition that leads to functional blindness in the effected eye. We aim to develop an oxygen delivery system consisting of oxygen nanobubbles (ONBs) that can mitigate retinal ischemia during a severe hypoxic event such as central retinal artery occlusion. ONBs were synthesized to encapsulate oxygen saturated molecular medical grade water. Stability, oxygen release, biocompatibility, reactive oxygen species, superoxide, MTT, and terminal uridine nick-end labeling assays were performed. Cell viability was evaluated, and safety experiments were conducted in rabbits. The ONBs were approximately 220 nm in diameter, with a zeta potential of -58.8 mV. Oxygen release studies indicated that 74.06 µg of O2 is released from the ONBs after 12 hours at 37°C. Cell studies indicated that ONBs are safe and cells are viable. There was no significant increase in reactive oxygen species, superoxide, or double-stranded DNA damage after ONB treatment. ONBs preserve mitochondrial function and viability. Histological sections from rabbit eyes indicated that ONBs were not toxic. The ONBs proposed have excellent oxygen holding and release properties to mitigate ischemic conditions in the retina. They are sterile, stable, and nontoxic. ONB technology was evaluated for its physical properties, oxygen release, sterility, stability, and safety. Our results indicate that ONBs could be a viable treatment approach to mitigate hypoxia during ischemic conditions in the eye upon timely administration.

Potential Antihuman Epidermal Growth Factor Receptor 2 Target Therapy Beneficiaries The Role of MRI-Based Radiomics in Distinguishing Human Epidermal Growth Factor Receptor 2-Low Status of Breast Cancer.

Multiparametric MRI radiomics could distinguish human epidermal growth factor receptor 2 (HER2)-positive from HER2-negative breast cancers. However, its value for further distinguishing HER2-low from HER2-negative breast cancers has not been investigated. To investigate whether multiparametric MRI-based radiomics can distinguish HER2-positive from HER2-negative breast cancers (task 1) and HER2-low from HER2-negative breast cancers (task 2). Retrospective. Task 1 310 operable breast cancer patients from center 1 (97 HER2-positive and 213 HER2-negative) task 2 213 HER2-negative patients (108 HER2-low and 105 HER2-zero) 59 patients from center 2 (16 HER2-positive, 27 HER2-low and 16 HER2-zero) for external validation. A 3.0 TT1-weighted contrast-enhanced imaging (T1CE), diffusion-weighted imaging (DWI)-derived apparent diffusion coefficient (ADC). Patients in center 1 were assigned to a training and internal validation cohort at a 21 ratio. Intratumoral and peritumoral features were extracted from T1CE and ADC. After dimensionality reduction, the radiomics signatures (RS) of two tasks were developed using features from T1CE (RS-T1CE), ADC (RS-ADC) alone and T1CE ADC combination (RS-Com). Mann-Whitney U tests, the least absolute shrinkage and selection operator, receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). For task 1, RS-ADC yielded higher area under the ROC curve (AUC) in the training, internal, and external validation of 0.7670.7250.746 than RS-T1CE (AUC 0.7330.6740.641). For task 2, RS-T1CE yielded higher AUC of 0.7650.7550.678 than RS-ADC (AUC 0.7060.6080.630). For both of task 1 and task 2, RS-Com achieved the best performance with AUC of 0.7930.7780.760 and 0.8200.7760.711, respectively, and obtained higher clinical benefit in DCA compared with RS-T1CE and RS-ADC. The calibration curves of all RS demonstrated a good fitness. Multiparametric MRI radiomics could noninvasively and robustly distinguish HER2-positive from HER2-negative breast cancers and further distinguish HER2-low from HER2-negative breast cancers. 3. Stage 2.

Toxicity Risk Score and Clinical Decline After Adjuvant Chemotherapy in Older Breast Cancer Survivors.

Chemotoxicity risk scores were developed to predict grade 3-5 chemotherapy toxicity in older women with early breast cancer. However, whether these toxicity risk scores are associated with clinically meaningful decline in patient health remains unknown. In a prospective study of women ≥65 with stage I-III breast cancer treated with chemotherapy, we assessed chemotoxicity risk using the Cancer and Aging Research Group-Breast Cancer (CARG-BC) score (categorized as low, intermediate, high). We measured patient health status before (T1) and after (T2) chemotherapy using a clinical frailty index (Deficit Accumulation Index DAI categorized as robust, prefrail, frail). The population of interest was robust women at T1. The primary outcome was decline in health status after chemotherapy, defined as a decline in DAI from robust at T1 to pre-frail or frail at T2. Multivariable logistic regression was used to examine the association between T1 CARG-BC score and decline in health status, adjusted for sociodemographic and clinical characteristics. Of the 348 robust women at T1, 83 (24%) experienced declining health status after chemotherapy, of whom 63% had intermediatehigh CARG-BC scores. After adjusting for sociodemographic and clinical characteristics, women with intermediate (OR 3.14, 95% CI 1.60-6.14, p < 0.001) or high (OR 3.80, 95% CI 1.35-10.67, p 0.01) CARG-BC scores had greater odds of decline in health status compared to women with low scores. In this cohort of older women with early breast cancer, higher CARG-BC scores prior to chemotherapy were associated with decline in health status after chemotherapy independent of sociodemographic and clinical risk factors.

Breast Cancer to Meningioma A Rare Case of Tumor-to-Tumor Metastasis.

Tumor-to-tumor metastasis (TTM) is defined as the hematogenous metastasis within a primary host tumor from a donor neoplasm. Since there is insufficient evidence regarding the pathophysiology, clinical course, and management of TTM, there are no precise guidelines for its management. A 73-year-old female patient diagnosed with breast cancer was found to have convexity meningioma. Since the size of tumor and peritumoral brain edema increased during follow-up period, the meningioma was treated with surgical resection. Postoperatively, histopathologic examination confirmed metastasis of invasive ductal carcinoma within a secretory meningioma. The final diagnosis was TTM of breast cancer in meningioma. Here, we report a rare case of intra-meningioma metastasis and a review of literature to provide a better understanding of this rare phenomenon.

Molecular Biology of Brain Metastases.

Brain metastases (BMs) often occur in patients with lung cancer, breast cancer, and melanoma and are the leading cause of morbidity and mortality. The incidence of BM has increased with advanced neuroimaging and prolonged overall survival of cancer patients. With the advancement of local treatment modalities, including stereotactic radiosurgery and navigation-guided microsurgery, BM can be controlled long-term, even in cases with multiple lesions. However, radiationchemotherapeutic agents are also toxic to the brain, usually irreversibly and cumulatively, and it remains difficult to completely cure BM. Thus, we must understand the molecular events that begin and sustain BM to develop effective targeted therapies and tools to prevent local and distant treatment failure. BM most often spreads hematogenously, and the blood-brain barrier (BBB) presents the first hurdle for disseminated tumor cells (DTCs) entering the brain parenchyma. Nevertheless, how the DTCs cross the BBB and settle on relatively infertile central nervous system tissue remains unknown. Even after successfully taking up residence in the brain, the unique tumor microenvironment is marked by restricted aerobic glycolysis metabolism and limited lymphocyte infiltration. Brain organotropism, certain phenotype of primary cancers that favors brain metastasis, may result from somatic mutation or epigenetic modulation. Recent studies revealed that exosome secretion from primary cancer or over-expression of proteolytic enzymes can pre-condition brain vasculoendothelial cells. The concept of the metastatic niche, where resident DTCs remain dormant and protected from systemic chemotherapy and antigen exposure before proliferation, is supported by clinical observation of BM in patients clearing systemic cancer and experimental evidence of the interaction between cancer cells and tumor-infiltrating lymphocytes. This review examines extant research on the metastatic cascade of BM through the molecular events that create and sustain BM to reveal clues that can assist the development of effective targeted therapies that treat established BMs and prevent BM recurrence.

Canine as a Comparative and Translational Model for Human Mammary Tumor.

Despite the advances in research and treatment of human breast cancer, its incidence rate continues to increase by 0.5% per year, and the discovery of novel therapeutic strategies for specific subtypes of human breast cancer remains challenging. Traditional laboratory mouse models have contributed tremendously to human breast cancer research. However, mice do not develop tumors spontaneously consequently, genetically engineered mouse models or patient-derived xenograft models are often relied upon for more sophisticated human breast cancer studies. Since human breast cancer develops spontaneously, there is a need for alternative, yet complementary, models that can better recapitulate the features of human breast cancer to better understand the molecular and clinical complexities of the disease in developing new therapeutic strategies. Canine mammary tumors are one such alternative model that share features with human breast cancer, including prevalence rate, subtype classification, treatment, and mutational profiles, all of which are described in this review.

Aspirin Use Is Associated With Improved Outcomes in Inflammatory Breast Cancer Patients.

Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer and has a high propensity for distant metastases. Our previous data suggested that aspirin (acetylsalicylic acid, ASA) use may be associated with reduced risk of distant metastases in aggressive breast cancer however, there are no reported studies on the potential benefit of ASA use in patients with IBC. Data from patients with non-metastatic IBC treated between 2000-2017 at two institutions, were reviewed. Overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) were performed using Kaplan-Meier analysis. Univariate and multivariable logistic regression models were used to identify significant associated factors. Of 59 patients meeting the criteria for analysis and available for review, 14 ASA users were identified. ASA users demonstrated increased OS ( ASA use during remission was associated with significantly improved OS and DMFS in patients with IBC. These results suggest that ASA may provide survival benefits to patients with IBC. Prospective clinical trials of ASA use in patients with high-risk IBC in remission should be considered.

Treatment of Breast Cancer-Related Lymphedema With Topical Tacrolimus A Prospective, Open-Label, Single-Arm, Phase II Pilot Trial.

Breast cancer-related lymphedema (BCRL) is a chronic, progressive side effect of breast cancer treatment, occurring in one-third of patients treated with axillary lymph node dissection and nodal radiotherapy. Cluster of differentiation 4-positive (CD4 We conducted this open-label, single-arm, phase II pilot trial from September 2020 to April 2021. Eighteen women with BCRL stage I or II BCRL were treated with topical tacrolimus for 6 months and followed up at 3 and 6 months. The primary outcome was arm volume, and secondary outcomes were the lymphedema index (L-Dex), health-related quality of life (HRQoL), lymph flow and function, and safety and feasibility of the trial design. The mean lymphedema arm volume and L-Dex reduced significantly by 130.44 ± 210.13 mL ( In this trial, treatment with tacrolimus was safe and feasible in women with stage I or II BCRL. Tacrolimus alleviated BCRL in terms of improved arm volume, L-Dex, and HRQoL. Assessments of lymph flow and function were positive, although inconclusive. Larger randomized controlled trials are required to verify these findings. ClinicalTrials.gov Identifier NCT04541290.

AKR1C2 Promotes Metastasis and Regulates the Molecular Features of Luminal Androgen Receptor Subtype in Triple Negative Breast Cancer Cells.

Patients with triple-negative breast cancer (TNBC) have an increased risk of distant metastasis compared to those with other subtypes. In this study, we aimed to identify the genes associated with distant metastasis in TNBC and their underlying mechanisms. We established patient-derived xenograft (PDX) models using surgically resected breast cancer tissues from 31 patients with TNBC. Among these, 15 patients subsequently developed distant metastases. Candidate metastasis-associated genes were identified using RNA sequencing. RNA sequencing of primary and PDX tumors showed that genes involved in steroid hormone biosynthesis, including AKR1C2, were significantly upregulated in patients who subsequently developed metastasis. Our data indicate that AKR1C2 is an important regulator of cancer growth and metastasis in TNBC and may be a critical determinant of LAR subtype features.

New tamoxifen analogs for breast cancer therapy synthesis, aromatase inhibition and

A new class of tamoxifen analogues, using McMurry reaction conditions, is described. The scheme involved the conversion of ketoprofen (

The effect of immediate lymphatic reconstruction on the post-operative drain output after axillary lymph node dissection for breast cancer A retrospective comparative study.

Axillary lymph node dissection (ALND) for breast cancer has been considered to be associated with a variety of complications, such as excessive postoperative wound drainage, prolonged drain placement, or seroma formation in the short term, or arm lymphedema in the long run. Immediate lymphedema reconstruction (ILR) has been proposed to reduce the occurrence of arm lymphedema by anastomosing the transected arm lymphatics to nearby branches of the axillary vein immediately after ALND. This study aims to demonstrate that ILR can also reduce the postoperative drainage amount. Between April 2020 and January 2022, a total of 76 breast cancer patients receiving ALND were reviewed. Forty four of them also received ILR immediately after ALND. The assignment of ILR surgery was non-random, based on patients willingness and plastic surgeons availability. The lymphatic vessels in the axillary wound were anastomosed with nearby terminal branches of the axillary vein under surgical microscope. Patients characteristics, including age, body mass index (BMI), neoadjuvant therapy, type of breast surgery, the occurrence of seroma formation, number of removed lymph nodes, number of positive nodes, and the drainage amount from the operative wounds were compared between ILR and non-ILR groups. No statistically significant difference was noted between groups in terms of age (56.5 ± 9.8 vs. 60.9 ± 10.7, p .09), BMI (22.6 ± 3.7 vs. 23.7 ± 3.8, p .27), type of breast surgery (p .32), the occurrence of seroma formation (p 1.0), the likelihood of receiving neoadjuvant therapy (p .12), number of lymph nodes removed (17.5 ± 7.6 vs. 17.4 ± 8.3, p .96), or number of positive nodes on final pathology (3.7 ± 5.4 vs. 4.8 ± 8.5, p .53) except the ILR group had statistically significantly less drainage amount than non-ILR group (39.3 ± 2.6 vs. 48.3 ± 3.7, p .046). For breast cancer patients receiving ALND, the immediate lymphatic reconstruction can reduce the postoperative drainage amount from the operative wound.

Challenging breast cancer through novel sulfonamide-pyridine hybrids design, synthesis, carbonic anhydrase IX inhibition and induction of apoptosis.

Cyclopropenone, Cyclopropeniminium Ion, and Cyclopropenethione as Novel Electrophilic Warheads for Potential Target Discovery of Triple-Negative Breast Cancer.

Because very few targets are currently available for drug development, triple-negative breast cancer (TNBC) has been defined as one of the most difficult diseases for chemotherapy. Herein, we describe a suite of novel electrophilic warheads, which we have used in chemical proteomics studies in a search for potential targets for TNBC. Binding site analysis revealed that these warheads can modify not only highly nucleophilic residues, including cysteine and lysine, but also weakly nucleophilic residues. Cys12 of Kirsten rat sarcoma (KRAS

Sq-2, a biotinylated annonaceous acetogenin, induces apoptosis, autophagy and S-phase arrest by activating the MAPK pathway in breast cancer cells.

<p indent0mm>Squamocin, an annonaceous acetogenin isolated from plants in the <italic>Annonaceae<italic> family, has antitumour activity. In this study, we report that Sq-2, a biotinylated squamocin monomer, has a favorable antitumour effect on MDA-MB-231 and SKBR3 breast cancer cells <italic>in vitro<italic>. MTT assays show that Sq-2 has a better antitumour effect on MDA-MB-231 cells than Sq-5 and Sq-6. Furthermore, RNA-Seq and KEGG enrichment analyses reveal that Sq-2 activates the MAPK signaling pathway, and results of western blot analysis demonstrate that Sq-2 activates the JNK and p38 pathways in MDA-MB-231 and SKBR3 cells. Flow cytometry and western blot analysis reveal that Sq-2 induces cell apoptosis by increasing the expressions of cleaved Caspase-3 and cleaved PARP as well as the ratio of BaxBcl-2. Inhibition of the Caspase family by Z-VAD-FMK attenuates the viability of MDA-MB-231 cells, indicating that Sq-2 induces apoptosis in a Caspase-dependent manner. Additionally, pretreatment with the p38 inhibitor SB203580 or JNK inhibitor SP600125 partially reverses the increase in the apoptosis rate and decrease in cell viability prompted by Sq-2. Furthermore, Sq-2 treatment decreases the expression level of CyclinD1 and increases the expression levels of p21, p27, CyclinA1, and CDK2, causing S-phase arrest in MDA-MB-231 and SKBR3 cells. Further study indicates that Sq-2 stimulates autophagy in MDA-MB-231 and SKBR3 cells, and inhibition of autophagy by bafilomycin A1 increases cell viability and promotes cell survival. Sq-2, a novel biotin-squamocin compound, shows a significant inhibitory effect on the propagation of SKBR3 and MDA-MB-231 breast cancer cells. Furthermore, Sq-2 treatment not only induces S-phase arrest and activates the JNK and p38 pathways to trigger apoptosis but also causes autophagy to promote apoptosis in MDA-MB-231 and SKBR3 cells. <p>.

Ribociclib-induced hepatotoxicity.

Cyclin-dependent kinase (CDK) 46 inhibitors have shown a different adverse effect. In this case, persistent grade 3 hepatoxicity was observed after ribociclib. Therefore, ribociclib therapy was stopped, and then palbociclib was introduced. Transaminase levels returned to normal by switching to palbociclib therapy. 71-year-old postmenopausal female patient with luminal subtypes of metastatic breast cancer treated with ribociclib. Grade 3 hepatotoxicity secondary to ribociclib developed. She was successfully treated with palbociclib 125 mg. In our case, palbociclib was started with a full dose, to increase treatment success. Starting with a 125 mg dose was not cause any toxicity. Nevertheless, laboratory follow-up is required in terms of neutropenia and increased transaminases.

Overcoming barriers Modelling the effect of potential future changes of organized breast cancer screening in Italy.

Organized breast cancer screening may not achieve its full potential due to organizational and cultural barriers. In Italy, two identified barriers were low attendance in Southern Italy and, in Italy as a whole, underscreening and overscreening in parts of the eligible population. The objective of this study was to identify potential changes to overcome these barriers and to quantify their costs and effects. To assess the impact of potential measures to improve breast cancer screening in Italy, we performed an evaluation of costs and effects for increasing adherence for Southern Italy and harmonizing screening intervals (biennial screening) for the whole of Italy, using an online tool (EU-TOPIA evaluation tool) based on the MIcrosimulation SCreening ANalysis (MISCAN) model. Increasing adherence in Southern Italy through investing in mobile screening units has an acceptable cost-effectiveness ratio of €9531 per quality-adjusted life year gained. Harmonizing the screening interval by investing in measures to reduce opportunistic screening and simultaneously investing in mobile screening units to reduce underscreening is predicted to gain 1% fewer life-years, while saving 19% of total screening costs compared to the current situation. Increasing adherence in Southern Italy and harmonizing the screening interval could result in substantial improvements at acceptable costs, or in the same benefits at lower costs. This example illustrates a systematic approach that can be easily applied to other European countries, as the online tools can be used by stakeholders to quantify effects and costs of a broad range of specific barriers, and ways to overcome them.

Prenatal Origins of Endometriosis Pathology and Pain Reviewing the Evidence of a Role for Low Testosterone.

Endometriosis is a polygenic, estrogen-dependent, inflammatory disorder of uncertain aetiology associated with pain, infertility and reduced quality of life. While the positive association between endometriosis and estrogen is established, a suite of recent studies has demonstrated an inverse association between the presence of endometriosis lesions and levels of testosterone both prenatally and postnatally. The following narrative review provides new insights into the roles of testosterone in the aetiology, diagnosis, and management of endometriosis and associated symptoms, especially pain. A relatively short anogenital distance (AGD) is indicative of lower levels of testosterone during fetal development. A shorter AGD has recently been correlated with both a higher risk of developing endometriosis in adult life, and with known correlates of endometriosis including earlier onset of reproductive cycling, lower ovarian follicle number, lower postnatal testosterone, and premature ovarian insufficiency. During adult life, lower levels of testosterone are positively associated with key comorbidities of endometriosis, including days per month of pelvic pain and increased pain sensitivity. Biochemically, lower levels of testosterone are associated with higher levels of pro-inflammatory IL-1β and lower levels of β-endorphin. In rodents, prenatal administration of testosterone to females reduces their pain sensitivity in adulthood. The emerging convergent links of endometriosis with low prenatal and postnatal testosterone provide evidence of a centrally mediated effect beginning in early prenatal development, and persisting through adult life, with notable effects on pain sensitivity. They generate a novel conceptual framework for understanding, studying and treating this disorder, whereby endometriosis is mediated by a combination of high estrogen in endometrial tissue with low systemic and ovarian testosterone.

HER2positive and HER2low in inflammatory breast cancer recurrence.

This study aimed to investigate the impact of HER2-low on the risk of recurrence in individuals with inflammatory breast cancer (IBC). 60 females with HER2-low and HER2-positive IBC underwent surgery between July 2020 and July 2022. Patients were divided into three groups of 20 patients (1) HRplusHER2-, (2) HRplusHERplus, and (3) HR-HER2plus. All patients underwent chemotherapy in adjuvant mode, following this scheme TCHdocetaxel and carboplatin plus Herceptin (HER2 target - 4 mgkg as the loading dose and 6 mgkg as subsequent doses throughout every 21 days, entire 52 weeks of Herceptin therapy). HRplusHERplus group had an OS of 76.9% compared with 77.0% in the group with the HRplusHER2plus subtype and 74.4% in the HR-HER2plus group. Moreover, recurrence-free survival was 19.1% for the HRplusHER2- group, 21.3% for the HRplusHERplus group, and 11.7% for the HR-HER2plus group. In our study, patients with HER2-low IBC could acquire a perfect response with preliminary systemic therapy, without disease progression or with stable disease on target alone. Further examination is important to decide on the most effective treatment regimens, in addition to mixing chemotherapy with HER2-low-focused on agents.

More recent insights into the breast cancer burden across BRICS-Plus Health consequences in key nations with emerging economies using the global burden of disease study 2019.

Brazil, Russia, India, China, South Africa, and 30 other Asian nations make up the BRICS-Plus, a group of developing countries that account for about half of the worlds population and contribute significantly to the global illness burden. This study aimed to analyzed the epidemiological burden of female breast cancer (BC) across the BRICS-Plus from 1990 to 2019 and studied the associations with age, period, birth cohort and countries sociodemographic index (SDI). The BC mortality and incidence estimates came from the 2019 Global Burden of Disease Study. We estimated cohort and period effects in BC outcomes between 1990 and 2019 using age-period-cohort (APC) modeling. The maximum likelihood (ML) of the APC-model Poisson with log (Y) based on the natural-spline function was used to estimate the rate ratio (RR). We used annualized rate of change (AROC) to quantify change over the previous 30 years in BC across BRICS-Plus and compare it to the global. In 2019, there were about 1.98 million female BC cases (age-standardized rate of 45.86 95% UI 41.91, 49.76) and 0.69 million deaths (age-standardized rate of 15.88 95% UI 14.66, 17.07) around the globe. Among them, 45.4% of incident cases and 51.3% of deaths were attributed to the BRICS-Plus. China (41.1% cases and 26.5% deaths) and India (16.1% cases and 23.1% deaths) had the largest proportion of incident cases and deaths among the BRICS-Plus nations in 2019. Pakistan came in third with 5.6% cases and 8.8% deaths. Over the past three decades, from 1990 to 2019, the BRICS-Plus regions greatest AROC was seen in Lesotho (2.61% 95%UI 1.99-2.99). The birth cohort impacts on BC vary significantly among the BRICS-Plus nations. Overall, the risk of case-fatality rate tended to decline in all BRICS-Plus nations, notably in South Asian Association for Regional Cooperation (SAARC) and China-ASEAN Free Trade Area (China-ASEAN FTA) countries, and the drop in risk in the most recent cohort was lowest in China and the Maldives. Additionally, there was a substantial negative link between SDI and case fatality rate (r The BC burden varies remarkably between different BRICS-Plus regions. Although the BRICS efforts to regulate BC succeeded, the overall improvements lagged behind those in high-income Asia-Pacific nations. Every BRICS-Plus country should strengthen specific public health approaches and policies directed at different priority groups, according to BRIC-Plus and other high-burden nations.

Designing home-based physical activity programs for rural cancer survivors A survey of technology access and preferences.

While technology advances have increased the popularity of remote interventions in underserved and rural cancer communities, less is understood about technology access and preferences for home-based physical activity programs in this cancer survivor population. To determine access, preferences, and needs, for a home-based physical activity program in rural cancer survivors. A Qualtrics Research Panel was recruited to survey adults with cancer across the United States. Participants self-reported demographics, cancer characteristics, technology access and usage, and preferences for a home-based physical activity program. The Godin Leisure Time Exercise Questionnaire (GLTEQ) assessed current levels of physical activity. Descriptive statistics included means and standard deviations for continuous variables, and frequencies for categorical variables. Independent samples t-tests explored differences between rural and non-rural participants. Participants (N298 mean age55.2 ± 16.5) had a history of cancer (mean age at diagnosis46.5), with the most commonly reported cancer type being breast (25.5%), followed by prostate (16.1%). 74.2% resided in rural hometowns. 95% of participants reported accessing the internet daily. On a scale of 0-100, computerlaptop (M63.4) and mobile phone (M54.6) were the most preferred delivery modes for a home-based physical activity intervention, and most participants preferred balanceflexibility (72.2%) and aerobic (53.9%) exercises. Desired intervention elements included a frequency of 2-3 times a week (53.5%) for at least 20 minutes (75.7%). While there were notable rural disparities present (e.g., older age at diagnosis, lower levels of education These findings provide insights into the preferred physical activity intervention (e.g., computer delivery, balanceflexibility exercises) in rural cancer survivors, while highlighting the need for personalization. Future efforts should consider these preferences when designing and delivering home-based interventions in this population.

Molecular subtypes predict the preferential site of distant metastasis in advanced breast cancer a nationwide retrospective study.

This study aimed to explore possible associations between molecular subtypes and site of distant metastasis in advanced breast cancer (ABC). 3577 ABC patients were selected from 21 hospitals of seven geographic regions in China from 2012-2014. A questionnaire was designed to collect medical information regarding demographic characteristics, risk factors, molecular subtype, recurrencemetastasis information, and disease-free survival (DFS). The cancers were classified into Luminal A, Luminal B, HER2-enriched and Triple Negative subtypes. Chi-square test and multivariate Cox proportional hazard models were performed to explore the associations between molecular subtypes and distant metastasis sites. A total of 2393 cases with molecular subtypes information were finally examined. Patients with Luminal A (51.1%) and Luminal B (44.7%) were most prone to bone metastasis, whereas liver metastasis was more frequently observed in HER2-enriched ABC patients (29.1%).The cumulative recurrence and metastasis rates of ABC patients at 36 months of DFS were the most significant within molecular types, of which Triple Negative was the highest (82.7%), while that of Luminal A was the lowest (58.4%). In the adjusted Cox regression analysis, Luminal B, HER2-enriched and Triple Negative subtypes increased the risk of visceral metastasis by 23%, 46% and 87% respectively. In addition, Triple Negative patients had a higher probability of brain metastasis (HR 3.07, 95% CI 1.04-9.07). Molecular subtypes can predict the preferential sites of distant metastasis, emphasizing that these associations were of great help in choices for surveillance, developing appropriate screening and cancer management strategies for follow-up and personalized therapy in ABC patients.

Relationship between polymorphisms in homologous recombination repair genes RAD51 G172T、XRCC2 XRCC3 and risk of breast cancer A meta-analysis.

Genetic variability in DNA double-strand break repair genes such as RAD51 gene and its paralogs XRCC2、XRCC3 may contribute to the occurrence and progression of breast cancer. To obtain a complete evaluation of the above association, we performed a meta-analysis of published studies. Electronic databases, including PubMed, EMBASE, Web of Science, and Cochrane Library, were comprehensively searched from inception to September 2022. The Newcastle-Ottawa Scale (NOS) checklist was used to assess all included non-randomized studies. Odds ratios (OR) with 95% confidence intervals (CI) were calculated by STATA 16.0 to assess the strength of the association between single nucleotide polymorphisms (SNPs) in these genes and breast cancer risk. Subsequently, the heterogeneity between studies, sensitivity, and publication bias were performed. We downloaded data from The Cancer Genome Atlas (TCGA) and used univariate and multivariate Cox proportional hazard regression (CPH) models to validate the prognostic value of these related genes in the R software. The combined results showed that there was a significant correlation between the G172T polymorphism and the susceptibility to breast cancer in the homozygote model (OR 1.841, 95% CI1.06-3.21, In conclusion, this meta-analysis suggests that Rad51 G172T polymorphism is likely associated with an increased risk of breast cancer, significantly in the Arab population. The relationship between the XRCC2 R188H polymorphism and breast cancer was not obvious. And T241M in XRCC3 may be associated with breast cancer risk, especially in the Asian population.

Emerging functions of CEBPβ in breast cancer.

Breast tumorigenesis relies on complex interactions between tumor cells and their surrounding microenvironment, orchestrated by tightly regulated transcriptional networks. CEBPβ is a key transcription factor that regulates the proliferation and differentiation of multiple cell types and modulates a variety of biological processes such as tissue homeostasis and the immune response. In addition, CEBPβ has well-established roles in mammary gland development, is overexpressed in breast cancer, and has tumor-promoting functions. In this review, we discuss context-specific roles of CEBPβ during breast tumorigenesis, isoform-specific gene regulation, and regulation of the tumor immune response. We present challenges in CEBPβ biology and discuss the importance of CEBPβ isoform-specific gene regulation in devising new therapeutic strategies.

Human antibodies targeting ENPP1 as candidate therapeutics for cancers.

Ectonucleotide pyrophosphatasephosphodiesterase 1 (ENPP1) is a type II transmembrane glycoprotein expressed in many tissues. High expression levels of ENPP1 have been observed in many cancer types such as lung cancer, ovarian cancer, and breast cancer. Such overexpression has been associated with poor prognosis in these diseases. Hence, ENPP1 is a potential target for immunotherapy across multiple cancers. Here, we isolated and characterized two high-affinity and specific anti-ENPP1 Fab antibody candidates, 17 and 3G12, from large phage-displayed human Fab libraries. After conversion to IgG1, the binding of both antibodies increased significantly due to avidity effects. Based on these antibodies, we generated antibody-drug conjugates (ADCs), IgG-based bispecific T-cell engagers (IbTEs), and CAR T-cells which all exhibited potent killing of ENPP1-expressing cells. Thus, these various antibody-derived modalities are promising therapeutic candidates for cancers expressing human ENPP1.

Bright future or blind alley CAR-T cell therapy for solid tumors.

Chimeric antigen receptor (CAR) T cells therapy has emerged as a significant breakthrough in adoptive immunotherapy for hematological malignancies with FDA approval. However, the application of CAR-T cell therapy in solid tumors remains challenging, mostly due to lack of suitable CAR-T target antigens, insufficient trafficking and extravasation to tumor sites, and limited CAR-T survival in the hostile tumor microenvironment (TME). Herein, we reviewed the development of CARs and the clinical trials in solid tumors. Meanwhile, a key-and-lock relationship was used to describe the recognition of tumor antigen via CAR T cells. Some strategies, including dual-targets and receptor system switches or filter, have been explored to help CAR T cells matching targets specifically and to minimize on-targetoff-tumor toxicities in normal tissues. Furthermore, the complex TME restricts CAT T cells activity through dense extracellular matrix, suppressive immune cells and cytokines. Recent innovations in engineered CARs to shield the inhibitory signaling molecules were also discussed, which efficiently promote CAR T functions in terms of expansion and survival to overcome the hurdles in the TME of solid tumors.

Identification and validation of a novel senescence-related biomarker for thyroid cancer to predict the prognosis and immunotherapy.

Cellular senescence is a hallmark of tumors and has potential for cancer therapy. Cellular senescence of tumor cells plays a role in tumor progression, and patient prognosis is related to the tumor microenvironment (TME). This study aimed to explore the predictive value of senescence-related genes in thyroid cancer (THCA) and their relationship with the TME. Senescence-related genes were identified from the Molecular Signatures Database and used to conduct consensus clustering across TCGA-THCA. Differentially expressed genes (DEGs) were identified between the clusters used to perform multivariate Cox regression and least absolute shrinkage and selection operator regression (LASSO) analyses to construct a senescence-related signature. TCGA dataset was randomly divided into training and test datasets to verify the prognostic ability of the signature. Subsequently, the immune cell infiltration pattern, immunotherapy response, and drug sensitivity of the two subtypes were analyzed. Finally, the expression of signature genes was detected across TCGA-THCA and GSE33630 datasets, and further validated by RT-qPCR. Three senescence clusters were identified based on the expression of 432 senescence-related genes. Then, 23 prognostic DEGs were identified in TCGA dataset. The signature, composed of six genes, showed a significant relationship with survival, immune cell infiltration, clinical characteristics, immune checkpoints, immunotherapy response, and drug sensitivity. Low-risk THCA shows a better prognosis and higher immunotherapy response than high-risk THCA. A nomogram with perfect stability constructed using signature and clinical characteristics can predict the survival of each patient. The validation part demonstrated that ADAMTSL4, DOCK6, FAM111B, and SEMA6B were expressed at higher levels in the tumor tissue, whereas lower expression of MRPS10 and PSMB7 was observed. In conclusion, the senescence-related signature is a promising biomarker for predicting the outcome of THCA and has the potential to guide immunotherapy.