Datasets:

Gaborandi

/

breast_cancer_pubmed_abstracts

like 2

Energy decomposition and waterswapping analysis to investigate the SNP associated DPD mediated 5-FU resistance.

5-fluorouracil is an essential component of systemic chemotherapy for colon, breast, head, and neck cancer patients. However, tumoral overexpression of the dihydropyrimidine dehydrogenase has rendered 5-FU clinically ineffective by inactivating it to 5-6-dihydro fluorouracil. The responses to 5-FU in terms of efficacy and toxicity greatly differ depending upon the population group, because of variability in the DPD activity levels. In the current study, key active site amino acids involved in the 5-FU inactivation were investigated by modelling the 3D structure of human DPD in a complex with 5-FU. The identified amino acids were analyzed for their possible missense mutations available in dbSNP database. Out of 12 missense SNPs, four were validated either by sequencing in the 1000 Genomes project or frequencygenotype data. The recorded validated missense SNPs were further considered to analyze the effect of their respective alterations on 5-FU binding. Overall findings suggested that population bearing the Glu611Val DPD mutation (rs762523739) is highly vulnerable to 5-FU resistance. From the docking, electrostatic complementarity, dynamics, and energy decomposition analyses it was found that the above mutation showed superior scores than the wild DPD -5FU complex. Therefore, prescribing prodrug NUC-3373 or DPD inhibitors (Gimeracil3-Cyano-2,6-Dihydroxypyridines) as adjuvant therapy may overcome the 5-FU resistance.

A systematic review and multilevel regression analysis reveals the comorbidity prevalence in cancer.

Comorbidities can have major implications for cancer care, as they might impact the timing of cancer diagnosis, compromise optimal care, affect treatment outcomes, and increase healthcare costs. Thus, it is important to comprehensively evaluate cancer comorbidities and examine trends over time. Here, we performed a systematic literature review on the prevalence and types of comorbidities for the five most common forms of cancer. Observational studies from Organisation for Economic Co-operation and Development (OECD) countries published between 1990 and 2020 in English or Dutch that used routinely collected data from a representative population were included. The search yielded 3,070 articles of which 161 were eligible for data analyses. Multilevel analyses were performed to evaluate determinants of variation in comorbidity prevalence and trends over time. The weighted average comorbidity prevalence was 33.4%, and comorbidities were the most common in lung cancer (46.7%) and colorectal cancer (40.0%), followed by prostate (28.5%), melanoma (28.3%), and breast (22.4%). The most common types of comorbidities were hypertension (29.7%), pulmonary diseases (15.9%), and diabetes (13.5%). After adjusting for gender, type of comorbidity index, age, data source (patient records versus claims), and country, a significant increase in comorbidities of 0.54% per year was observed. Overall, a large and increasing proportion of the oncological population is dealing with comorbidities, which could be used to inform and adapt treatment options to improve health outcomes and reduce healthcare costs.

Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data.

Genome-wide association studies (GWAS) have identified around 200 loci associated with breast cancer risk. However, protein targets for these loci remain largely unknown. Identifying protein targets and biomarkers can improve the understanding of cancer biology and etiology and identify high-risk individuals for cancer prevention. In this study, we investigated genetically predicted levels of 1,142 circulating proteins with breast cancer risk in 133,384 cases and 113,789 controls of European ancestry included in the Breast Cancer Association Consortium (BCAC). We identified 22 blood protein biomarkers associated with the risk of overall breast cancer at a false discovery rate (FDR) <0.05, including nine proteins encoded by genes located at least 500kb away from previously reported risk variants for breast cancer. Analyses focusing on 124 encoding genes located at GWAS-identified breast cancer risk loci found 20 proteins associated with overall breast cancer risk and one protein associated with triple-negative breast cancer risk at FDR <0.05. Adjustment for the GWAS-identified risk variants significantly attenuated the association for 13 of these proteins, suggesting that these proteins may be the targets of these GWAS-identified risk loci. The identified proteins are involved in various biological processes, including glutathione conjugation, STAT5 signaling, and NF-κB signaling pathways. Our study identified novel protein targets and risk biomarkers for breast cancer risk.

Periodic Mesoporous Ionosilica Nanoparticles for BODIPY Delivery and Photochemical Internalization of siRNA.

Periodic Mesoporous Ionosilica Nanoparticles (PMINPs) made via co-condensation reactions starting from an ionosilica precursor and a porphyrin derivative were used for simultaneous BODIPYsiRNA delivery in cancer cells. We observed high BODIPY loading capacities and efficiencies of the PMINPs that are triggered by anion exchange. siRNA adsorption took place on the surface of the nanoparticles, whereas BODIPY was encapsulated within the core of the nanoparticles. BODIPY release was found to be pH-dependent. Our results indicate 94% BODIPY release after 16h at pH 4, whereas only 2% were released at pH 7.4. Furthermore, complexation with siRNA against luciferase gene was observed at the surface of PMINPs and gene silencing through its delivery via photochemical internalization (PCI) mechanism was efficient in MDA-MB-231 breast cancer cells expressing stable luciferase.

Camptothecin loaded casein nanosystem for tuning the therapeutic efficacy against highly metastatic triple-negative breast cancer cells.

The heterogenic of TNBC and the side effects of chemo drugs lead to the failure of therapy. Protein-based nanoplatforms have emerged as an important domain in protein-engineered biomedicine for delivering anticancer therapeutics. Protein-based nanosystems are biocompatible and biodegradable, with a long half-life and high purity. TNBC is sensitive to DNA-damaging chemo drugs. In this study, we used 10-hydroxy camptothecin, which causes DNA damage in cancer cells. However, the inappropriate solubility and toxic side effects limit its application in cancer therapy. We encapsulated 10-Hydroxycamptothecin in biocompatible casein by synthesizing nanoparticles from it. The synthesized CS and CCS NPs showed excellent biocompatibility in fibroblast cell lines L929, NIH-3T3, and zebrafish embryos. Enhanced uptake of CCS NPs in zebrafish embryos and 4T1 cells, cancer cell toxicity of nearly 80-85%, sub-cellular mitochondrial localization, alterations of mitochondrial membrane potential, lysosomal localization, and reactive oxygen species generation that causes cancer cell apoptosis have been observed. Growth inhibition of 4T1 cell colonies and antimetastatic activity were also noted. Further upregulation of γ-H2AX which causes DNA damage, downregulation of the PARP protein related to DNA repair, and increased level of the CHOP protein marker for endoplasmic reticulum stress-mediated cell death were observed. The 3-D model of 4T1 cells exhibited deep tumor penetration with significant therapeutic efficacy for CCS NPs. These results imply that casein-based nanoformulation could open a new scope for safe and affordable cancer therapy in TNBC.

Participation in breast cancer screening and its influence on other cancer screening invitations study in women aged 56 years old in four French departments.

Today, women 50 years of age are offered three types of cancer screening in France. However, participation is not optimal. The aim was to describe (1) participation in organised breast cancer screening (OS) of women aged 56 years old, and the influence of this participation on colorectal and cervical cancer screening, (2) the reasons for non-participation in breast cancer OS, and (3) the reasons for screening before age 50. A questionnaire was sent to 56-year-old women in four French departments to identify their participation behaviour in three breast cancer OS invitations and their reasons for non-participation. Three groups were determined according to the number of participations in breast cancer OS (3, 1-2 and 0). We described the quantitative responses and grouped the qualitative responses thematically. A total of 4634 women responded to the questionnaire. Seventy-six percent had undergone all three breast cancer OS, 16% irregular and 7% non-participant. Among women who irregularly perform breast cancer OS, 50.5% also irregularly perform colorectal cancer OS. Women who participated in all three invitations for the breast cancer OS performed more smear tests than women in the other groups. Many of the irregular participants or non-participants underwent opportunistic screening, often initiated before the age of 50. The reasons for non-participation in breast cancer OS were mainly medical or participation in opportunistic screening. There is no fundamental opposition to participation in breast cancer screening. However, it remains of the utmost importance that women should be better informed about OS and its benefits.

Combined proliferation and apoptosis index provides better risk stratification in breast cancer.

Breast cancer (BC) risk stratification is critical for predicting behaviour and guiding management decision-making. Despite the well-established prognostic value of cellular proliferation in BC, the interplay between proliferation and apoptosis remains to be defined. In this study, we hypothesised that the combined proliferation and apoptosis indices can provide a more accurate in vivo growth rate measure and a precise prognostic predictor. Apoptotic and mitotic figures were counted in whole slide images (WSI) generated from haematoxylin and eosin-stained sections of 1545 BC cases derived from two well-defined BC cohorts. Counts were carried out visually within defined areas. There was a significant correlation between mitosis and apoptosis scores. High apoptotic counts were associated with features of aggressive behaviour including high grade, high pleomorphism score, and hormonal receptor negativity. Although the mitotic index (MI) and apoptotic index (AI) were independent prognostic indicators, the prognostic value was synergistically higher when combined. BC patients with a high combined AI and MI had the shortest survival. Replacing the mitosis score with the mitosis-apoptosis index, in the Nottingham grading system, revealed that the modified grade with the new score had a higher significant association with BC-specific survival with a higher hazard ratio. Apoptotic figures count provides additional prognostic value in BC when combined with MI, such a combination can be implemented to assess the behaviour of BC and provides an accurate prognostic indicator. This can be considered when using artificial intelligence algorithms to assess proliferation in BC.

Therapeutic Reduction Mammoplasty Experience of a Single Institute.

Breast cancer is the most common malignancy in women worldwide as reported by the World Health Organization. The concept of oncoplastic breast surgery appeared as an extension of breast-conserving surgery, applying breast reduction techniques with more acceptable aesthetic and functional outcomes. The purpose of the present study was to describe the breast cancer population of a single institute submitted to lumpectomy and bilateral immediate breast reduction or mastopexy and its complications. This is a retrospective observational study including patients submitted to lumpectomy and immediate bilateral breast reduction or mastopexy. Patients and tumour characteristics, surgical technique, complications, follow-up period, and recurrence data were obtained and analyzed. A total of 49 patients were submitted to lumpectomy and bilateral breast therapeutic reductionmastopexy, with a mean age of 56.47 ±8.58 years and a mean body mass index of 28.68kgm The low rates of minor and major complications show that immediate therapeutic breast reduction can be a suitable approach in selected cases.

Radiological Evaluation of a Malignant Gastrointestinal Stromal Tumor in a Female Patient With the Coincidental Detection of Primary Breast Cancer A Case Report.

Gastrointestinal stromal tumors (GIST) are a rare and unique group of mesenchymal tumors arising from the gastrointestinal tract, omentum, mesentery, and retroperitoneum. Though they have certain typical radiological features that can differentiate them from epithelial tumors, it is often difficult to differentiate them from other non-epithelial tumors. Their features also vary depending on their size, site of origin, etc. When differentiation from other mesenchymal tumors on histopathology is difficult, receptor tyrosine kinase (C-KIT proto-oncogeneCD117) and gastrointestinal stromal tumor (GIST-1) discovered on GIST1 (DOG-1) expression are confirmatory. The concurrent presence of other primary cancers with GISTs has been described in the literature, among which most have been of gastrointestinal origin. Few cases of primary breast cancer in GIST have been described. Lymph nodal metastasis is rarely encountered in GIST, and metastasis to the breast is even rarer. We present a case of a 39-year-old female with non-specific symptoms who was referred for ultrasonography (USG) and computed tomography (CT) that showed a small intestinal GIST along with a breast lump and axillary lymphadenopathy that were labeled as metastases from the GIST on frozen sections however, they were later diagnosed as primary breast cancer with axillary metastases on the histopathology and immunohistochemistry of the excision biopsy specimens post-surgery. The patient underwent surgical resection and chemotherapy.

Malmö Breast ImaginG database objectives and development.

We describe the design and implementation of the Malmö Breast ImaginG (M-BIG) database, which will support research projects investigating various aspects of current and future breast cancer screening programs. Specifically, M-BIG will provide clinical data to1.investigate the effect of breast cancer screening on breast cancer prognosis and mortality2.develop and validate the use of artificial intelligence and machine learning in breast image interpretation and3.develop and validate image-based radiological breast cancer risk profiles. The M-BIG database is intended to include a wide range of digital mammography (DM) and digital breast tomosynthesis (DBT) examinations performed on women at the Mammography Clinic in Malmö, Sweden, from the introduction of DM in 2004 through 2020. Subjects may be included multiple times and for diverse reasons. The image data are linked to extensive clinical, diagnostic, and demographic data from several registries. To date, the database contains a total of 451,054 examinations from 104,791 women. During the inclusion period, 95,258 unique women were screened. A total of 19,968 examinations were performed using DBT, whereas the rest used DM. We describe the design and implementation of the M-BIG database as a representative and accessible medical image database linked to various types of medical data. Work is ongoing to add features and curate the existing data.

Trends in Survival and Surgical Methods in Patients Surgically Treated for Metastatic Spinal Tumors 25-Year Experience in a Single Institution.

This study aimed to examine trends in postoperative survival and surgical methods over a 25-year period in patients surgically treated for metastatic spinal tumors. We performed a retrospective study of patients who underwent surgical treatment for metastatic spinal tumors between 1996 and 2020. For trend analysis, the study cohort was divided into three groups according to the year of surgery 1996-2004, 2005-2012, and 2013-2020. A Kaplan-Meier survival analysis was performed to examine survival, and the log-rank test was used to compare the survival of the top six common cancers among the periods. The surgical methods were grouped and examined as follows fixation only, palliative decompression and fixation, gross total removal and fixation, and total This study included a total of 608 patients. There were 78 patients in 1996-2004, 236 in 2005-2012, and 294 in 2013-2020. Regarding the overall survival trend, the group 2013-2020 had a significantly improved survival as compared to the other two groups ( During the past 25 years, significant survival improvement was observed in patients with lung, kidney, and breast cancers. There was no improvement in survival in patients with liver, colorectal, and prostate cancers. In terms of surgical techniques, palliative decompression and fixation only procedures increased, while gross total tumor removal declined.

Barriers and facilitators to provide multidisciplinary care for breast cancer patients in five Latin American countries A descriptive-interpretative qualitative study.

Multidisciplinary care (MDC) remains a cornerstone for breast cancer management as it is associated with improved quality of care and patient outcomes. However, the adoption of MDC practice is heterogeneous and has been poorly explored in Latin America. The objective was to describe barriers and possible facilitators for providing MDC to breast cancer patients in five Latin American countries. A panel of experts with an active clinical practice in Bolivia, Colombia, Ecuador, Mexico, and Uruguay was convened to identify barriers and facilitators to MDC. This study is a qualitative synthesis of a structured discussion regarding the state of MDC in the setting of breast cancer. Experts recognized that most oncology practices in Latin America do not apply a multidisciplinary approach for breast cancer patients. Predominant barriers for MDC are fragmentation of health services, being understaffed, inadequate infrastructure, and geographic disparities. Access to MDC varies widely in the region, with significant heterogeneity documented within countries. MDC practice was described as being more common in the private sector in Ecuador and Uruguay, while it is more widely implemented in public institutions of Colombia and Bolivia. Establishing quality MDC remains a challenge for oncology practices in Latin America. Addressing regional issues and identifying specific local needs is warranted to encourage the adoption of an effective multidisciplinary approach and, consequently, improve clinical outcomes. Active involvement of all stakeholders is required to build locally solutions and should involve institutions, health professionals, and patients. Research was funded by Productos Roche S.A.

Segmental thoracic spinal anesthesia versus general anesthesia for breast cancer surgery A prospective randomized-controlled open-label trial.

Breast surgery is associated with moderate-to-severe postoperative pain, nausea, and vomiting. For this, neuraxial anesthesia might be a better alternative to general anesthesia (GA), providing superior analgesia, with higher patient satisfaction and lesser incidence of nausea vomiting. This randomized-controlled open-label trial was done to compare segmental spinal and GA for breast cancer surgery. The present study enrolled 56 female patients scheduled to undergo breast cancer surgery. They were randomly divided into two groups, group G (received standard GA) and group TS (received segmental thoracic spinal anesthesia with 0.5% isobaric levobupi vacaine at T5-T6 inter spaces). The primary objective of this study was patient satisfaction with the anesthetic technique, while secondary objectives were hemodynamic changes, perioperative complications, time of first rescue analgesic, total opioid consumption in first 24 h, and surgeon satisfaction score. Data were expressed as mean (SD) or number (%) as indicated and were compared using Chi-square, Fishers exact, or Students Patient in group TS had significantly higher satisfaction score median 5 (IQR 1) compared to patients in group G median 4 (IQR 3.5) ( Segmental thoracic spinal anesthesia technique provides better satisfaction with superior postoperative analgesia and fewer complications in patients undergoing breast cancer surgery compared to GA.

Causal Discovery in High-dimensional, Multicollinear Datasets.

As the cost of high-throughput genomic sequencing technology declines, its application in clinical research becomes increasingly popular. The collected datasets often contain tens or hundreds of thousands of biological features that need to be mined to extract meaningful information. One area of particular interest is discovering underlying causal mechanisms of disease outcomes. Over the past few decades, causal discovery algorithms have been developed and expanded to infer such relationships. However, these algorithms suffer from the curse of dimensionality and multicollinearity. A recently introduced, non-orthogonal, general empirical Bayes approach to matrix factorization has been demonstrated to successfully infer latent factors with interpretable structures from observed variables. We hypothesize that applying this strategy to causal discovery algorithms can solve both the high dimensionality and collinearity problems, inherent to most biomedical datasets. We evaluate this strategy on simulated data and apply it to two real-world datasets. In a breast cancer dataset, we identified important survival-associated latent factors and biologically meaningful enriched pathways within factors related to important clinical features. In a SARS-CoV-2 dataset, we were able to predict whether a patient (1) had Covid-19 and (2) would enter the ICU. Furthermore, we were able to associate factors with known Covid-19 related biological pathways.

Association between endocrine therapy and cognitive decline in breast cancer based on propensity score matching.

To study the In this study, the epidemiological questionnaire information was collected from 226 female breast cancer endocrine treatment patients who visited the Breast Clinic of Longhua Hospital Affiliated to Shanghai University of Chinese Medicine from November 2020 to February 2022, and the results of the overall cognitive function, the function test of each cognitive domain, the patients self-cognition, quality of life, and emotional status evaluation of the patients. In this study, according to the principle of random matching, the nearest matching method with a matching tolerance of 0.2 and a matching ratio of 12 was used for orientation score matching. After the covariant such as age, BMI, and duration of education were balanced, the effects of the duration of endocrine therapy on the overall cognitive function and the functions of each cognitive domain were analyzed. In 226 cases of female breast cancer patients (who went through) the endocrine therapy, the propensity score matching was performed, ultimately, 99 were ruled out, successful matched ones were 49 of the cognition-decline group and 78 of the standard group. With age, education time, BMI and other covariates balanced, the endocrine therapy duration was the risk factor of the cognition impairment ( The endocrine therapy duration was the risk factor for the cognition impairment of the breast cancer patients, and with prolonged endocrine treatment, there was a rising (an increasing) risk for the cognition impairment.

Pseudoangiomatous Stromal Hyperplasia Radiologic-Pathologic Correlation.

Pseudoangiomatous stromal hyperplasia (PASH) is a benign mesenchymal proliferative lesion of the breast. PASH is postulated to be hormonally induced and predominantly occurs in premenopausal women and postmenopausal women on menopausal hormone therapy. Clinical presentation varies from screen-detected lesions to palpable masses. Imaging findings of PASH are nonspecific. The most common mammographic findings are an oval or round circumscribed non-calcified mass or developing asymmetry. On US, PASH is often seen as an oval hypoechoic mass that may be circumscribed and can have an echogenic rim, or, when manifest as mammographic asymmetry, US may show a corresponding non-mass focal area of echogenic tissue. Limited studies have investigated the MRI appearance, with PASH most often manifesting as non-mass enhancement, or, less often, as an oval or irregular mass with persistent kinetics. Histopathologically, PASH can be mistaken for a fibroadenoma or phyllodes tumor and has features overlapping low-grade angiosarcoma. Assessment of radiologic-pathologic concordance is particularly important as PASH is often an incidental finding, adjacent to the targeted lesion at histopathology. Surgical excision or repeat core-needle biopsy is necessary for discordant suspicious cases. After a benign, concordant diagnosis of PASH, the patient may resume routine screening.

Diagnostic Contrast-Enhanced Mammography Performed Immediately Prior to Same-Day Biopsy An Analysis of Index Lesion Enhancement Compared to Histopathology and Follow-up in Patients With Suspicious Ultrasound Findings.

To measure the diagnostic performance of contrast-enhanced mammography (CEM) for the index lesion when it is performed the same day prior to biopsy in patients with suspicious findings at US. This IRB-approved retrospective study compared radiologist original reports of the presence or absence of index lesion enhancement on CEM to biopsy results and follow-up. The most suspicious lesion or the larger of equally suspicious lesions recommended for biopsy by US after a diagnostic workup including mammography was considered the index lesion. CEM exams were performed the same day, immediately prior to the scheduled biopsy, as requested by the radiologist recommending the biopsy. Numeric variables were summarized with means and standard deviations, or medians and the minimum and maximum, where appropriate. Biopsy demonstrated cancer in 64.7% (200309) of index lesions. Of these, 197200 demonstrated enhancement for a sensitivity of 98.5% (95% CI 95.7%-99.7%) (197200) and the negative predictive value of CEM for non-enhancing index lesions was 95.1% (5861 95% CI 86.1%-98.4%). The three false negative exams were two grade 1 ER HER2- invasive ductal cancers that were 6 mm and 7 mm in size, and a 3-mm grade 2 ductal carcinoma in situ in a complex cystic and solid mass. False positive exams made up 20.6% (51248) of the positive exams. Diagnostic CEM showed high sensitivity and specificity for cancer in lesions with suspicious US findings. CEM may reduce the need for some biopsies, and negative CEM may support a true negative biopsy result.

The lived experience of breast cancer patients on adjuvant endocrine therapy Side effects and coping strategies during the first year of medication initiation.

EstroGene database reveals diverse temporal, context-dependent and directional estrogen receptor regulomes in breast cancer.

As one of the most successful cancer therapeutic targets, estrogen receptor-α (ERESR1) has been extensively studied in decade-long. Sequencing technological advances have enabled genome-wide analysis of ER action. However, reproducibility is limited by different experimental design. Here, we established the EstroGene database through centralizing 246 experiments from 136 transcriptomic, cistromic and epigenetic datasets focusing on estradiol-treated ER activation across 19 breast cancer cell lines. We generated a user-friendly browser ( httpsestrogene.org ) for data visualization and gene inquiry under user-defined experimental conditions and statistical thresholds. Notably, documentation-based meta-analysis revealed a considerable lack of experimental details. Comparison of independent RNA-seq or ER ChIP-seq data with the same design showed large variability and only strong effects could be consistently detected. We defined temporal estrogen response metasignatures and showed the association with specific transcriptional factors, chromatin accessibility and ER heterogeneity. Unexpectedly, harmonizing 146 transcriptomic analyses uncovered a subset of E2-bidirectionally regulated genes, which linked to immune surveillance in the clinical setting. Furthermore, we defined context dependent E2 response programs in MCF7 and T47D cell lines, the two most frequently used models in the field. Collectively, the EstroGene database provides an informative resource to the cancer research community and reveals a diverse mode of ER signaling.

Robust biomarker discovery through multiplatform multiplex image analysis of breast cancer clinical cohorts.

Spatial profiling of tissues promises to elucidate tumor-microenvironment interactions and enable development of spatial biomarkers to predict patient response to immunotherapy and other therapeutics. However, spatial biomarker discovery is often carried out on a single patient cohort or imaging technology, limiting statistical power and increasing the likelihood of technical artifacts. In order to analyze patient cohorts profiled on different platforms, we developed methods for comparative data analysis from three disparate multiplex imaging technologies 1) cyclic immunofluorescence data we generated from 102 breast cancer patients, 63 with clinical followup, in addition to publicly available 2) imaging mass cytometry and 3) multiplex ion-beam imaging data. We demonstrate similar single-cell phenotyping results across breast cancer patient cohorts imaged with these three methods and identify cellular abundance and proximity-based biomarkers with prognostic value across platforms. In multiple platforms, we identified T cell infiltration as independently associated with longer survival in high-proliferation breast tumors. Functional marker analysis of T cells in these tissues showed enrichment for activated and spatially clustered T cells. A comparison of six spatial analysis methods revealed robust spatial biomarkers, including tumor-macrophage and tumor-fibroblast proximity associated with poor prognosis in estrogen receptor-positive and triple-negative tumors, respectively. Our methods enable assembly of larger clinical cohorts from diverse platforms to aid in prognostic spatial biomarker identification and validation. Our single-cell spatial analysis of multiple clinical cohorts uncovered novel biomarkers of patient outcome in breast cancer. Additionally, our data, software, and methods will help advance spatial characterization of the tumor microenvironment.

Identification and characterization of a proliferative cell population in estrogen receptor-positive metastatic breast cancer through spatial and single-cell transcriptomics.

Intratumor heterogeneity is a hallmark of most solid tumors, including breast cancers. We applied spatial transcriptomics and single-cell RNA-sequencing technologies to profile spatially resolved cell populations within estrogen receptor-positive (ER Spatial transcriptomics and single-cell RNA-sequencing were performed on two patient-derived xenografts (PDXs) of ER-high metastatic breast cancers with opposite estrogen-mediated growth responses estrogen-suppressed GS3 (80-100% ER) and estrogen-stimulated SC31 (30-75% ER) models. The analyses included samples treated with and without 17β-estradiol. The findings were validated via scRNA-seq analyses on ER-low estrogen-accelerating PDX, GS1 (5% ER). The results from our spatial and single-cell analyses were further supported by the analysis of a publicly available single cell dataset and a protein-based dual immunohistochemical (IHC) evaluation using three important clinical markers i.e., ER, progesterone receptor (PR), and Ki67. The translational implication of these results was assessed by clinical outcome analyses on public breast cancer cohorts. Our novel space-gene-function study revealed a proliferative cell population in addition to three major spatially distinct compartments within ER For the first time, our study elucidated a proliferative cell population distinctly distributed in ER

Organoid generation from mouse mammary tumors captures the genetic heterogeneity of clinically relevant copy number alterations.

Breast cancer metastases exhibit many different genetic alterations, including copy number amplifications. Using publicly available datasets, we identify copy number amplifications in metastatic breast tumor samples and using our organoid-based metastasis assays, and we validate FGFR1 is amplified in collectively migrating organoids. Because the heterogeneity of breast tumors is increasingly becoming relevant to clinical practice, we demonstrate our organoid method captures genetic heterogeneity of individual tumors.

Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA polyubiquitination.

The unique arginine dependencies of cancer cell proliferation and survival creates metabolic vulnerability. Here, we investigate the impact of extracellular arginine availability on DNA replication and genotoxic resistance. Using DNA combing assays, we find that when extracellular arginine is limited, cancer cells are arrested at S-phase and DNA replication forks slow or stall instantly until arginine is re-supplied. The translation of new histone H4 is arginine-dependent and impacts DNA replication and the expression of newly synthesized histone H4 is reduced in the avascular nutrient-poor breast cancer xenograft tumor cores. Furthermore, we demonstrate that increased PCNA occupancy and HLTF-catalyzed PCNA K63-linked polyubiquitination protects arginine-starved cells from hydroxyurea-induced, DNA2-catalyzed nascent strand degradation. Finally, arginine-deprived cancer cells are tolerant to genotoxic insults in a PCNA K63-linked polyubiquitination-dependent manner. Together, these findings reveal that extracellular arginine is the linchpin for nutrient-regulated DNA replication. Such information could be leveraged to expand current modalities or design new drug targets against cancer.

Single-cell RNA sequencing reveals dysregulated fibroblast subclusters in prurigo nodularis.

Prurigo nodularis (PN) is an intensely pruritic, chronic inflammatory skin disease that disproportionately affects black patients. However, the pathogenesis of PN is poorly understood. We performed single-cell transcriptomic profiling, ligand receptor analysis and cell trajectory analysis of 28,695 lesional and non-lesional PN skin cells to uncover disease-identifying cell compositions and genetic characteristics. We uncovered a dysregulated role for fibroblasts (FBs) and myofibroblasts as a key pathogenic element in PN, which were significantly increased in PN lesional skin. We defined seven unique subclusters of FBs in PN skin and observed a shift of PN lesional FBs towards a cancer-associated fibroblast (CAF)-like phenotype, with WNT5A CAFs increased in the skin of PN patients and similarly so in squamous cell carcinoma (SCC). A multi-center PN cohort study subsequently revealed an increased risk of SCC as well as additional CAF-associated malignancies in PN patients, including breast and colorectal cancers. Systemic fibroproliferative diseases were also upregulated in PN patients, including renal sclerosis and idiopathic pulmonary fibrosis. Ligand receptor analyses demonstrated increased FB1-derived WNT5A and periostin interactions with neuronal receptors MCAM and ITGAV, suggesting a fibroblast-neuronal axis in PN. Type I IFN responses in immune cells and increased angiogenesispermeability in endothelial cells were also observed. As compared to atopic dermatitis (AD) and psoriasis (PSO) patients, increased mesenchymal dysregulation is unique to PN with an intermediate Th2Th17 phenotype between atopic dermatitis and psoriasis. These findings identify a pathogenic role for CAFs in PN, including a novel targetable WNT5A fibroblast subpopulation and CAF-associated malignancies in PN patients.

The FGFR1 Signaling Pathway Upregulates the Oncogenic Transcription Factor FOXQ1 to Promote Breast Cancer Cell Growth.

FGFR1 is a receptor tyrosine kinase deregulated in certain breast cancers (BCs) with a poor prognosis. Although FGFR1-activated phosphorylation cascades have been mapped, the key genes regulated by FGFR1 in BC are largely unclear. FOXQ1 is an oncogenic transcription factor. Although we found that activation of FGFR1 robustly upregulated FOXQ1 mRNA, how FGFR1 regulates

Erratum A Long Non-coding RNA Lnc712 Regulates Breast Cancer Cell Proliferation Erratum.

This corrects the article DOI 10.7150ijbs.36429..

PAnno A pharmacogenomics annotation tool for clinical genomic testing.

A novel PTEN mutant caused by polymorphism in cis-regulatory elements is involved in chemosensitivity in breast cancer.

Phosphatase and tensin homolog (

Improved platform for breast cancer circulating tumor cell enrichment and characterization with next-generation sequencing technology.

Circulating tumor cells (CTCs) represent cells shed from the primary tumor or metastatic sites and can be used to monitor treatment response and tumor recurrence. However, CTCs circulate in extremely low numbers making in-depth analysis beyond simple enumeration challenging when collected from peripheral blood. Furthermore, tumor heterogeneity, a hallmark of many tumors, especially breast cancer, further complicates CTC characterization. To overcome this limitation, we developed a platform based on the large-scale isolation of CTCs by apheresis, allowing us to collect CTCs in large numbers, which were preserved live in liquid nitrogen for further characterization. Flow cytometry followed by cell sorting (FACS) was performed using a combination of antibodies directed against cell surface markers of white blood cells (CD45) and epithelial tumor cells (CK8). Analysis of subpopulations CD45- and CK8- by bulk RNA sequencing (RNAseq) and the CD45-CK8 positive population by single-cell RNAseq was performed. The CD45- population was enriched using CD45 magnetic beads separation and examined by IHC for pan-cytokeratin and immunofluorescence (IF) for specific markers, including the elusive circulating cancer stem cells (CSCs). CSC-rich mammospheres were grown in vitro for further analysis and treated to examine their response to chemotherapeutic agents. Finally, mammospheres were transplanted into the mammary fat pad and bone of immunodeficient mice to examine tumor growth in vivo. This platform enables the detection and collection of CTCs in early and late-stage breast cancer patients of every subtype. Markers including CD4424, ALDH1 and CXCR4 were identified by IF and showed high expression following mammosphere culture, which responded predictably to chemotherapeutic agents. Mammospheres were also transplanted into nude mice and induced tumors in the mammary fat pad and bone following intra-tibial transplantation. Finally, bulk RNA analysis of the FACS isolated CD45- and CK8- cells showed a clear separation of CD45- away from CD45 populations. Single-cell RNAseq of the FACS isolated CD45-CK8 cells showed the presence of 4-5 clusters, confirming the high degree of heterogeneity of CTCs. Our platform for large-scale isolation of CTCs using apheresis is suitable for an in-depth analysis of the cancer phenotype and may eventually allow evaluation in real-time of the disease process to optimize cancer regimens.

Combined inhibition of PARP and ATR synergistically potentiates the antitumor activity of HER2-targeting antibody-drug conjugate in HER2-positive cancers.

The therapeutic management of various HER2-positive malignancies involves the use of HER2-targeted antibody-drug conjugates (ADCs). The primary mechanism of action of ADCs is the release of cytotoxic chemicals, which leads to single- or double-strand DNA breaks and cell death. Since both endogenous and exogenous sources of DNA damage are unavoidable, cells have evolved DNA damage-repair mechanisms. Therefore, combining inhibitors of DNA damage repair and HER2-targeted ADCs may be a practical strategy for treating HER2-positive cancers. Effects of the HER2-targeted ADC, DS-8201, in combination with PARPi (AZD2281), a DNA damage repair inhibitor that targets poly(ADP-ribose) polymerase, and ATRi (BAY1895344), which inhibits the serinethreonine kinase ATR, were determined by assessing cell-growth inhibition, apoptosis and cell-cycle arrest, as well as using

An overview of the correlation between IPI and prognosis in primary breast lymphoma.

Primary breast lymphoma (PBL), with diffuse large B-cell lymphoma (DLBCL) as the most histopathological type, is a rare disease with a poor prognosis. The International Prognostic Index (IPI) is an important clinical characteristic for risk stratification of PBL patients with different prognoses. However, the prognostic value of the IPI in PBL is controversial and needs to be refined. In this review, we described the clinical characteristics, pathogenesis, and treatment of PBL, with emphasis on the prognostic value of the IPI, its updated versions and IPIs for certain subtypes. A total of 9 types of IPIs were presented. In addition, the key issues with the various treatment modalities available were addressed, as well as the role of rituximab in therapy. We also summarized the current evidence and future challenges facing other types of prognostic indices. In particular, prospective clinical studies of treatment are rare, and the available data were mainly obtained from retrospective case series that included a small number of patients. Therefore, our conclusions and recommendations cannot serve as formal guidelines. However, this review attempts to provide an unbiased analysis of published data to provide clinicians with useful assistance in the treatment of this uncommon form of extranodal lymphoma.

Synergistic activity of ABT-263 and ONC201TIC10 against solid tumor cell lines is associated with suppression of anti-apoptotic Mcl-1, BAG3, pAkt, and upregulation of pro-apoptotic Noxa and Bax cleavage during apoptosis.

A major underlying cause of the resistance of solid tumor cells to cancer therapy is the evasion of cell death following anti-cancer drug treatment. We explored the combination of TRAIL-inducing compound ONC201TIC10 and Bcl-xLBcl-2 inhibitor ABT-263 to target the extrinsic and intrinsic apoptotic pathways, respectively, in solid tumor cell lines (N 13) derived from different tissues (colon, prostate, lung, breast, ovary, bladder). We found an IC50 range of 0.83-20.10 μM for ONC201 and 0.06-14.75 μM for ABT-263 among the 13 cancer cell lines. We show that combination of ONC201 and ABT-263 produces a strong synergistic effect leading to tumor cell death, and that the combination is not toxic to human fibroblast cells. In OVCAR-3 ovarian cancer cells, 2.5 μM ONC201 and 1.25 μM ABT-263 yielded 37% and 27% inhibition of viability, respectively, while the combination of the two agents yielded 92% inhibition of viability, resulting in a high synergy score of 52 conversely, the same combination in the HFF-1 human fibroblast cells yielded 2.45% inhibition of viability and a synergy score of 6.92 (synergy scores were calculated using SynergyFinder scores greater than 10 are considered synergistic). We also found that the combination of these two agents resulted in synergistic caspase activation and PARP cleavage consistent with induction of apoptosis. Combination therapy-induced cell death correlated with decreased levels of Mcl-1, BAG3, pAkt, and upregulation of Noxa along with Bax cleavage during apoptosis at 48 hours, and ATF4, TRAIL, and DR5 induction at 24 hours. There was some heterogeneity in the cell lines with regard to these responses. Our data provide evidence for synergy from the combination of ONC201 and ABT-263 against human solid tumor cell lines associated with alterations in cell death and pro-survival mediators. The combination of ONC201 and ABT-263 merits further exploration

Moderately hypofractionated radiation therapy for breast cancer A Brazilian cohort study.

Results from numerous clinical trials have led to a consensus that moderately hypofractionated radiation therapy is the ideal postoperative irradiation treatment plan in patients with breast cancer (BC). However, there are specific situations such as chest wall (with or without breast reconstruction) and regional node irradiation that still face obstacles in its widespread use. There is a lack of evidence supporting the use of moderately hypofractionated irradiation from the Latin American context. This study aims to describe the profile and clinical outcomes of patients treated with moderate hypofractionation for both early-stage (Stage I and II) and locally advanced BC (Stage III) regardless of the type of surgery in a Brazilian Oncology Center. All patients with non-metastatic BC who were treated with moderately hypofractionated schedules of 40Gy in 15 fractions or 42.4Gy in 16 fractions between 2010 to 2019 at Hospital Sírio-Libanês, Brazil were retrospectively analyzed. The rates of local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distance recurrence-free survival (DRFS) and overall survival (OS) were estimated. Acute and late toxicity profiles were accessed for the entire cohort. A total of 670 patients were included. The median age was 57 years and the median follow-up time was 31 months. Most of the patients had stage I and II breast cancer, and 81.6% underwent breast-conserving surgery. Of the 123 women who underwent mastectomy treatment, 29% ( In this Brazilian institution experience, moderately hypofractionated irradiation to the breast, chest wall (with or without breast reconstruction), and regional lymph nodes was safe and with an acceptable toxicity profile. None.

Cost containment analysis and access to treatment associated with adopting hypofractionated radiation therapy from the Brazilian perspective.

Estimates show that breast cancer, the leading cause of cancer death in females worldwide, will continue to increase in incidence, highlighting the need for increased treatment capacity. While postoperative radiation therapy (RT) is commonly used to reduce recurrence and mortality, research has shown that moderately hypofractionated radiation therapy (HFRT) and 5-fraction HFRT are equally safe and effective and can reduce treatment costs. This study aimed to compare the cost of conventional RT (50Gy25), moderately HFRT (40.05Gy15), and 5-fraction HFRT (26Gy5) for breast cancer patients in Brazil. The cost of each RT regimen was calculated using the International Atomic Energy Agencys Radiotherapy Cost Estimator Tool. The potential annual savings were then estimated by applying the cost of each regime to the 2020 Brazilian cancer incidence rates. The average costs per patient for 25 fractions, 15 fractions, and 5 fractions are $2,699.20, $1,711.98, and $929.81, respectively. The annual cost savings associated with treating 70% of patients with 15 fraction HFRT and 30% of patients with 5 fraction HFRT as compared to treating all patients with 25 fraction RT is $72,929,315.40. The estimated annual productivity of 1 LINAC machine for 25 fractions, 15 fractions, and 5 fractions is 338, 647, and 1,310 patients, respectively. The cost analysis revealed decreased patients costs and potential for increased EBRT access associated with HFRT in the Brazilian perspective. None.

Breast and Cervical cancer disparities in Alabama current scenario, ongoing efforts to reduce the disparity gaps, and what more we could be doing.

Over the years, we have made considerable progress in our understanding of the biology of various cancers leading to advancements in their management strategies. Consequently, we have witnessed steady improvements in survival rates of cancer patients post-diagnosis. The progress however, has been slow for some cancer types and the advances in cancer care have not benefited all the communities equally in the United States. The state of Alabama has one of the most diverse demographics in the country and as a result, we witness significant health disparities among our populations. Breast and cervical cancers are the two major cancer types that disparately affect the women in our state. Here, we describe the extent of disparities in the diagnosis and death rates from these cancers in the state of Alabama and discuss potential underlying causes affecting the health outcomes. We also discuss ongoing efforts undertaken to reduce the disparity gaps and provide a perspective for addressing these disparities more effectively.

Effects of dyadic-based physical activity intervention on cancer-related fatigue among cancer survivors A scoping review.

Cancer-related fatigue is one of the most common adverse reactions to cancer survivors, which has a significant impact on the daily life. As a traumatic event, cancer not only brings great physical and mental harm to patients, but also poses a threat to the physical and psychological health of caregivers. Current studies have shown that physical activity improves cancer-related fatigue in cancer survivors. And studies have suggested that dyadic interventions are more effective in improving patient outcomes and may also provide some benefits to caregivers. But the literature on the effects of dyadic-based physical activity on improving cancer-related fatigue has not been synthesized. This scoping review described the scope and impact of studies on cancer-related fatigue with dyadic-based physical activity interventions. Six databases which is PubMed, Cochrane Library, Web of Science, Embase, CINAHL and Medline were searched for all studies of dyadic-based physical activity interventions with outcome measures including cancer-related fatigue published since the inception of the databases through May 2022. The search strategy was developed based on PICO principles. This article includes 6 pre and post-test designs and 2 randomized controlled trial design. The majority of participants were survivors with breast and lung cancer. The overall results showed that the effectiveness of dyadic-based physical activity interventions in improving cancer-related fatigue was unsatisfactory. This scoping review suggests that current dyadic-based physical activity interventions are not well-researched among cancer survivors. In the future, more high-quality studies with more sophisticated and rigorous interventions are needed.

Reconstructing mutational lineages in breast cancer by multi-patient-targeted single-cell DNA sequencing.

Single-cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells however, most genomic regions sequenced in single cells are non-informative. To overcome this issue, we developed a multi-patient-targeted (MPT) scDNA-seq method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 patients with triple negative-breast cancer (TNBC), which showed that 3 tumors were monoclonal and 2 tumors were polyclonal. From these data, we reconstructed mutational lineages and identified early mutational and copy-number events, including early

By integrating single-cell RNA-seq and bulk RNA-seq in sphingolipid metabolism, CACYBP was identified as a potential therapeutic target in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a heterogeneous disease with a dismal prognosis for advanced tumors. Immune-associated cells in the microenvironment substantially impact LUAD formation and progression, which has gained increased attention in recent decades. Sphingolipids have a profound impact on tumor formation and immune infiltration. However, few researchers have focused on the utilization of sphingolipid variables in the prediction of LUAD prognosis. The goal of this work was to identify the major sphingolipid-related genes (SRGs) in LUAD and develop a valid prognostic model based on SRGs. The most significant genes for sphingolipid metabolism (SM) were identified using the AUCell and WGCNA algorithms in conjunction with single-cell and bulk RNA-seq. LASSO and COX regression analysis was used to develop risk models, and patients were divided into high-and low-risk categories. External nine provided cohorts evaluated the correctness of the models. Differences in immune infiltration, mutation landscape, pathway enrichment, immune checkpoint expression, and immunotherapy were also further investigated in distinct subgroups. Finally, cell function assay was used to verify the role of CACYBP in LUAD cells. A total of 334 genes were selected as being most linked with SM activity for further investigation, and a risk model consisting of 11 genes was established using lasso and cox regression. According to the median risk value, patients were split into high- and low-risk groups, and the high-risk group had a worse prognosis. The low-risk group had more immune cell infiltration and higher expression of immune checkpoints, which illustrated that the low-risk group was more likely to benefit from immunotherapy. It was verified that CACYBP could increase the ability of LUAD cells to proliferate, invade, and migrate. The eleven-gene signature identified in this research may help physicians create individualized care plans for LUAD patients. CACYBP may be a new therapeutic target for patients with advanced LUAD.

Association of

Germline Patients enrolled in a prospective natural history study of hereditary gastric cancer who underwent at least one colonoscopy were evaluated. Out of 300 patients with In summary, a majority of

Optimized Radiomics Nomogram Based on Automated Breast Ultrasound System A Potential Tool for Preoperative Prediction of Metastatic Lymph Node Burden in Breast Cancer.

Axillary lymph node dissection (ALND) can be safely avoided in women with T1 or T2 primary invasive breast cancer (BC) and one to two metastatic sentinel lymph nodes (SLNs). However, cancellation of ALND based solely on SLN biopsy (SLNB) may lead to adverse outcomes. Therefore, preoperative assessment of LN tumor burden becomes a new focus for ALN status. This study aimed to develop and validate a nomogram incorporating the radiomics score (rad-score) based on automated breast ultrasound system (ABUS) and other clinicopathological features for evaluating the ALN status in patients with early-stage BC preoperatively. Totally 354 and 163 patients constituted the training and validation cohorts. They were divided into ALN low burden (<3 metastatic LNs) and high burden (≥3 metastatic LNs) based on the histopathological diagnosis. The radiomics features of the segmented breast tumor in ABUS images were extracted and selected to generate the rad-score of each patient. These rad-scores, along with the ALN burden predictors identified from the clinicopathologic characteristics, were included in the multivariate analysis to establish a nomogram. It was further evaluated in the training and validation cohorts. High ALN burdens accounted for 11.2% and 10.8% in the training and validation cohorts. The rad-score for each patient was developed based on 7 radiomics features extracted from the ABUS images. The radiomics nomogram was built with the rad-score, tumor size, US-reported LN status, and ABUS retraction phenomenon. It achieved better predictive efficacy than the nomogram without the rad-score and exhibited favorable discrimination, calibration and clinical utility in both cohorts. We developed an ABUS-based radiomics nomogram for the preoperative prediction of ALN burden in BC patients. It would be utilized for the identification of patients with low ALN burden if further validated, which contributed to appropriate axillary treatment and might avoid unnecessary ALND.

Correlation between the Warburg effect and progression of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is ineligible for hormonal therapy and Her-2-targeted therapy due to the negative expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2. Although targeted therapy and immunotherapy have been shown to attenuate the aggressiveness of TNBC partially, few patients have benefited from them. The conventional treatment for TNBC remains chemotherapy. Chemoresistance, however, impedes therapeutic progress over time, and chemotherapy toxicity increases the burden of cancer on patients. Therefore, introducing more advantageous TNBC treatment options is a necessity. Metabolic reprogramming centered on glucose metabolism is considered a hallmark of tumors. It is described as tumor cells tend to convert glucose to lactate even under normoxic conditions, a phenomenon known as the Warburg effect. Similar to Darwinian evolution, its emergence is attributed to the selective pressures formed by the hypoxic microenvironment of pre-malignant lesions. Of note, the Warburg effect does not disappear with changes in the microenvironment after the formation of malignant tumor phenotypes. Instead, it forms a constitutive expression mediated by mutations or epigenetic modifications, providing a robust selective survival advantage for primary and metastatic lesions. Expanding evidence has demonstrated that the Warburg effect mediates multiple invasive behaviors in TNBC, including proliferation, metastasis, recurrence, immune escape, and multidrug resistance. Moreover, the Warburg effect-targeted therapy has been testified to be feasible in inhibiting TNBC progression. However, not all TNBCs are sensitive to glycolysis inhibitors because TNBC cells flexibly switch their metabolic patterns to cope with different survival pressures, namely metabolic plasticity. Between the Warburg effect-targeted medicines and the actual curative effect, metabolic plasticity creates a divide that must be continuously researched and bridged.

Libyan cancer patients at King Hussein Cancer Center for more than a decade, the current situation, and a future vision.

Since 2011, the Libyan civil war crisis had affected all dimensions of livelihood including cancer care. This has resulted in a steady incline in the number of Libyan patients with cancer seeking oncologic care and management in Tunisia, Egypt and Jordan, among others. King Hussein Cancer Center (KHCC) has been one of the main destinations for Libyan patients with cancer for more than a decade. We are reporting on the characteristics of Libyan patients with cancer presenting to KHCC during the past fourteen years. We performed a retrospective chart review of all Libyan patients with cancer presenting to KHCC between 2006 and 2019. A total of 3170 records were included in the final analysis. The overall sample was predominantly adults (71%) with a male-to-female ratio of 11.2. Overall, the most common referred cancers to KHCC were breast (21%), hematolymphoid (HL) (17%), and gastrointestinal tract (GIT) (16.2%) cancers. Breast cancer was the most common among adult females (41.7%), GIT among adult males (23.6%), and HL among pediatrics (38.5%). Around 37.8% of patients presented with distant metastasis at their first encounter at KHCC, among which 14.7% were candidates for palliative care. The sustenance of treatment for Libyan patients with cancer requires extensive collaboration between governmental and private sectors. The Libyan oncological landscape could benefit from national screening and awareness programs, twining programs and telemedicine, introduction of multidisciplinary boards, and the formulation of a national cancer registry. Adopting the successful models at KHCC can help to augment the oncology services within the Libyan healthcare sector.

Bibliometric analysis of global research on physical activity and sedentary behavior in the context of cancer.

Numerous studies focusing on sedentary behavior (SB) and physical activity (PA) in the context of cancer have been reported in recent years. We analyzed and visualized studies on SB and PA in patients with cancer over the last 20 years using scientometric methods, to provide insights on gaps and deficiencies in the literature, and to inform future research guidelines. All relevant studies in the field from 2001 to October 2022 were reviewed using bibliometric tools, including VOSviewer, Bibliometric online analysis platform, and biblioshiny, to determine the most influential countries, institutions, journals, and authors. We explored current research hotpots and potential research trends, based on keyword clustering and dynamic changes. Our research focuses on PA, SB, and cancer across the entire cancer continuum, from primary prevention to treatment to cancer survivorship. Scientometric analysis identified 4,382 relevant manuscripts on SB and PA in the context of cancer, with a 10-fold increase in articles over the past 20 years. The United States, Canada, and Australia were the most influential countries. The journal, By using bibliometrics, we conducted a comprehensive review of SB and PA in cancer-related studies. The current research focused on exercise and sedentariness in breast cancer patients and the role of PA in improving quality of life in survivorship. Emerging research foci were generally around cancer prehabilitation programs and remote intervention issues for PA. In addition, some publication deficits are noted studies of PA and SB in less common cancers the recommended doses and intensities of exercise for cancer the timing of interventions for prehabilitation and the establishment of individualized exercise protocols. These deficiencies align with the needs for future research topics.

A nomogram based on combining clinical features and contrast enhanced ultrasound is not able to identify Her-2 over-expressing cancer from other breast cancers.

The aim of this study was to evaluate whether a predictive model based on a contrast enhanced ultrasound (CEUS)-based nomogram and clinical features (Clin) could differentiate Her-2-overexpressing breast cancers from other breast cancers. A total of 152 pathology-proven breast cancers including 55 Her-2-overexpressing cancers and 97 other cancers from two units that underwent preoperative CEUS examination, were included and divided into training (n 102) and validation cohorts (n 50). Multivariate regression analysis was utilized to identify independent indicators for developing predictive nomogram models. The area under the receiver operating characteristic (AUC) curve was also calculated to establish the diagnostic performance of different predictive models. The corresponding sensitivities and specificities of different models at the cutoff nomogram value were compared. In the training cohort, 7 clinical features (menstruation, larger tumor size, higher CA153 level, BMI, diastolic pressure, heart rate and outer upper quarter (OUQ)) enlargement in CEUS with The main finding of the study was that the predictive model based on a CEUS-based nomogram and clinical features could not differentiate Her-2-overexpressing breast cancers from other breast cancers.

Ovarian Real-World International Consortium (ORWIC) A multicentre, real-world analysis of epithelial ovarian cancer treatment and outcomes.

Much drug development and published analysis for epithelial ovarian cancer (EOC) focuses on early-line treatment. Full sequences of treatment from diagnosis to death and the impact of later lines of therapy are rarely studied. We describe the establishment of an international network of cancer centers configured to compare real-world treatment pathways in UK, Portugal, Germany, South Korea, France and Romania (the Ovarian Real-World International Consortium ORWIC). 3344 patients diagnosed with EOC (2012-2018) were analysed using a common data model and hub and spoke programming approach applied to existing electronic medical records. Consistent definition of line of therapy between sites and an efficient approach to analysis within the limitations of local information governance was achieved. Median age of participants was 53-67 years old and 5-29% were ECOG >1. Between 62% and 84% of patients were diagnosed with late-stage disease (FIGO III-IV). Sites treating younger and fitter patients had higher rates of debulking surgery for those diagnosed at late stage than sites with older, more frail patients. At least 21% of patients treated with systemic anti-cancer therapy (SACT) had recurrent disease following second-line therapy (2L) up to 11 lines of SACT treatment were recorded for some patients. Platinum-based SACT was consistently used across sites at 1L, but choices at 2L varied, with hormone therapies commonly used in the UK and Portugal. The use (and type) of maintenance therapy following 1L also varied. Beyond 2L, there was little consensus between sites on treatment choice trial compounds and unspecified combinations of other agents were common. Specific treatment sequences are reported up to 4L and the establishment of this network facilitates future analysis of comparative outcomes per line of treatment with the aim of optimizing available options for patients with recurrent EOC. In particular, this real-world network can be used to assess the growing use of PARP inhibitors. The real-world optimization of advanced line treatment will be especially important for patients not usually eligible for involvement with clinical trials. The resources to enable this analysis to be implemented elsewhere are supplied and the network will seek to grow in coverage of further sites.

Cancer beliefs and screening behaviors The impact of neighborhood and other social determinants of health.

Beliefs about cancer influence breast and colorectal cancer (CRC) screening behavior. Screening rates for these cancers differ in the contiguous neighborhoods of East Harlem (EH), Central Harlem (CH), and the Upper East Side (UES), which have distinct socio-demographic compositions. We assessed the belief-screening behavior relationship in these neighborhoods. The 2019 Community Cancer Needs Survey included adults eligible for breast andor colorectal cancer screening. Raking was used to generate neighborhood-specific distribution estimates. Categorical variables were compared using Chi-square tests. Stepwise logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between cancer beliefs and screening. Our weighted sample included 147,726 respondents. Screening was 75% in CH, 81% in EH, and 90% in the UES for breast cancer, and 71%, 76%, and 92% for CRC, respectively. The fatalistic belief Cancer beliefs were inconsistently associated with breast and CRC screening across three NYC neighborhoods. This suggests that a given belief may either motivate or deter screening, depending upon context or interpretation. Once access is addressed, efforts seeking to enhance screening rates should consider implications of communities varying beliefs.

Prognostic value of alkaline phosphatase and bone-specific alkaline phosphatase in breast cancer A systematic review and meta-analysis.

Numerous studies have reported the clinical value of alkaline phosphatase (ALP) and its bone-specific isoforms (bone-specific alkaline phosphatase (BAP)) in breast cancer. The purpose of this meta-analysis was to summarize the prognostic value of serum ALP and BAP in breast cancer, especially focused on bone metastasis and survival. PRISMA guidelines were followed to conduct this review. Observational studies were searched in PubMed, Cochcrane Library and EMBASE to January 1, 2022. Data were extracted to explore the prognostic value of ALP and BAP. The quality of the included studies was assessed and the outcome effects were evaluated. Subgroup and sensitivity analyses were performed to explore the potential sources of heterogeneity. Publication bias was assessed. There was a total of 53 studies with 22,436 patients included. For the primary outcome of survival, high levels of both ALP and BAP were associated with short survival time. The hazard ratio of high ALP level on overall survival was 1.72 (95% CI 1.37, 2.16,

Goji berry (Lycium barbarum) inhibits the proliferation, adhesion, and migration of oral cancer cells by inhibiting the ERK, AKT, and CyclinD cell signaling pathways an in-vitro study.

Womens Metaphors About BRCA Gene Testing and How They Can Inform Health Communication Theory and Practice.

Genetic testing can detect whether an individual carries a harmful variant in the

Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering †.

Nimesulide is a nonsteroidal anti-inflammatory drug and a COX-2 inhibitor with antitumor and antiproliferative activities that induces apoptosis in oral, esophagus, breast, and pancreatic cancer cells. Despite being removed from the market due to hepatotoxicity, nimesulide is still an important research tool being used to develop new anticancer drugs. Multiple studies have been done to modify the nimesulide skeleton to develop more potent anticancer agents and related compounds are promising scaffolds for future development. As such, establishing a mechanism of action for nimesulide remains an important part of realizing its potential. Here, we show that nimesulide enhances TRAIL-induced apoptosis in resistant pancreatic cancer cells by promoting clustering of DR5 in the plasma membrane. In this way, nimesulide acts like a related compound, DuP-697, which sensitizes TRAIL-resistant colon cancer cells in a similar manner. Our approach applies a time-resolved FRET-based biosensor that monitors DR5 clustering and conformational states in the plasma membrane. We show that this tool can be used for future high-throughput screens to identify novel, nontoxic small molecule scaffolds to overcome TRAIL resistance in cancer cells.

Molecular dynamics simulations reveal the effect of mutations in the RING domains of BRCA1-BARD1 complex and its relevance to the prognosis of breast cancer.

The N-terminal RING-RING domain of BRCA1-BARD1 is an E3 ubiquitin ligase complex that plays a critical role in tumor suppression through DNA double stranded repair mechanism. Mutations in the BRCA1-BARD1 heterodimer RING domains were found to have an association with breast and ovarian cancer by a way of hampering the E3 ubiquitin ligase activity. Herein, the molecular mechanism of interaction, conformational change due to the specific mutations on the BRCA1-BARD1 complex at atomic level has been examined by employing molecular modeling techniques. Sixteen mutations have been selected for the study. Molecular dynamics simulation results reveal that the mutant complexes have more local perturbation with a high residual fluctuation in the zinc binding sites and central helix. A few of the BRCA1 (V11A, I21V, I42V, R71G, I31M and L51W) mutants have been experimentally identified that do not impair E3 ligase activity, display an enhanced number of H-bonds and non-bonded contacts at the interacting interface as revealed by MD simulation. The mutation of BRCA1 (C61G, C64Y, C39Y and C24R) and BARD1 (C53W, C71Y and C83R) zinc binding residues displayed a smaller number of significant H-bonds, other interactions and also loss of some of the hotspot residues. Additionally, most of the mutant complexes display relatively lower electrostatic energy, H-bonding and total stabilizing energy as compared to wild-type. The current study attempts to unravel the role of BRCA1-BARD1 mutations and delineates the structural and conformational dynamics in the progression of breast cancer.Communicated by Ramaswamy H. Sarma.

Discovery of novel VEGFR2-TK inhibitors by phthalimide pharmacophore based virtual screening, molecular docking, MD simulation and DFT.

Currently, numerous potent chemotherapeutic agents are available in the market but most of them show poor pharmacokinetics, lethal effects and drug resistance during their enduring use. The increased cancer cases, deaths and need of better treatment stimulates us to give newer lifesaving anticancer drugs. The phthalimide derivatives are structurally diverse and exert potential anticancer activity. In this regard, the 3D QSAR Pharmacophore model was developed and validated using fifty-eight phthalimide derivatives. The validation parameters corroborated the reliability and statistical robustness of CEASER Hypo 1. Three databases-NCI Open, Drug Bank, and Asinex were submitted to ADMET and drug-like filtering 117893 drug-like compounds were mapped on CEASER Hypo 1 and 362 hits with IC

The synergistic effect of physical activity and nutrition to improve the quality of life in breast cancer patients a systemic review.

Medical recommendations for balanced control of exercise, physical activity, and nutritional intake after breast cancer diagnosis remain unclear. Therefore, this review aims to summarize effective exercise methods and dietary opinions by reviewing clinical trial results. We systematically reviewed studies that evaluated 1) the relationship between exercise methods and quality of life improvement in patients with breast cancer and 2) the recommendations for physical activity, exercise, nutrition, and potential ways to improve life after breast cancer. To conduct this literature review, we searched the PubMed database for articles published until October 1, 2022, using the terms physical activity OR exercise, breast cancer, and nutrition. After a primary review of the retrieved articles, we included clinical trials in this systematic review. We hypothesized that physical activity improves the quality of life after the onset of breast cancer, suggesting that a balanced approach to aerobic exercise and resistance exercise increases the efficacy of anticancer treatment. From a nutritional point of view, it is recommended that both physical activity and diet management are necessary for patients with breast cancer. Customized exercise and diet can help with weight loss, the reduction of cancer-induced fatigue, the regulation of hormonal changes, the reduction of inflammatory factors, and the improvement of mental health and vitality. Understanding the integrated mechanisms of physical activity and nutritional balance will improve the quality of life of patients with breast cancer. Therefore, it is necessary to continuously advance exercise programs and develop an alimentary balance control program.

Hedgehog blockade remodels the gut microbiota and the intestinal effector CD8

Given the gut microbiomes rise as a potential frontier in cancer pathogenesis and therapy, leveraging microbial analyses in the study of breast tumor progression and treatment could unveil novel interactions between commensal bacteria and disease outcomes. In breast cancer, the Hedgehog (Hh) signaling pathway is a potential target for treatment due to its aberrant activation leading to poorer prognoses and drug resistance. There are limited studies that have investigated the influences of orally administered cancer therapeutics, such as Vismodegib (a pharmacological, clinically used Hh inhibitor) on the gut microbiota. Using a 4T1 mammary carcinoma mouse model and 16 S rRNA sequencing, we longitudinally mapped alterations in immunomodulating gut microbes during mammary tumor development. Next, we identified changes in the abundance of commensal microbiota in response to Vismodegib treatment of 4T1 mammary tumor-bearing mice. In addition to remodeling gut microbiota, Vismodegib treatment elicited an increase in proliferative CD8

Quantitative assessment of Siglec-15 expression in lung, breast, head, and neck squamous cell carcinoma and bladder cancer.

Immune checkpoint blockade with programmed cell death (PD-1)programmed death-ligand 1 (PD-L1) inhibitors has resulted in significant progress in the treatment of various cancer types. However, not all patients respond to PD-1PD-L1 blockade, underscoring the importance of identifying new potential targets for immunotherapy. One promising target is the immune system modulator Siglec-15. In this study, we assess Siglec-15 expression in solid tumors, with a focus on lung, breast, head and neck squamous and bladder cancers. Using quantitative immunofluorescence (QIF) with a previously validated antibody, we found increased Siglec-15 expression in both tumor and immune cells in all the four cancer types. Siglec-15 was seen to be predominantly expressed by the stromal immune cells (83% in lung, 70.1% in breast, 95.2% in head and neck squamous cell and 89% in bladder cancers). Considerable intra-tumoral heterogeneity was noted across cancer types. As previously described for non-small cell lung cancer (NSCLC), Siglec-15 expression was seen to be mutually exclusive to PD-L1 in all the four cancer types, although this differential expression was maintained but somewhat diminished in head and neck squamous cell carcinoma (HNSCC). Siglec-15 was not prognostic either for overall survival (OS) or progression-free survival (PFS). In summary, we show broad expression of this potential immune modulatory target in a wide range of cancer types. These data suggest potential future clinical trials in these tumor types.

Quantitative measurement of HER2 expression to subclassify ERBB2 unamplified breast cancer.

The efficacy of the antibody drug conjugate (ADC) Trastuzumab deruxtecan (T-DXd) in HER2 low breast cancer patients suggests that the historicalconventional assays for HER2 may need revision for optimal patient care. Specifically, the conventional assay is designed to distinguish amplified HER2 from unamplified cases but is not sensitive enough to stratify the lower ranges of HER2 expression. Here we determine the optimal dynamic range for unamplified HER2 detection in breast cancer and then redesign an assay to increase the resolution of the assay to stratify HER2 expression in unamplified cases. We used the AQUA™ method of quantitative immunofluorescence to test a range of antibody concentrations to maximize the sensitivity within the lower range of HER2 expression. Then, using a cell line microarray with HER2 protein measured by mass spectrometry we determined the amount of HER2 protein in units of attomolsmm

Expert consensus on the diagnosis and treatment of young breast cancer in China (2022 Edition).

Young breast cancer patients are associated with high-risk clinicopathological features and poor prognosis, leading to unique medical and psychosocial needs and calling for special attention in clinical practice. In recent years, the incidence of young breast cancer has gradually increased worldwide, and several international committees have formed some consensuses on young breast cancer management. In China, there is a higher proportion of young breast cancer patients with younger age of onset and different clinical problems, lacking clear evidence-based medicine and guidelines. Based on the characteristics of young breast cancer and present situation of diagnosis and treatment in China, more than 100 experts from multiple specialities including surgery, internal medicine, radiotherapy, gynecology and reproduction had a deep discussion around the hot topics in young breast cancer, involving germline BRCA12 gene mutation, chemotherapy, endocrine therapy, fertility preservation and gynecological conditions, and formulated the Expert consensus on the diagnosis and treatment of young breast cancer in China (2022 Edition). This consensus is made according to the progress of clinical research worldwide and combined with the clinical practice in China, with the aims of standardizing and optimizing the diagnosis and treatment of young breast cancer in China, promoting the development of relevant clinical research, and further improving the prognosis and quality of life of young breast cancer patients. 年轻乳腺癌患者具有相对高危的临床病理特征和较差的预后，存在独特的医疗和心理社会需求，需要在临床上特别关注。近年来，年轻乳腺癌在全球范围内逐渐增多，已有多个国际组织针对其管理形成一定共识。中国年轻乳腺癌比例更高、发病年龄更低，面临的临床问题也有所不同，不少问题尚缺乏明确的循证医学证据和指南。基于中国年轻乳腺癌患者的特点和诊疗现状，100多位来自外科、内科、放疗科、妇科和生殖科的专家们针对BRCA12基因胚系突变、化疗、内分泌治疗、生育力保护和妇科问题等热点进行了深入探讨，以国内外临床研究进展为基础，结合中国的临床实践，形成了《中国年轻乳腺癌诊疗专家共识（2022版）》，旨在规范和优化中国年轻乳腺癌的诊疗，促进相关临床研究的开展，以进一步改善年轻乳腺癌患者的预后和生活质量。.

The World Health Organization (WHO) declared breast cancer (BC) as the most prevalent cancer in the world. With its prevalence and severity, there have been several breakthroughs in developing treatments for the disease. Targeted therapy treatments limit the damage done to healthy tissues. These targeted therapies are especially potent for luminal and HER-2 positive type breast cancer. However, for triple negative breast cancer (TNBC), the lack of defining biomarkers makes it hard to approach with targeted therapy methods. Protein-protein interactions (PPIs) have been studied as possible targets for drug action. However, small molecule drugs are not able to cover the entirety of the PPI binding interface. Peptides were found to be more suited to the large or flat PPI surfaces, in addition to their better pharmacokinetic properties. In this study, computational methods was used in order to verify whether peptide drug inhibitors are good drug candidates against the ubiquitin protein, UBE2C by conducting docking, MD and MMPBSA analyses. Results show that while the lead peptide, T20-M shows good potential as a peptide drug, its binding affinity towards UBE2C is not enough to overcome the natural UBE2C-ANAPC2 interaction. Further studies on modification of T20-M and the analysis of other peptide leads are recommended.

Silver sulfide coated alginate radioenhancer for enhanced X-ray radiation therapy of breast cancer.

A wide range of high-Z nanomaterials are fabricated to decrease radiation dose by sensitizing cells to irradiation through various mechanisms such as ROS generation enhancement. Alginate-coated silver sulfide nanoparticles (Ag

Maternal lifestyle and nutrient intakes during pregnancy and exclusive breastfeeding in relation to risk factors for breast cancer The Japan Environment and Childrens Study.

Breastfeeding has many benefits for infant growth and maternal health, such as reducing breast cancer risk. However, data on maternal factors influencing breastfeeding are insufficient. To clarify the associations between maternal lifestyle and diet during pregnancy and exclusive breastfeeding (EBF), we conducted a prospective study of pregnant women within the framework of the Japan Environment and Childrens Study (a nationwide birth cohort study). Of 97,413 pregnant women recruited between January 2011 and March 2014, 27,775 with a singleton first live birth whose dietary data during pregnancy and lactation data were complete were eligible. Using logistic regression, we evaluated the associations between lifestyle factors including smoking and prepregnancy body mass index and intake of nutrients (macronutrients, isoflavones, and dietary fiber), some of which are known risk factors of breast cancer, and EBF for one month postpartum (initiation of EBF). To investigate the associations of these factors with EBF for 6 months (continuation of EBF), 9582 women who had successfully completed one-month EBF were further followed up. Smoking and prepregnancy obesity were inversely associated with the initiation and continuation of EBF. Intakes of protein, fat, isoflavone, and dietary fiber were positively associated (p

The impact of endocrine disrupting compounds and carcinogens in wastewater Implications for breast cancer.

The incidence of breast cancer is often associated with geographic variation which indicates that a persons surrounding environment can be an important etiological factor in cancer development. Environmental risk factors can include exposure to sewage- or wastewater, which consist of a complex mixture of pathogens, mutagens and carcinogens. Wastewater contains primarily carbonaceous, nitrogenous and phosphorus compounds, however it can also contain trace amounts of chemical pollutants including toxic metal cations, hydrocarbons and pesticides. More importantly, the contamination of drinking water by wastewater is a potential source of exposure to mammary carcinogens and endocrine disrupting compounds. Organic solvents and other pollutants often found in wastewater have been detected in various tissues, including breast and adipose tissues. Furthermore, these pollutants such as phenolic compounds in some detergents and plastics, as well as parabens and pesticides can mimic estrogen. High estrogen levels are a well-established risk factor for estrogen-receptor (ER) positive breast cancer. Therefore, exposure to wastewater is a risk factor for the initiation, progression and metastasis of breast cancer. Carcinogens present in wastewater can promote tumourigenesis through various mechanisms, including the formation of DNA adducts, gene mutations and oxidative stress. Lastly, the presence of endocrine disrupting compounds in wastewater can have negative implications for ER-positive breast cancers, where these molecules can activate ERα to promote cell proliferation, survival and metastasis. As such, strategies should be implemented to limit exposure, such as providing funding into treatment technologies and implementation of regulations that limit the production and use of these potentially harmful chemicals.

Capsaicin-loaded alginate nanoparticles embedded polycaprolactone-chitosan nanofibers as a controlled drug delivery nanoplatform for anticancer activity.

Nanocarrier-based drug delivery systems have been designed into various structures that can effectively prevent cancer progression and improve the therapeutic cancer index. However, most of these delivery systems are designed to be simple nanostructures with several limitations, including low stability and burst drug release features. A nano-in-nano delivery technique is explored to address the aforementioned concerns. Accordingly, this study investigated the release behavior of a novel nanoparticles-in-nanofibers delivery system composed of capsaicin-loaded alginate nanoparticles embedded in polycaprolactone-chitosan nanofiber mats. First, alginate nanoparticles were prepared with different concentrations of cationic gemini surfactant and using nanoemulsion templates. The optimized formulation of alginate nanoparticles was utilized for loading capsaicin and exhibited a diameter of 19.42 ± 1.8 nm and encapsulation efficiency of 98.7 % ± 0.6 %. Likewise, blend polycaprolactone-chitosan nanofibers were prepared with different blend ratios of their solutions (i.e., 1000, 8020, 6040) by electrospinning method. After the characterization of electrospun mats, the optimal nanofibers were employed for embedding capsaicin-loaded alginate nanoparticles. Our findings revealed that embedding capsaicin-loaded alginate nanoparticles in polycaprolactone-chitosan nanofibers, prolonged capsaicin release from 120 h to more than 500 h. Furthermore, the results of in vitro analysis demonstrated that the designed nanoplatform could effectively inhibit the proliferation of MCF-7 human breast cells while being nontoxic to human dermal fibroblasts (HDF). Collectively, the prepared nanocomposite drug delivery platform might be promising for the long-term and controlled release of capsaicin for the prevention and treatment of cancer.

A review on the role of LINC00173 in human cancers.

Long intergenic non-protein coding RNA 173 (LINC00173) is a long non-coding RNA with especial function in the tumorigenic process. Studies in different types of cancers support an oncogenic role for LINC00173 except for studies in B-cell precursor acute lymphoblastic leukemia, cervical cancer, pancreatic cancer and gastric cancer. In breast and lung cancers, both oncogenic and tumor suppressor roles have been reported for LINC00173. LINC00173 can serve as a molecular sponge for miRNAs. miR-218Etk, miR-511-5pVEGFA, miR-182-5pAGER, miR-765NUTF2, miR-765PLP2, miR-182-5pFBXW7, miR-338-3pRab25, miR‑641RAB14 and miR-1275BCL2 are examples of the miRNAmRNA axes being regulated by LINC00173 in the context of cancer. The current review provides a summary of different studies on the role of LINC00173 in these cancers.

Early breast cancer in women aged 35 years or younger A large national multicenter French population-based case control-matched analysis.

There is a scarcity of data exploring early breast cancer (eBC) in very young patients. We assessed shared and intrinsic prognostic factors in a large cohort of patients aged ≤35, compared to a control group aged 36 to 50. Patients ≤50 were retrospectively identified from a multicentric cohort of 23,134 eBC patients who underwent primary surgery between 1990 and 2014. Multivariate Cox analyses for DFS and OS were built. To assess the independent impact of age, 1 to 3 case-control analysis was performed by matching ≤35 and 36-50 years patients. Of 6481 patients, 556 were aged ≤35, and 5925 from 36 to 50. Age ≤35 was associated with larger tumors, higher grade, ER-negativity, macroscopic lymph node involvement (pN macro), lymphovascular invasion (LVI), mastectomy, and chemotherapy (CT) use. In multivariate analysis, age ≤35 was associated with worse DFS HR 1.56, 95% CI 1.32-1.84 p < 0.001, and OS HR 1.29, 95% CI 1.03-1.60 p 0.025, as were high grade, large tumor, LVI, pN macro, ER-negativity, period of diagnostic, and absence of ET or CT (for DFS). Adverse prognostic impact of age ≤35 was maintained in the case control-matched analysis for DFS HR 1.56, 95%CI 1.28-1.91, p < 0.001, and OS HR 1.33, 95%CI 1.02-1.73, p 0.032. When only considering patients ≤35, ER, tumor size, nodal status, and LVI were independently associated with survival in this subgroup. Age ≤35 is associated with less favorable presentation and more aggressive treatment strategies. Our results support the poor prognosis value of young age, which independently persisted when adjusting for other prognostic factors and treatments.

Design, synthesis, and discovery of Eudistomin Y derivatives as lysosome-targeted antiproliferation agents.

Eudistomin Y is a novel class of β-carbolines of marine origin with potential antiproliferation activity against MDA-MB-231 cells (triple-negative breast carcinoma). However, the subcellular target or the detailed mechanism against cancer cell proliferation has not yet been identified. In this study, based on its special structure, a novel series of Eudistomin Y fluorescent derivatives were designed and synthesized by enhancing the electron-donor effect of N-9 to endow it with fluorescent properties through N-alkylation. The structure-activity relationships against the proliferation of cancer cells were also analyzed. A quarter of Eudistomin Y derivatives showed much higher potency against cancer cell proliferation than the original Eudistomin Y

Concordance of cancer drug therapy information derived from routinely collected hospital admissions data and the Systemic Anti-Cancer Therapy (SACT) dataset, for older women diagnosed with early invasive breast cancer in England.

Evaluating uptake of oncological treatments, and subsequent outcomes, depends on data sources containing accurate and complete information about cancer drug therapy (CDT). This study aimed to evaluate the consistency of CDT information in the Hospital Episode Statistics Admitted Patient Care (HES-APC) and Systemic Anti-Cancer Therapy (SACT) datasets for early invasive breast cancer (EIBC). The study included women (50 years) diagnosed with EIBC in England from 2014 to 2019 who had surgery within six months of diagnosis. Concordance of CDT recorded in HES-APC (identified using OPCS codes) and SACT was evaluated at both patient-level and cycle-level. Factors associated with CDT use captured only in HES-APC were assessed using statistical models. The cohort contained 129,326 women with EIBC. Overall concordance between SACT and HES-APC on CDT use was 94 %. Concordance increased over the study period (91-96 %), and there was wide variation across NHS trusts (lowest decile of trusts had concordance≤77 % highest decile≥99 %). Among women receiving CDT, 9 % (n 278131693) of use was not captured in SACT incompleteness was worst (18 %47259) among women aged 80 and those diagnosed in 2014 (21%11215401). OPCS codes in HES-APC were good at identifying patient-level and cycle-level use of trastuzumab or FEC chemotherapy (fluorouracil, epirubicin, cyclophosphamide), with 89 % and 93 % concordance with SACT respectively (patient-level agreement). Among cycles of solely oral CDT recorded in SACT, only 24 % were captured in HES-APC, compared to 71 % for intravenoussubcutaneous CDT. Combining information in HES-APC and SACT provides a more complete picture of CDT treatment in women aged 50 receiving surgery for EIBC than using either data source alone. HES-APC may have particular value in identifying CDT use among older women, those diagnosed less recently, and in NHS trusts with low SACT data returns.

Psychological distress and decision-making factors for prophylactic bilateral mastectomy in cancer-unaffected BRCA12 pathogenic variant carriers.

Women carrying a BRCA12 pathogenic variant have increased risk for breast cancer and may opt for risk-reducing bilateral mastectomy. In this study, we examine which demographic, psychosocial, and personality factors are associated with their decision to undergo risk-reducing bilateral mastectomy. Cancer-unaffected women with a pathogenic variant in BRCA1 or BRCA2 were recruited before receiving their genetic test result and completed follow-up including decision to undergo mastectomy over 6-8 months after genetic test result disclosure. Anxiety, depression, breast cancer worry, personality and sociodemographic data were assessed. A total of 125 cancer-unaffected women were included in the analysis. Participants were found to have higher anxiety levels than the general female population regardless of mastectomy decision. Breast cancer worry was higher among women who opted for risk-reducing mastectomy and did not decrease over time. By contrast, women who did not opt for surgery experienced decreasing levels of breast cancer worry. Regression analysis found that women with a pathogenic variant in BRCA1, younger women and women with higher breast cancer worry were more likely to opt for surgery. Our study provides valuable insights into the factors that influence women with a BRCA12 pathogenic variant to undergo risk-reducing mastectomy. These findings may be helpful in understanding individual differences in decision-making concerning preventive options and show the need to address negative anticipatory feelings associated with carrying a pathogenic variant in a high breast cancer risk gene in clinical care. This article is protected by copyright. All rights reserved.

Design, Synthesis, and Biological Evaluation of a Potent Dual EZH2-BRD4 Inhibitor for the Treatment of Some Solid Tumors.

Enhancer of zeste homolog 2 (EZH2) mediates the trimethylation of histone 3 lysine 27 (H3K27) to promote gene silencing. Inhibition of EZH2 is a viable strategy for cancer treatment however, only a small subset of hematological malignancies are sensitive to small-molecule EZH2 inhibitors. EZH2 inhibitors cause H3K27 acetylation in most solid tumors, leading to drug resistance. Bromodomain-containing protein 4 (BRD4) inhibitors were reported to enhance the sensitivity of solid tumors to EZH2 inhibitors. Thus, we designed and evaluated a series of dual EZH2-BRD4 inhibitors. ZLD-2, the most promising compound, exhibited potent inhibitory activity against EZH2 and BRD4. Compared to the EZH2 inhibitor GSK126, ZLD-2 displayed potent antiproliferation activity against breast, lung, bladder, and pancreatic cancer cells. In vivo, ZLD-2 exhibited antitumor activity in a BxPC-3 mouse xenograft model, whereas GSK126 promoted tumor growth. Thus, ZLD-2 may be a lead compound for treating solid tumors.

Psychological impact of risk-stratified screening as part of the NHS Breast Screening Programme multi-site non-randomised comparison of BC-Predict versus usual screening (NCT04359420).

Adding risk stratification to standard screening via the NHS Breast Screening Programme (NHSBSP) allows women at higher risk to be offered additional prevention and screening options. It may, however, introduce new harms such as increasing cancer worry. The present study aimed to assess whether there were differences in self-reported harms and benefits between women offered risk stratification (BC-Predict) compared to women offered standard NHSBSP, controlling for baseline values. As part of the larger PROCAS2 study (NCT04359420), 5901 women were offered standard NHSBSP or BC-Predict at the invitation to NHSBSP. Women who took up BC-Predict received 10-year risk estimates high (≥8%), above average (moderate) (5-7.99%), average (2-4.99%) or below average (low) (<2%) risk. A subset of 662 women completed questionnaires at baseline and at 3 months (n 511) and 6 months (n 473). State anxiety and cancer worry scores were low with no differences between women offered BC-Predict or NHSBSP. Women offered BC-Predict and informed of being at higher risk reported higher risk perceptions and cancer worry than other women, but without reaching clinical levels. Concerns that risk-stratified screening will produce harm due to increases in general anxiety or cancer worry are unfounded, even for women informed that they are at high risk.

Targeting the E3 ligase NEDD4 as a novel therapeutic strategy for IGF1 signal pathway-driven gastric cancer.

The IGF1 signal pathway is highly activated in some subtype of gastric cancer(GC) that exhibits poor survival and chemotherapy resistance. Although the results of clinical trials of anti-IGF1R monoclonal antibodies and IGF-1R inhibitors have been mostly disappointing in unselected cancer patients, some patients benefit from anti-IGF1R therapy in these failed studies. Therefore, it is necessary to characterize the complex IGF signaling in GC and help refine the strategies targeting the IGF1 pathway. We found that GC cell lines exhibit differential responses to the specific IGF1R inhibitor OSI906. According to the phosphorylation status of Akt upon the OSI906 treatment, we divided the GC cell lines into IGF1R-dependent and IGF1R-independent cells. Both in vitro and in vivo experiments indicate that Dox-induced knockdown of NEDD4 significantly suppresses tumor growth of IGF1R-dependent GC cells and NEDD4 overexpression promotes tumor growth of IGF1R-dependent GC cells. In contrast, the proliferation of IGF1R-independent GC cells is not affected by NEDD4 silencing and overexpression. The rescue experiments show that a PTEN-IRS1 axis is required for NEDD4-mediated regulation of Akt activation and tumor growth in GC cells. Clinically, NEDD4 is expressed higher in IGF1-high GC tissues compared with IGF1-low GC tissues and normal tissues, and the co-high expression of NEDD4 and IGF1 predicts a worse prognosis in GC patients. Taken together, our study demonstrated that NEDD4 specifically promotes proliferation of GC cells dependent on IGF1IGF1R signaling by antagonizing the protein phosphatase activity of PTEN to IRS1, and targeting NEDD4 may be a promising therapeutic strategy for IGF1 signal pathway-driven gastric cancer.

Epigenetic alterations impede epithelial-mesenchymal transition by modulating centrosome amplification and MycRAS axis in triple negative breast cancer cells.

Alterations in centrosome proteins may result in centrosome abnormalities such as disorganized spindles and centrosome amplification, leading to aneuploidy and genomic instability. Centrosomes exhibit unique epigenetic properties in which structural or positional information is propagated through somatic lineage by non-genetic pathways. Excessive centrosome amplification in breast cancer is accompanied by efficient clustering and loss of E-cadherin, indicating an important adaptive mechanism of cancer. This study sought to elucidate the effect of epigenetic alterations on centrosome amplification, epithelial-mesenchymal transition (EMT) and apoptosis in triple negative human breast adenocarcinoma derived MDA-MB-231 cell line. The results obtained here show that siRNA mediated silencing of DNMT1 and specific inhibition of HDAC1 HDAC2 by Tricostatin A (TSA) synergistically inhibit cell proliferation through modulation of centrosome proteins γ-tubulin, TUBGCP2 and pericentrin. In addition, induction of apoptosis was observed by downregulation of Bcl2, upregulation of Bax and activation of PARP cleavage. Inhibition of EMT was confirmed through upregulation of E-cadherin and downregulation of N-cadherin and vimentin. Similarly, downregulation of Myc, RAS and CDK2, which plays important roles in proliferation and survival, was observed. Nuclear protein analysis revealed downregulation in the nuclear translocation of E2F1, which regulates centrosome amplification and metastasis in breast cancer. In conclusion, this study confirmed the role of epigenetic regulators in centrosome amplification and suggests that inhibition of DNA methylation and histone deacetylation-mediated chromatin remodelling synergistically disrupt EMT through modulation of centrosome amplification and MycRAS axis to potentiate apoptosis and attenuate cell proliferation in triple negative breast cancer cells.

Virtual elastography ultrasound via generative adversarial network for breast cancer diagnosis.

Elastography ultrasound (EUS) imaging is a vital ultrasound imaging modality. The current use of EUS faces many challenges, such as vulnerability to subjective manipulation, echo signal attenuation, and unknown risks of elastic pressure in certain delicate tissues. The hardware requirement of EUS also hinders the trend of miniaturization of ultrasound equipment. Here we show a cost-efficient solution by designing a deep neural network to synthesize virtual EUS (V-EUS) from conventional B-mode images. A total of 4580 breast tumor cases were collected from 15 medical centers, including a main cohort with 2501 cases for model establishment, an external dataset with 1730 cases and a portable dataset with 349 cases for testing. In the task of differentiating benign and malignant breast tumors, there is no significant difference between V-EUS and real EUS on high-end ultrasound, while the diagnostic performance of pocket-sized ultrasound can be improved by about 5% after V-EUS is equipped.

DNMT3a-dermatopontin axis suppresses breast cancer malignancy via inactivating YAP.

Breast cancer (BC) is the most common malignant tumor in women worldwide, and its recurrence and metastasis negatively affect patient prognosis. However, the mechanisms underlying its tumorigenesis and progression remain unclear. Recently, the influence of dermatopontin (DPT), which is an extracellular matrix protein, has been proposed in the development of cancer. Here we found that DNMT3a-mediated DPT, promoter hypermethylation results in the downregulation of DPT expression in breast cancer and its low expression correlated with poor prognosis. Notably, DPT directly interacted with YAP to promote YAP Ser127 phosphorylation, and restricted the translocation of endogenous YAP from the cytoplasm to the nucleus, thereby suppressing malignant phenotypes in BC cells. In addition, Ectopic YAP overexpression reversed the inhibitory effects of DPT on BC growth and metastasis. Our study showed the critical role of DPT in regulating BC progression, making it easier to explore the clinical potential of modulating DPTYAP activity in BC targeted therapies.

Racial and ethnic disparities in cervical and breast cancer screenings by nativity and length of U.S. residence.

Previous studies of disparities in breast and cervical cancer screenings have focused on broad racialethnic groups or nativity status without accounting for immigration histories. Recent theoretical work argues for using intersectional approaches and examining within-group inequalities. Utilizing multiple years of National Health Interview Survey (NHIS) data, we examined between- and within-group Papanicolaou (Pap) test and mammogram screening based on nativity and length of U.S. residence for Asian and Hispanic women, along with non-Hispanic Black and White women. The study samples consist of 54,900 women ages 21-64 without a hysterectomy who responded to questions about Pap test screening and 36,300 women ages 40-64 who responded to questions about mammogram screening. Asian and Hispanic women were further stratified by nativity and, for immigrants, length of time in the United States. Logistic regression analysis was used to identify significant associations with Pap test and mammogram screenings. Recent Asian and Hispanic immigrants had the lowest Pap test and mammogram rates among all other groups, while Black (and White women for mammograms) women had the highest rates. After accounting for age, marital status, health insurance, education, employment status, and income, both Asian groups had lower odds, and Black and all Hispanic groups had higher odds of Pap test screening compared with White women. Similar results were observed for mammogram screening, except that long-term immigrantU.S.-born Asian and U.S.-born Hispanic women did not have significantly different odds compared with White women. In general, the strength and direction of most sociodemographic variables were similar across groups for Pap test screening but differed for mammogram screening. The between-group differences identified emphasize the disparities in screening between racialethnic groups while the within-group differences suggest the need to examine whether more targeted outreach efforts and prevention messages can increase screening for specific groups.

The utilization of artificial intelligence applications to improve breast cancer detection and prognosis.

Breast imaging faces challenges with the current increase in medical imaging requests and lesions that breast screening programs can miss. Solutions to improve these challenges are being sought with the recent advancement and adoption of artificial intelligent (AI)-based applications to enhance workflow efficiency as well as patient-healthcare outcomes. rtificial intelligent tools have been proposed and used to analyze different modes of breast imaging, in most of the published studies, mainly for the detection and classification of breast lesions, breast lesion segmentation, breast density evaluation, and breast cancer risk assessment. This article reviews the background of the Conventional Computer-aided Detection system and AI, AI-based applications in breast medical imaging for the identification, segmentation, and categorization of lesions, breast density and cancer risk evaluation. In addition, the challenges, and limitations of AI-based applications in breast imaging are also discussed.

Folic-acid adorned alginate-polydopamine modified paclitaxelZn-CuO nanocomplex for pH triggered drug release and synergistic antitumor efficacy.

Targeted chemotherapy is a prominent cancer treatment research trend that intends to boost the efficacy of drug delivery to cancer cells. The present work aimed to design, a folate-decorated biologically inspired alginate-polydopamine capped zinc doped copper oxide nanoparticles (Zn-CuO) loaded with paclitaxel (Zn-CuOPTXAlgPDA-FA) as a simple, efficient, and versatile nanoplatform. Interestingly, Zn species doped in CuO frameworks significantly improved paclitaxel (PTX) molecule loading efficiency without requiring any additional functionalization and fostered the increased antitumor efficacy by precisely delivering them in tumors acidic microenvironment by obliterating the formed coordination connections between the host as well as guest species. According to DLS, average size of nanocomplex was 196 ± 5.01 nm with ȥ-potential -31.4 ± 1.54 mV. PTX encapsulation and loading efficiencies were 75.2 ± 1.54 % and 18.54 ± 2.31 %, respectively. Furthermore, nanocomplex demonstrates high stability and biocompatibility in vitro. Under an acidic environment (pH 5.0), there was greater PTX release compared to normal physiological conditions. Moreover, Zn-CuOPTXAlgPDA-FA NPs showed remarkable internalization efficiency in MCF-7 cells and demonstrated strong cytotoxicity with IC

Human Cytochrome P450 17A1 Structures with Metabolites of Prostate Cancer Drug Abiraterone Reveal Substrate-Binding Plasticity and a Second Binding Site.

Abiraterone acetate is a first-line therapy for castration-resistant prostate cancer. This prodrug is deacetylated in vivo to abiraterone, which is a potent and specific inhibitor of cytochrome P450 17A1 (CYP17A1). CYP17A1 performs two sequential steps that are required for the biosynthesis of androgens that drive prostate cancer proliferation analogous to estrogens in breast cancer. Abiraterone can be further metabolized in vivo on the steroid A ring to multiple metabolites that also inhibit CYP17A1. Despite its design as an active-site directed substrate analog, abiraterone and its metabolites demonstrate mixed competitivenoncompetitive inhibition. To understand their binding, we solved X-ray structures of CYP17A1 with three primary abiraterone metabolites. Despite different conformations of the steroid A ring and substituents, all three bound in the CYP17A1 active site with the steroid core packed against the I helix and the A ring C3 keto or hydroxyl oxygen forming a hydrogen bond with N202 similar to abiraterone itself. The structure of CYP17A1 with 3-keto, 5α-abiraterone was solved to 2.0 Å, the highest resolution to date for a CYP17A1 complex. This structure had additional electron density near the FG loop which is likely a second molecule of the inhibitor, and which may explain the noncompetitive inhibition. Mutation of the adjacent Asn52 to Tyr positions its side chain in this space, maintains enzyme activity, and prevents binding of the peripheral ligand. Collectively, our findings provide further insight into abiraterone metabolite binding and CYP17A1 function.

Cellular transformation promotes the incorporation of docosahexaenoic acid into the endolysosome-specific lipid bis(monoacylglycerol)phosphate in breast cancer.

Bis(monoacylglycero)phosphates (BMPs), a class of lipids highly enriched within endolysosomal organelles, are key components of the lysosomal intraluminal vesicles responsible for activating sphingolipid catabolic enzymes. While BMPs are understudied relative to other phospholipids, recent reports associate BMP dysregulation with a variety of pathological states including neurodegenerative diseases and lysosomal storage disorders. Since the dramatic lysosomal remodeling characteristic of cellular transformation could impact BMP abundance and function, we employed untargeted lipidomics approaches to identify and quantify BMP species in several in vitro and in vivo models of breast cancer and comparative non-transformed cells and tissues. We observed lower BMP levels within transformed cells relative to normal cells, and consistent enrichment of docosahexaenoic acid (226) fatty acyl chain-containing BMP species in both human- and mouse-derived mammary tumorigenesis models. Our functional analysis points to a working model whereby 226 BMPs serve as reactive oxygen species scavengers in tumor cells, protecting lysosomes from oxidant-induced lysosomal membrane permeabilization. Our findings suggest that breast tumor cells might divert polyunsaturated fatty acids into BMP lipids as part of an adaptive response to protect their lysosomes from elevated reactive oxygen species levels, and raise the possibility that BMP-mediated lysosomal protection is a tumor-specific vulnerability that may be exploited therapeutically.

MARCO is a potential prognostic and immunotherapy biomarker.

Macrophage receptor with collagenous structure (MARCO), a novel immune checkpoint expressed on tumor-associated macrophages, has antitumor therapeutic properties. However, the association between MARCO and patient prognosis, immune infiltration, and ICI immunotherapy needs to be studied urgently. MARCO distribution in cancer tissues was investigated using the TCGA and GTEx databases. The PrognoScan and KM Plotter databases was used to assess the MARCO prognosis. TIMER2.0, GEPIA, cBioPortal, and GSEA all confirmed the link between MARCO and immune infiltration, mutation profile, and enrichment pathway analysis. Data visualization was implemented by R language. In general, MARCO had a substantial impact on the prognosis of cancer patients and was expressed differently in cancer and adjacent normal tissues. High expression of MARCO was associated with poorer OS in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), lung squamous cell carcinoma (LUSC), colon adenocarcinoma (COAD), and prostate adenocarcinoma (PRAD). However, high expression of MARCO had a better PFI in brain lower-grade glioma (LGG) and skin cutaneous melanoma (SKCM). We discovered that MARCO expression was lowest in pancreatic adenocarcinoma (PAAD) and rectum adenocarcinoma (READ) stage 1, BLCA stage 2, LUSC and stomach adenocarcinoma (STAD) stage 3, and liver hepatocellular carcinoma (LIHC) stage 4. Subsequently, we analyzed the correlation between MARCO and 47 immune checkpoints and observed that MARCO was positively connected with CD80, CD86, and leukocyte-associated immunoglobulin-like receptor 1(LAIR1) in most cancers. In COAD, MARCO has the most microsatellite instability (MSI). In addition, we discovered that high expression of MARCO patients had a better prognosis after immune checkpoint inhibitor (ICI) treatment in SKCM. Finally, GSEA revealed a significant correlation between MARCO and TNFNFκB signaling, KRAS signaling, PI3KAKTmTOR pathway, IL-6-STAT3 signaling, TGFβ pathway, and p53 pathway. This study comprehensively investigated the relationship between MARCO and clinical prognosis, immune infiltration, and ICI immunotherapy in various cancers. We demonstrated the potential of MARCO as an emerging biomarker, exploring new avenues for future tumor immunotherapy.

Amide proton transfer (APT) imaging of breast cancers and its correlation with biological status.

To assess the usefulness of amide proton transfer (APT) imaging to predict the biological status of breast cancers. Sixty-six patients (age range 31-85 years, mean 58.9 years) with histopathologically proven invasive ductal carcinomas of 2 cm or larger in diameter were included in this study. 3D APT weighted imaging was conducted on a 3 T scanner. Mean APT signal intensity (SI) was analyzed in relation to biological subtypes, Ki-67 labeling index, and nuclear grades (NGs). The triple-negative (TN) cancers (n 10 2.75 ± 0.42%) showed significantly higher APT SI than the luminal type cancers (n 48 1.74 ± 0.83) and HER2 cancers (n 8 1.83 ± 0.21) (P 0.0007, 0.03). APT SI had weakly positive correlation with the Ki-67 labeling index (r 0.38, P 0.002). The mean APT SIs were significantly higher for high-Ki-67 (>30%) (n 31 2.25 ± 0.70) than low-Ki-67 (≤30%) cancers (n 35 1.60 ± 0.79) (P 0.0007). There was no significant difference in the APT SIs between NG 1-2 (n 31 1.71 ± 0.84) and NG 3 (n 35 2.08 ± 0.76%) cancers (P 0.06). TN and high-Ki-67 breast cancers showed high APT SIs. APT imaging can help to predict the biological status of breast cancers.

Preoperative localization of breast lesions Comparing digital breast tomosynthesis-guided radioactive seed localization versus standard 2D stereotactic radioactive seed localization.

To compare single seed digital breast tomosynthesis-guided radioseed localization (DBT-L) to standard 2D stereotactic-guided radioseed localization (SGL) of the breast. A retrospective review of a large tertiary cancer centers database yielded 68 women who underwent preoperative DBT-L from March 2019-December 2019 and a matched cohort of 65 women who underwent SGL during the same period. The electronic medical record and radiology were reviewed for patient characteristics including breast density, exam technique, pre- and post-operative pathology, exam duration, and radiation dose to the patient. To compare margin outcomes between the groups, the chi-square test of independence was used to compare continuous outcomes such as exam duration and total dose, the Wilcoxon rank sum test was used. DBT-L and SGL localization targets included biopsy marker (6268, 91% vs 5565, 85%), distortion (468, 6% vs 265, <3%), focal asymmetry (168 and 165, < 2% for both), calcifications (168, <2% vs 465, 6%), and anatomic landmarks (0% vs 365, 5%). 72% and 71% of localizations were performed for malignant pathology in the DBT-L and SGL groups, respectively. The median duration of DBT-L was 8.3 min vs 10.3 min for SGL, representing statistically significant time savings (p 0.003). The median total organ dose of DBT-L was 8.6 mGy vs 10.4 mGy for SGL, representing statistically significant dose savings (p 0.018). The incidence of positive margins at surgery was not statistically different between the groups (p 0.26). DBT-L demonstrates both time and dose savings for the patient compared to SGL without compromising surgical outcome.

Intention matters Success rate of bilateral salpingo-oophorectomy at the time of vaginal hysterectomy for pelvic organ prolapse.

The objective of this study was to determine the incidence of successful bilateral salpingo-oophorectomy at the time of vaginal hysterectomy for pelvic organ prolapse and to evaluate associated factors and success rate over time. This was a retrospective chart review of all women who underwent vaginal hysterectomy for pelvic organ prolapse who were consented for bilateral salpingo-oophorectomy if possible and including extraordinary measures between 2014 and 2019 at a tertiary medical center. Baseline demographic data along with prolapse stage, operative findings, operative time, and complications were recorded. Univariate analysis using the Pearsons chi-square test, the students t-test or Mann Whitney U test when appropriate and multivariable logistic regression was performed to determine predictors of successful vaginal bilateral salpingo-oophorectomy. A total of 453 eligible patients were included. 420 patients (92.7 %) were consented for bilateral salpingo-oophorectomy if possible and 33 patients (7.3 %) were consented for including extraordinary measures. The success rate of vaginal bilateral salpingo-oophorectomy in all patients was 57.9 % (n 262). Of the patients consented for extraordinary measures, the success rate was 93.9 % (n 31), compared to a success rate of 55 % (n 231) in the if possible group. A concurrent posterior repair was found to have higher odds of successful bilateral salpingo-oophorectomy (adjOR 1.75 95 % CI 1.17-2.61). Successful bilateral salpingo-oophorectomy extended operative time by 14 min (154 min vs 140 min, p < 0.001). Compared to patients in the unsuccessful group, the successful group had a higher proportion of the following indications a family history of ovarian cancer, personal breast cancer history or patient request for definitive removal. When the pre-operative intention to perform bilateral salpingo-oophorectomy at the time of vaginal hysterectomy for pelvic organ prolapse is high, the success rate is nearly 40% higher when compared to an opportunistic procedure. This suggests that success is closely linked to the surgeons determination to complete this procedure vaginally.

A matched case-control study of the prognosis of early breast cancer in patients with Li-Fraumeni syndrome (BREAST TP53).

Breast cancer (BC) is the most common type of cancer in premenopausal women with germline TP53 pathogenic variants (mTP53) (Li Fraumeni syndrome - LFS). However, little is known about the BC prognosis in these patients. This study analyzed the BC-related oncologic outcomes of patients with LFS. We evaluated a cohort of LFS patients with BC in comparison with a control cohort of BC patients with no pathogenic variant in a hereditary cancer panel. The primary endpoint was recurrence-free survival (RFS). Due to the risk of second malignancies in LFS, only locoregional and distant recurrences were considered events for RFS. Secondary endpoints included rates of contralateral BC, overall survival (OS), and breast cancer-specific survival (BCSS). Forty-one patients were evaluated in the mTP53 group and 82 in the control group. Median age at BC diagnosis was 40 and 41 years, respectively. The mTP53 group received less adjuvant radiotherapy than the control group (63.4% vs 93.9%, P < 0.001). Other relevant baseline characteristics and treatment received were similar between groups. 5y-RFS rates were 79.4% in the mTP53 versus 93.6% in the control group (HR 2.43, 95%CI 0.74-8.01, P 0.143) and were not impacted by the use of adjuvant radiotherapy. 5y-BCSS rates were 92.2% and 98.6%, respectively (HR 1.87, IC95% 0.25-13.48, P 0.534). Our results showed no statistically significant difference in BC-related RFS and BCSS between patients with mTP53 and a control group with no pathogenic variant. Larger multicentric studies are warranted to confirm these results.

Taxane rechallenge during metastatic disease in HER-2 negative breast cancer patients Clinical activity, tolerance and survival results.

Taxanes are major drugs for metastatic breast cancer (MBC) treatment, and are generally well tolerated, making them attractive for therapeutic reintroduction (rechallenge) during metastatic course. In view of the paucity of current literature, we questioned the usefulness of taxane rechallenge in a population of patients previously treated with taxanes in a metastatic setting. From the local database of a French cancer center, we retrospectively identified 756 patients diagnosed with ERHER2-, or triple negative MBC, and treated between 2008 and 2021. Among them, 58 patients (7.8%) were rechallenged with taxanes. Clinical characteristics, response rates, and survival were retrospectively evaluated and compared to patients who received taxanes only once. Compared to non-rechallenged population, patients treated with taxane rechallenge were significantly younger, with better general status, and received more treatment. First taxane exposure led to better tumor response and was more frequently discontinued for reasons other than progression, compared to the non-rechallenged population. Taxane rechallenge led to an objective response rate of 27.6%, and a clinical benefit rate of 46.6%, with a median progression-free survival (PFS) of 5.7 months, and a median overall survival (OS) of 11.6 months. We also found a PFS2PFS1 ratio >1.3 in 55.2% of the rechallenge population. Although only a minority of MBC patients are concerned, taxane rechallenge appears to be a pragmatic option with an acceptable tolerance, and good efficacy, especially when these drugs have shown clinical activity earlier in the disease course, andor have been stopped for reasons other than progression.

Estrogen therapy after breast cancer diagnosis and breast cancer mortality risk.

The safety of local estrogen therapy in patients on adjuvant endocrine treatment is questioned, but evidence on the issue is scarce. This nested case-control registry-based study aimed to investigate whether estrogen therapy affects breast cancer mortality risk in women on adjuvant endocrine treatment. In a cohort of 15,198 women diagnosed with early hormone receptor (HR)-positive breast cancer and adjuvant endocrine treatment, 1262 women died due to breast cancer and were identified as cases. Each case was matched with 10 controls. Exposure to estrogen therapy with concurrent use of aromatase inhibitors (AIs), tamoxifen, or both sequentially, was compared between cases and controls. No statistically significant difference in breast cancer mortality risk was seen in patients with exposure to estrogen therapy concurrent to endocrine treatment, neither in short-term or in long-term estrogen therapy use. The study strengthens current evidence on local estrogen therapy use in breast cancer survivors, showing no increased risk for breast cancer mortality in patients on adjuvant AIs or tamoxifen.

The Role of Attachment Styles on Quality of Life and Distress Among Early-Stage Female Breast Cancer Patients A Systematic Review.

Cancer patients quality of life (QoL) and distress are affected by dispositional factors such as attachment anxiety or avoidance. In this review, we aimed to provide a thorough overview of the relationship between attachment dimensions and QoL and distress among early-stage breast cancer patients. Following PRISMA guidelines, we conducted a systematic search using PubMed, PsycINFO, Scopus, Cinahl, Google Scholar, and PMC Europe. We reviewed 8 eligible studies describing 1180 patients. Insecure attachment appeared to be related to poorer QoL and higher distress levels. Avoidant attachment was more frequent and was more often associated with more negative outcomes. Healthcare providers should consider investigating modifiable personality traits in the immediate post diagnosis period to identify patients more vulnerable to mental health problems, deliver personalized care, and reduce emotional burden.

Cognitive function and breast cancer molecular subtype before and after chemotherapy.

Chemotherapy-related cognitive impairment has been reported in patients with breast cancer and received growing attention due to increased survival rate. However, cognitive outcome according to pathological tumor features, especially human epidermal growth factor receptor (HER2) status, has not been clearly elucidated. Despite its potential link with cognitive status through neuroinflammatory response, existing research is sparse and limited to cross-sectional studies. In this observational cohort study, 52 breast cancer patients received a series of neuropsychological examinations before and after chemotherapy. Patients performances were compared with normative data, and analyzed with Reliable Change Indices and mixed-model analysis of covariance. Results showed that there was a higher percentage of HER2

Socioeconomic inequalities in waiting times for planned and cancer surgery Evidence from Spain.

Waiting times act as a non-price rationing mechanism to bring together the demand for and the supply of public healthcare services and ensure equal access independently of ability to pay. This study tests for the presence of socioeconomic inequalities in waiting times for ten publicly-funded planned and cancer surgeries in Catalonia (Spain) in 2015-2019. Socioeconomic status (SES), measured by four categories (very low, low, middle, high), is based on co-payment levels for medicines which depend on patients income. Using administrative data, we estimate the association between SES and waiting times controlling for patient characteristics and hospital fixed effects. Compared to patients with low SES, patients with middle SES wait 2-6 fewer days for hip replacement, cataract surgery, and hysterectomy, and less than a day for breast cancer surgery. These inequalities arise within hospitals and are not explained by patient nor hospital characteristics. For some surgeries, the results also show that patients with higher SES are more likely to voluntarily exit the waiting list and have a lower probability of having a surgery canceled for medical reasons and dying while waiting.

Therapeutic Role of Tamoxifen for Triple-Negative Breast Cancer Leveraging the Interaction Between ERβ and Mutant p53.

The absence of effective therapeutic targets and aggressive nature of triple-negative breast cancer (TNBC) renders this disease subset difficult to treat. Although estrogen receptor beta (ERβ) is expressed in TNBC, studies on its functional role have yielded inconsistent results. However, recently, our preclinical studies, along with other observations, have shown the potential therapeutic utility of ERβ in the context of mutant p53 expression. The current case study examines the efficacy of the selective estrogen receptor modulator tamoxifen in p53-mutant TNBC with brain metastases. Significant increase in ERβ protein expression and anti-proliferative interaction between mutant p53 and ERβ were observed after cessation of tamoxifen therapy, with significant regression of brain metastases. This case study provides supporting evidence for the use of tamoxifen in p53-mutant, ERβTNBC, especially in the setting of brain metastasis.

Dissecting the role of cancer-associated fibroblast-derived biglycan as a potential therapeutic target in immunotherapy resistance A tumor bulk and single-cell transcriptomic study.

Cancer-associated fibroblasts (CAFs) are correlated with the immunotherapy response. However, the culprits that link CAFs to immunotherapy resistance are still rarely investigated in real-world studies. This study aims to systematically assess the landscape of fibroblasts in cancer patients by combining single-cell and bulk profiling data from pan-cancer cohorts. We further sought to decipher the expression, survival predictive value and association with immunotherapy response of biglycan (BGN), a proteoglycan in the extracellular matrix, in multiple cohorts. Pan-cancer tumor bulks and 27 single-cell RNA sequencing cohorts were enrolled to investigate the correlations and crosstalk between CAFs and tumor or immune cells. Specific secreting factors of CAFs were then identified by expression profiling at tissue microdissection, isolated primary fibroblasts and single-cell level. The role of BGN was further dissected in additional three bulk and five single-cell profiling datasets from immunotherapy cohorts and validated in real-world patients who have received PD-1 blockade using immunohistochemistry and immunofluorescence. CAFs were closely correlated with immune components. Frequent crosstalk between CAFs and other cells was revealed by the CellChat analysis. Single-cell regulatory network inference and clustering identified common and distinct regulators for CAFs across cancers. The BGN was determined to be a specific secreting factor of CAFs. The BGN served as an unfavourable indicator for overall survival and immunotherapy response. In the real-world immunotherapy cohort, patients with high BGN levels presented a higher proportion of poor response compared with those with low BGN (46.7% vs. 11.8%) and a lower level of infiltrating CD8 T cells was also observed. We highlighted the importance of CAFs in the tumor microenvironment and revealed that the BGN, which is mainly derived from CAFs, may be applicable in clinical practice and serve as a therapeutic target in immunotherapy resistance.

Assessment of knowledge, understanding and awareness of Chinese women clinical staff towards menopause hormone therapy a survey study.

Menopausal Hormone Therapy (MHT) is recommended for climacteric peri- and postmenopausal symptoms. The rate of use of MHT in China is much lower than the western regions. Therefore, a survey was conducted for the understanding and utilization of MHT among clinical staff in various hospitals of China. A total of 3216 eligible questionnaires were included for the evaluation. According to 19.2% participant opinion, MHT could relieve menopausal symptoms, whereas the majority had no knowledge of the benefits and risks of MHT. The most common concern about MHT was the risk of cancer and about 430 (13.4%) and 176 (5.5%) participants were apprehensive that MHT could increase the risk of breast and endometrial cancer, respectively. This survey demonstrated that the knowledge of clinical staff was not comprehensive and they should be educated more about the use of MHT so that this knowledge can be imbibed into the general population.Impact Statement

Concentration QTc Analysis of Giredestrant Overcoming QTHR Confounding in the Presence of Drug-Induced Heart Rate Changes.

Concentration-QTc (C-QTc) analysis has become a common approach for evaluating proarrhythmic risk and delayed cardiac repolarization of oncology drug candidates. Significant heart rate (HR) change has been associated with certain classes of oncology drugs and can result in over- or under-estimation of the true QT prolongation risk. Since oncology early clinical trials typically lack a placebo control arm or time-matched, treatment-free baseline electrocardiogram (ECG) collection, significant HR change brings additional challenges to C-QTc analysis in the oncology setting. In this work, a spline-based correction method (QTcSPL) was explored to mitigate the impact of HR changes in giredestrant C-QTc analysis. Giredestrant is a selective estrogen receptor degrader (SERD) being developed for the treatment of patients with estrogen receptor-positive (ER) breast cancer. A dose-related HR decrease has been observed in patients under giredestrant treatment, with significant reductions (>10 bpm) observed at supratherapeutic doses. The QTcSPL method demonstrated superior functionality to reduce the correlation between QTc and HR as compared with the Fridericia correction (QTcF). The effect of giredestrant exposure on QTc was evaluated at the clinical dose of 30 mg and supratherapeutic dose of 100 mg based on a prespecified linear mixed effect model. The upper 90% confidence interval of ΔQTcSPL and ΔQTcF were below the 10 ms at both clinical and supratherapeutic exposures, suggesting giredestrant has a low risk of QT prolongation at clinically relevant concentrations. This work demonstrated the use case of QTcSPL to address HR confounding challenges in the context of oncology drug development for the first time.

Feasibility and usability of a personalized mHealth app for self-management in the first year following breast cancer surgery.

This study investigated the feasibility and usability of a personalized mobile health (mHealth) app for self-management during the year following breast cancer surgery. Twenty-nine participants were instructed to use an app and smart band immediately after discharge. Only 18 completed the study. Their perceived necessity and satisfaction for main domains and app were assessed at 1, 2, 4, 6, 9, and 12 months. A self-reporting questionnaire assessed usability at 12 months. Consequently, retention rate as measures of feasibility showed a mean of 75.8%. Exercise and diet management were the most accessed app domains. Perceived necessity was higher than satisfaction. The mean usability score was 80.2. Most participants found the app useful and effective as a delivery for healthcare. Further, 94% of them were willing to pay for and recommend it. Thus, mHealth app can help breast cancer patients improve their healthy behaviors and healthcare further. This study provides insights for designing long-term randomized controlled trials using mHealth interventions.

Chemical composition and anticancer activity of the essential oil from

The search for new bioactive substances with anticancer activity and the understanding of their mechanisms of action are high priorities in the research effort toward more effective cancer treatments. In this article, we analyzed, for the first time, the chemical composition of the essential oil (EO) hydrodistilled from the aerial parts of

Differential contractility regulates cancer stem cell migration.

Cancer stem cells (CSCs) are known to have a high capacity for tumor initiation and the formation of metastases. We have previously shown that in collagen constructs mimetic of aligned extracellular matrix architectures observed in carcinomas, breast CSCs demonstrate enhanced directional and total motility compared to more differentiated carcinoma populations. Here, we show that CSCs maintain increased motility in diverse environments including on 2D elastic polyacrylamide gels of various stiffness, 3D randomly oriented collagen matrices, and ectopic cerebral slices representative of a common metastatic site. A consistent two-fold increase of CSC motility across platforms suggests a general shift in cell migration mechanics between well-differentiated carcinoma cells and their stem-like counterparts. To further elucidate the source of differences in migration, we demonstrate that CSCs are less contractile than the whole population (WP) and develop fewer and smaller focal adhesions, and show that enhanced CSC migration can be tuned via contractile forces. The WP can be shifted to a CSC-like migratory phenotype using partial myosin-II inhibition. Inversely, CSCs can be shifted to a less migratory WP-like phenotype using microtubule-destabilizing drugs that increase contractility or by directly enhancing contractile forces. This work begins to reveal the mechanistic differences driving CSC migration and raises important implications regarding the potentially disparate effects of microtubule-targeting agents on the motility of different cell populations.

A Two-Step Feature Selection Radiomic Approach to Predict Molecular Outcomes in Breast Cancer.

Breast Cancer (BC) is the most common cancer among women worldwide and is characterized by intra- and inter-tumor heterogeneity that strongly contributes towards its poor prognosis. The Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal Growth Factor Receptor 2 (HER2), and Ki67 antigen are the most examined markers depicting BC heterogeneity and have been shown to have a strong impact on BC prognosis. Radiomics can noninvasively predict BC heterogeneity through the quantitative evaluation of medical images, such as Magnetic Resonance Imaging (MRI), which has become increasingly important in the detection and characterization of BC. However, the lack of comprehensive BC datasets in terms of molecular outcomes and MRI modalities, and the absence of a general methodology to build and compare feature selection approaches and predictive models, limit the routine use of radiomics in the BC clinical practice. In this work, a new radiomic approach based on a two-step feature selection process was proposed to build predictors for ER, PR, HER2, and Ki67 markers. An in-house dataset was used, containing 92 multiparametric MRIs of patients with histologically proven BC and all four relevant biomarkers available. Thousands of radiomic features were extracted from post-contrast and subtracted Dynamic Contrast-Enanched (DCE) MRI images, Apparent Diffusion Coefficient (ADC) maps, and T2-weighted (T2) images. The two-step feature selection approach was used to identify significant radiomic features properly and then to build the final prediction models. They showed remarkable results in terms of F1-score for all the biomarkers 84%, 63%, 90%, and 72% for ER, HER2, Ki67, and PR, respectively. When possible, the models were validated on the TCGATCIA Breast Cancer dataset, returning promising results (F1-score 88% for the ERER- classification task). The developed approach efficiently characterized BC heterogeneity according to the examined molecular biomarkers.

Evaluating the Performance of Algorithms in Axillary Microwave Imaging towards Improved Breast Cancer Staging.

Breast cancer is the most common and the fifth deadliest cancer worldwide. In more advanced stages of cancer, cancer cells metastasize through lymphatic and blood vessels. Currently there is no satisfactory neoadjuvant (i.e., preoperative) diagnosis to assess whether cancer has spread to neighboring Axillary Lymph Nodes (ALN). This paper addresses the use of radar Microwave Imaging (MWI) to detect and determine whether ALNs have been metastasized, presenting an analysis of the performance of different artifact removal and beamformer algorithms in distinct anatomical scenarios. We assess distinct axillary region models and the effect of varying the shape of the skin, muscle and subcutaneous adipose tissue layers on single ALN detection. We also study multiple ALN detection and contrast between healthy and metastasized ALNs. We propose a new beamformer algorithm denominated Channel-Ranked Delay-Multiply-And-Sum (CR-DMAS), which allows the successful detection of ALNs in order to achieve better Signal-to-Clutter Ratio, e.g., with the muscle layer up to 3.07 dB, a Signal-to-Mean Ratio of up to 20.78 dB and a Location Error of 1.58 mm. In multiple target detection, CR-DMAS outperformed other well established beamformers used in the context of breast MWI. Overall, this work provides new insights into the performance of algorithms in axillary MWI.

A Comprehensive Landscape of Imaging Feature-Associated RNA Expression Profiles in Human Breast Tissue.

The expression abundance of transcripts in nondiseased breast tissue varies among individuals. The association study of genotypes and imaging phenotypes may help us to understand this individual variation. Since existing reports mainly focus on tumors or lesion areas, the heterogeneity of pathological image features and their correlations with RNA expression profiles for nondiseased tissue are not clear. The aim of this study is to discover the association between the nucleus features and the transcriptome-wide RNAs. We analyzed both microscopic histology images and RNA-sequencing data of 456 breast tissues from the Genotype-Tissue Expression (GTEx) project and constructed an automatic computational framework. We classified all samples into four clusters based on their nucleus morphological features and discovered feature-specific gene sets. The biological pathway analysis was performed on each gene set. The proposed framework evaluates the morphological characteristics of the cell nucleus quantitatively and identifies the associated genes. We found image features that capture population variation in breast tissue associated with RNA expressions, suggesting that the variation in expression pattern affects population variation in the morphological traits of breast tissue. This study provides a comprehensive transcriptome-wide view of imaging-feature-specific RNA expression for healthy breast tissue. Such a framework could also be used for understanding the connection between RNA expression and morphology in other tissues and organs. Pathway analysis indicated that the gene sets we identified were involved in specific biological processes, such as immune processes.

Design of Ultra-Wideband Phased Array Applicator for Breast Cancer Hyperthermia Therapy.

Focused microwave-hyperthermia therapy has recently emerged as a key technology in the treatment of breast cancer due to non-invasive treatment. An applicator of a three-ring phased array consisting of ultra-wideband (UWB) microstrip antennas was designed for breast cancer therapy and operates at 0.915 GHz and 2.45 GHz. The proposed antenna has an ultra-wideband from 0.7 GHz to 5.5 GHz with resonant frequencies of 0.915 GHz and 2.45 GHz and dimensions of 15 × 43.5 × 1.575 mm

The Antioxidant and Proapoptotic Effects of

An MTS cell viability assay was performed on MDA-MB-231 and MCF-7 cells, along with cell cycle analysis, cell death ELISA, Western blot analysis and an ROS production assay to decipher the mechanism of death. LC-MSMS was also performed to identify the chemical composition of this ethanolic extract. The results show a selective antiproliferative effect on both cell lines with no effect on normal mesenchymal stem cells. Further analysis suggested the activation of the apoptotic pathway as reflected by the increase in cellular and DNA fragmentation and alterations in apoptotic proteins such as Bax, Bcl-2 and c-PARP. ScBEE was also found to exhibit antioxidant effect, as shown by a decrease in ROS production. The underlying mechanism of action was explained by the presence of several bioactive compounds identified by LC-MSMS, including alkaloids, terpenoids and phenols, which are elaborated in the manuscript. This study highlights the antioxidant and anticancerous properties of