In-silico study of the impact of system design parameters on microcalcification detection in wide-angle digital breast tomosynthesis.

Purpose: Accurate detection of microcalcifications ( µ Calcs ) is crucial for the early detection of breast cancer. Some clinical studies have indicated that digital breast tomosynthesis (DBT) systems with a wide angular range have inferior µ Calc detectability compared with those with a narrow angular range. This study aims to (1) provide guidance for optimizing wide-angle (WA) DBT for improving µ Calcs detectability and (2) prioritize key optimization factors. Approach: An in-silico DBT pipeline was constructed to evaluate µ Calc detectability of a WA DBT system under various imaging conditions: focal spot motion (FSM), angular dose distribution (ADS), detector pixel pitch, and detector electronic noise (EN). Images were simulated using a digital anthropomorphic breast phantom inserted with 120 µ m µ Calc clusters. Evaluation metrics included the signal-to-noise ratio (SNR) of the filtered channel observer and the area under the receiver operator curve (AUC) of multiple-reader multiple-case analysis. Results: Results showed that FSM degraded µ Calcs sharpness and decreased the SNR and AUC by 5.2% and 1.8%, respectively. Non-uniform ADS increased the SNR by 62.8% and the AUC by 10.2% for filtered backprojection reconstruction with a typical clinical filter setting. When EN decreased from 2000 to 200 electrons, the SNR and AUC increased by 21.6% and 5.0%, respectively. Decreasing the detector pixel pitch from 85 to 50 µ m improved the SNR and AUC by 55.6% and 7.5%, respectively. The combined improvement of a 50 µ m pixel pitch and EN200 was 89.2% in the SNR and 12.8% in the AUC. Conclusions: Based on the magnitude of impact, the priority for enhancing µ Calc detectability in WA DBT is as follows: (1) utilizing detectors with a small pixel pitch and low EN level, (2) allocating a higher dose to central projections, and (3) reducing FSM. The results from this study can potentially provide guidance for DBT system optimization in the future.

Estimation of the absorbed dose in simultaneous digital breast tomosynthesis and mechanical imaging.

Purpose: Use of mechanical imaging (MI) as complementary to digital mammography (DM), or in simultaneous digital breast tomosynthesis (DBT) and MI - DBTMI, has demonstrated the potential to increase the specificity of breast cancer screening and reduce unnecessary biopsies compared with DM. The aim of this study is to investigate the increase in the radiation dose due to the presence of an MI sensor during simultaneous image acquisition when automatic exposure control is used. Approach: A radiation dose study was conducted on clinically available breast imaging systems with and without an MI sensor present. Our estimations were based on three approaches. In the first approach, exposure values were compared in paired clinical DBT and DBTMI acquisitions in 97 women. In the second approach polymethyl methacrylate (PMMA) phantoms of various thicknesses were used, and the average glandular dose (AGD) values were compared. Finally, a rectangular PMMA phantom with a 45 mm thickness was used, and the AGD values were estimated based on air kerma measurements with an electronic dosemeter. Results: The relative increase in exposure estimated from digital imaging and communications in medicine headers when using an MI sensor in clinical DBTMI was 11.9 % ± 10.4 . For the phantom measurements of various thicknesses of PMMA, the relative increases in the AGD for DM and DBT measurements were, on average, 10.7 % ± 3.1 and 11.4 % ± 3.0 , respectively. The relative increase in the AGD using the electronic dosemeter was 11.2 % ± < 0.001 in DM and 12.2 % ± < 0.001 in DBT. The average difference in dose between the methods was 11.5 % ± 3.3 . Conclusions: Our measurements suggest that the use of simultaneous breast radiography and MI increases the AGD by an average of 11.5 % ± 3.3 . The increase in dose is within the acceptable values for mammography screening recommended by European guidelines.

MRPL13 is a metastatic and prognostic marker of breast cancer: A silico analysis accompanied with experimental validation.

BACKGROUND: Although progress has been made in accurate diagnosis and targeted treatments, breast cancer (BC) patients with metastasis still present a grim prognosis. With the continuous emergence and development of new personalized and precision medicine targeting specific tumor biomarkers, there is an urgent need to find new metastatic and prognostic biomarkers for BC patients. METHODS: We were dedicated to identifying genes linked to metastasis and prognosis in breast cancer through a combination of in silico analysis and experimental validation. RESULTS: A total of 25 overlap differentially expressed genes were identified. Ten hub genes (namely MRPL13, CTR9, TCEB1, RPLP0, TIMM8B, METTL1, GOLT1B, PLK2, PARL and MANBA) were identified and confirmed. MRPL13, TCEB1 and GOLT1B were shown to be associated with the worse overall survival (OS) and were optionally chosen for further verification by western blot. Only MRPL13 was found associated with cell invasion, and the expression of MRPL13 in metastatic BC was significantly higher than in primary BC. CONCLUSION: We proposed MRPL13 could be a potential novel biomarker for the metastasis and prognosis of breast cancer.

Genetically engineered CD276-anchoring biomimetic nanovesicles target senescent escaped tumor cells to overcome chemoresistant and immunosuppressive breast cancer.

Chemotherapy-induced cellular senescence leads to an increased proportion of cancer stem cells (CSCs) in breast cancer (BC), contributing to recurrence and metastasis, while effective means to clear them are currently lacking. Herein, we aim to develop new approaches for selectively killing senescent-escape CSCs. High CD276 (95.60%) expression in multidrug-resistant BC cells, facilitates immune evasion by low-immunogenic senescent escape CSCs. CALD1, upregulated in ADR-resistant BC, promoting senescent-escape of CSCs with an anti-apoptosis state and upregulating CD276, PD-L1 to promote chemoresistance and immune escape. We have developed a controlled-released thermosensitive hydrogel containing pH- responsive anti-CD276 scFV engineered biomimetic nanovesicles to overcome BC in primary, recurrent, metastatic and abscopal humanized mice models. Nanovesicles coated anti-CD276 scFV selectively fuses with cell membrane of senescent-escape CSCs, then sequentially delivers siCALD1 and ADR due to pH-responsive MnP shell. siCALD1 together with ADR effectively induce apoptosis of CSCs, decrease expression of CD276 and PD-L1, and upregulate MHC I combined with Mn2+ to overcome chemoresistance and promote CD8+T cells infiltration. This combined therapeutic approach reveals insights into immune surveillance evasion by senescent-escape CSCs, offering a promising strategy to immunotherapy effectiveness in cancer therapy.

Visible-short wavelength near infrared hyperspectral imaging coupled with multivariate curve resolution-alternating least squares for diagnosis of breast cancer.

This study investigates the application of visible-short wavelength near-infrared hyperspectral imaging (Vis-SWNIR HSI) in the wavelength range of 400-950 nm and advanced chemometric techniques for diagnosing breast cancer (BC). The research involved 56 ex-vivo samples encompassing both cancerous and non-cancerous breast tissue from females. First, HSI images were analyzed using multivariate curve resolution-alternating least squares (MCR-ALS) to exploit pure spatial and spectral profiles of active components. Then, the MCR-ALS resolved spatial profiles were arranged in a new data matrix for exploration and discrimination between benign and cancerous tissue samples using principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA). The PLS-DA classification accuracy of 82.1 % showed the potential of HSI and chemometrics for non-invasive detection of BC. Additionally, the resolved spectral profiles by MCR-ALS can be used to track the changes in the breast tissue during cancer and treatment. It is concluded that the proposed strategy in this work can effectively differentiate between cancerous and non-cancerous breast tissue and pave the way for further studies and potential clinical implementation of this innovative approach, offering a promising avenue for improving early detection and treatment outcomes in BC patients.

Electrochemical biosensors for early detection of breast cancer.

Breast cancer continues to be a significant contributor to global cancer deaths, particularly among women. This highlights the critical role of early detection and treatment in boosting survival rates. While conventional diagnostic methods like mammograms, biopsies, ultrasounds, and MRIs are valuable tools, limitations exist in terms of cost, invasiveness, and the requirement for specialized equipment and trained personnel. Recent shifts towards biosensor technologies offer a promising alternative for monitoring biological processes and providing accurate health diagnostics in a cost-effective, non-invasive manner. These biosensors are particularly advantageous for early detection of primary tumors, metastases, and recurrent diseases, contributing to more effective breast cancer management. The integration of biosensor technology into medical devices has led to the development of low-cost, adaptable, and efficient diagnostic tools. In this framework, electrochemical screening platforms have garnered significant attention due to their selectivity, affordability, and ease of result interpretation. The current review discusses various breast cancer biomarkers and the potential of electrochemical biosensors to revolutionize early cancer detection, making provision for new diagnostic platforms and personalized healthcare solutions.

Synergistic effect of bazedoxifene and abemaciclib co­treatment in triple­negative breast cancer cells in vitro.

Triple-negative breast cancer (TNBC) is an aggressive disease with the capability of metastasizing quickly. However, treatment options for patients with TNBC still remain limited. CDK4/6 inhibitors have been approved by the U.S. Food and Drug Administration and are administered for the treatment of hormone receptor-positive breast cancer subtypes, but not yet for TNBC. Although pre-clinical research is being conducted on their efficacy in treating TNBC, acquired resistance to CDK4/6 inhibitors is now a growing clinical problem. One of the identified resistance mechanisms is through the IL-6/STAT3 signaling pathway. In the present study, the CDK4/6 inhibitor, abemaciclib, was tested in combination with the IL-6 inhibitor, bazedoxifene, on human (SUM159 and MDA-MB-231) and murine (4T1) TNBC cell lines. Both abemaciclib and bazedoxifene monotherapies inhibited cell cycle progression and cell viability, migration and invasion, and induced apoptosis; however, the combination treatment exerted a greater effect than either monotherapy. These findings support the concept of CDK4/6 and IL-6 dual inhibition as a novel targeted therapy against TNBC.

Molecular Subtypes of Breast Cancer in a Tertiary Centre in Edo State: South-South Nigeria.

BACKGROUND: Breast cancer constitutes a significant public health issue in most resource-constrained nations due to its high morbidity and mortality rates. There is a paucity of knowledge of the molecular subtypes of breast cancer in Nigeria primarily due to the lack of immunohistochemistry. This study aims to identify the molecular subtypes of histologically confirmed breast cancer cases at the University of Benin Teaching Hospital, Benin City, Nigeria, using ER, PR and HER2/neu as immunohistochemical biomarkers. MATERIALS AND METHOD: Breast cancer specimens received in the Histopathology department of the University of Benin Teaching Hospital between 2019 and 2021 were used for this study. Representative sections of paraffin-embedded blocks were recut for histological typing, tumour grading, and immunohistochemistry. RESULTS: A total of 330 cases were evaluated in this study. The average age was 49 years, with a M:F of 40.3:1. The most frequent histological type was invasive breast cancer (92.1%). Two hundred and forty-two (73.3%) cases were categorized as grade II tumours. The steroid hormone receptor positivity was 39.4%. Oestrogen and Progesterone receptor positivity were 39.4% and 22.1%, respectively. HER2/neu was positive in 16.4% of the cases. Triple-negative breast cancer (TNBC) was the most common molecular subtype, accounting for 49.4% of cases. Luminal A, Luminal B, and HER2/neu enriched subtypes were each found in 34.2%, 5.2%, and 11.2% of cases, respectively. CONCLUSION: Triple-negative breast cancers predominated among the study population and were more common in high-grade tumours with unfavourable histological types and among women who were younger than their Caucasian counterparts.

CONTEXTE: Le cancer du sein constitue un problème de santé publique majeur dans la plupart des nations aux ressources limitées en raison de son taux élevé de morbidité et de mortalité. Il existe une pénurie de connaissances sur les sous-types moléculaires du cancer du sein au Nigeria, principalement en raison du manque d'immunohistochimie. Cette étude vise à identifier les sous-types moléculaires des cas de cancer du sein confirmés histologiquement à l'Hôpital Universitaire de Benin, Benin City, Nigeria, en utilisant les biomarqueurs immunohistochimiques ER, PR et HER2/neu. MATÉRIAUX ET MÉTHODE: Les échantillons de cancer du sein reçus dans le département d'histopathologie de l'Hôpital Universitaire de Benin entre 2019 et 2021 ont été utilisés pour cette étude. Des sections représentatives de blocs inclus en paraffine ont été recoupées pour le typage histologique, le classement des tumeurs et l'immunohistochimie. RÉSULTATS: Un total de 330 cas ont été évalués dans cette étude. L'âge moyen était de 49 ans, avec un rapport H de 40,3:1. Le type histologique le plus fréquent était le cancer du sein invasif (92,1 %). Deux cent quarante-deux (73,3 %) cas ont été classés comme des tumeurs de grade II. La positivité des récepteurs hormonaux stéroïdiens était de 39,4 %. Les récepteurs des œstrogènes et de la progestérone étaient positifs dans 39,4 % et 22,1 % des cas, respectivement. HER2/neu était positif dans 16,4 % des cas. Le cancer du sein triple négatif (CSTN) était le sous-type moléculaire le plus courant, représentant 49,4 % des cas. Les sous-types Luminal A, Luminal B et enrichi en HER2/neu ont été trouvés dans 34,2 %, 5,2 % et 11,2 % des cas, respectivement. CONCLUSION: Les cancers du sein triple négatif prédominaient parmi la population étudiée et étaient plus fréquents dans les tumeurs de haut grade avec des types histologiques défavorables et chez les femmes plus jeunes que leurs homologues caucasiennes.

Gastrin-releasing peptide receptor as theranostic target in estrogen-receptor positive breast cancer: A preclinical study of the theranostic pair [55Co]Co- and [177Lu]Lu-DOTA-RM26.

BACKGROUND: Patients with advanced metastatic estrogen receptor-positive breast cancer often develop resistance to standard treatments, leading to uncontrolled progression. Thus, innovative therapies are urgently needed. The gastrin-releasing peptide receptor (GRPR) is overexpressed in various cancers, including breast cancer, making it an interesting theranostic target. RM26, a GRPR-targeting antagonist, has demonstrated promising in vivo kinetics in prostate cancer models. This study evaluated the theranostic capabilities of [55Co]Co-/[177Lu]Lu-DOTA-RM26 in vitro in estrogen receptor-positive breast cancer cells and assessed the diagnostic potential of [55Co]Co-DOTA-RM26 in vivo in a breast cancer mouse model. METHODS: We analyzed the binding specificity of [57Co]Co-/[177Lu]Lu-DOTA-RM26 in T47D breast cancer cells, using [57Co]Co-DOTA-RM26 as a surrogate for [55Co]Co-DOTA-RM26. The therapeutic efficacy of increasing [177Lu]Lu-DOTA-RM26 concentrations was determined via viability assay in vitro. Ex vivo biodistribution of [57Co]Co-DOTA-RM26 (17.2 ± 2.7 kBq, 33 ± 5.2 pmol/mouse) was investigated in 12 mice (n= 4/group) with orthotopic breast cancer tumors. The mice were sacrificed at 4 and 24 h post-injection (pi), including a blocking group (20 nmol of unlabeled [Tyr4]-Bombesin) at 4 h pi. For imaging, two tumor-bearing mice underwent [55Co]Co-DOTA-RM26 PET/CT, 4 and 24 h pi (2.8 ± 0.2 MBq, 167.5 ± 0.5 pmol/mouse), with or without GRPR blocking. RESULTS: In vitro studies revealed high, specific binding of [57Co]Co-DOTA-RM26 (43 ± 1 % of total added activity per 106 cells (%IA/106)) and [177Lu]Lu-DOTA-RM26 (37 ± 4 %IA/106). The activity was predominantly localized at the cell surface: 71 ± 3 % and 80 ± 6 % for [57Co]Co-DOTA-RM26 and [177Lu]Lu-DOTA-RM26, respectively. [177Lu]Lu-DOTA-RM26 significantly reduced cell viability at all activity concentrations >0.625 MBq/mL (p < 0.0001), with cell viability below 1 % at concentrations ≥5 MBq/mL. Biodistribution data (n = 12) indicated a high, specific tumor uptake of [57Co]Co-DOTA-RM26, surpassing all other tissues significantly at both time points, 3.7 ± 0.6 % of the injected activity per gram (%IA/g) 4 h pi and 0.98 ± 0.05 %IA/g 24 h pi. The kidneys showed the second-highest uptake (2.0 ± 0.1 %IA/g 4 h pi), followed by the pancreas (1.4 ± 0.4 %IA/g 4 h pi). PET/CT imaging with [55Co]Co-DOTA-RM26 supported the biodistribution data and, distinctly visualized the tumor 24 h pi and showed an improved tumor-to-background compared to the earlier time points. Effective GRPR blocking significantly reduced tumor uptake in the PET images 24 h pi. CONCLUSION: These findings suggest that the theranostic pair [55Co]Co-/[177Lu]Lu-DOTA-RM26 holds significant promise as a theranostic agent for estrogen receptor-positive breast cancer.

Window of opportunity trials with immune checkpoint inhibitors in triple-negative breast cancer.

Patients with triple-negative breast cancer (TNBC) have a relatively poor clinical outcome. The immune checkpoint inhibitor (ICI) pembrolizumab combined with chemotherapy is the current standard of care in TNBC patients with stage II and III. Monotherapy with ICIs has not been comprehensively assessed in the neoadjuvant setting in TNBC patients, given unfavorable results in metastatic trials. ICIs, however, have been tested in the window of opportunity (WOO) before surgery or standard chemotherapy-based neoadjuvant treatment. The WOO design is well suited to assess an ICI alone or in combination with other ICIs, targeted therapy, radiotherapy or cryotherapy, and measure their pharmacodynamic and clinical effect in this treatment-naive population. Some patients show a good response to ICIs in WOO studies. Biomarkers like tumor-infiltrating lymphocytes, programmed death ligand-1, and interferon-γ signature may predict activity and may identify patients likely to benefit from ICIs. Moreover, an increase in tumor-infiltrating lymphocytes, programmed death ligand-1 expression or T cell receptor expansion following administration of ICIs in the WOO setting could potentially inform of immunotherapy benefit, which would allow tailoring further treatment. This article reviews WOO trials that assessed immunotherapy in the early-stage TNBC population, and how these results could be translated to test de-escalation strategies of neoadjuvant chemotherapy and immunotherapy without compromising a patient's prognosis.

Clinical significance of serum estradiol monitoring in women receiving adjuvant aromatase inhibitor for hormone receptor-positive early breast cancer.

PURPOSE: The limited understanding of long-term estradiol (E2) suppression poses challenges to the effectiveness of adjuvant therapy with aromatase inhibitors (AI), necessitating comprehensive serum E2 monitoring to address this issue. Therefore, our objective was to investigate serum E2 levels in women undergoing adjuvant AI treatment and evaluate the significance of such monitoring. PATIENTS AND METHODS: In this prospective cohort study, we recruited women who had received adjuvant AI treatment, including those who underwent ovarian function suppression (OFS). Serum E2 levels were measured using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The primary endpoint was the proportion of women with E2 levels exceeding 2.72 pg/mL, indicating inadequate suppression achieved with AI therapy. RESULTS: A total of 706 patients were enrolled, including 482 women with OFS in combination with AI. Among them, 116 women (16.4 %) exhibited E2 levels exceeding 2.72 pg/mL. The majority of serum E2 elevations (77.6 %) occurred within the first two years of initiating endocrine therapy. Younger age, no prior chemotherapy, shorter duration of the current treatment regimen, and lower follicle stimulating hormone (FSH) levels were associated with inadequate E2 suppression. Serum E2 concentrations demonstrated dynamic variations and occasional rebound following adjuvant AI therapy. CONCLUSIONS: Despite receiving adjuvant AI treatment for nearly two years, a certain proportion of patients failed to achieve the adequate threshold of E2 suppression. Our findings emphasize the significance of monitoring serum E2 levels during adjuvant AI therapy, particularly within the first two years. Further research is imperative to facilitate a more comprehensive comprehension of E2 monitoring.

Genomic and clinical landscape of metastatic hormone receptors-positive breast cancers carrying ESR1 alterations.

BACKGROUND: Somatic genetic alterations of the estrogen receptor 1 gene (ESR1) are enriched in endocrine therapy-resistant, estrogen receptor-positive (ER+) metastatic breast cancer (mBC). Herein, we investigated and compared the clinical and genomic landscape of ESR1-mutant (ESR1MUT) and ESR1 wild type (ESR1WT) ER+/ human epidermal growth factor receptor 2 (HER2)- mBCs. METHODS: Clinical and genomic data were retrieved from cBioPortal using the publicly-available MSK MetTropism dataset. Metastatic, ER+/HER2- mBC samples were included in the analysis. Only oncogenic and likely oncogenic alterations according to OncoKB were included. Statistical analyses were carried out using alpha level of 0.05, with a false discovery rate threshold of 10% for multiple comparisons using the Benjamini-Hochberg method. RESULTS: Among 679 samples, 136 ESR1MUT among 131 tumors were found (19.2%). The frequency of ESR1MUT was higher in ductal versus lobular mBC (21.2% versus 13.8%, P = 0.052) and enriched in liver metastasis compared with other sites (22.5% versus 12.7%; q = 0.02). Compared with ESR1WT mBC, ESR1MUT tumors showed higher fraction of genome altered (FGA) {[0.28 interquartile range (IQR), 0.15-0.43] versus 0.22 (0.11-0.38); P = 0.04} and tumor mutational burden (TMB) [4.89 (IQR 3.46-6.85) versus 3.92 (2.59-6.05) mut/Mb; P = 0.001]. Tumors harboring p.E380X alterations showed higher TMB compared with those with H11-12 alterations [8.24 (IQR 5.06-15.3) versus 4.89 (IQR 3.46-6.75) mut/Mb; P = 0.01]. Genetic alterations of TP53 were enriched in ESR1WT tumors (36% versus 14%) [odds ratio (OR) 3.17, 95% confidence interval (CI) 1.88-5.64, q = 0.001]. Considering signaling pathways, ESR1MUT tumors showed a lower occurrence of TP53 (OR 0.48, 95% CI 0.30-0.74; q = 0.003) and MAPK (OR 0.29, 95% CI 0.11-0.65; q = 0.009) alterations. TP53 (q < 0.001), CDH1 (q < 0.001), and ERBB2 (q < 0.001) demonstrated mutual exclusivity with ESR1MUT. CONCLUSIONS: ER+/HER2- mBCs carrying ESR1MUT exhibit a divergent genomic background, characterized by a lower prevalence of TP53 and MAPK pathway alterations. Less common ESR1 alterations falling outside the H11-H12 region seem to occur in tumors with higher TMB, deserving further investigation to understand their potential actionability.

Data quality assessment of the Dutch Breast Implant Registry by automated data verification using medical billing data.

BACKGROUND: The Dutch Breast Implant Registry (DBIR) provides real-time population-based data to monitor and improve the quality and safety of breast implants and to trace patients in the event of an (inter)national recall. To serve these main goals, the capture rate and percentage of implants that are actually registered should be known and data should be complete. This study aimed to describe an automated verification process for capture rates and data completeness using medical billing data as the external source. METHODS: DBIR-data on reconstructive permanent breast implants and tissue expanders (TEs) from 2019 were compared to medical billing data. At the hospital level, the capture rate of DBIR and accuracy of the selected data points were assessed. RESULTS: In total, 2389 implants (1420 patients) were included from 12 participating hospitals (11% of all healthcare institutions registering in DBIR). DBIR had capture rates of 99% to 114% for inserted permanent implants and TEs and 49% for explanted permanent implants and TEs. Among the 9015 data points analyzed in DBIR, 8861 (98%) matched the medical billing data. Mastopexy had the highest matching percentage (100%) and capsulectomy the lowest (86%). CONCLUSION: This study showed varying capture rates in DBIR depending on the intervention group, indicating that registration of DBIR-data and medical billing codes could be further optimized. Data accuracy was high as only 2% of data points did not correspond to medical billing data. For future data verification, other external data sources could be explored, including sources that enable verification of cosmetic implants.

Recent update on IGF-1/IGF-1R signaling axis as a promising therapeutic target for triple-negative breast cancer.

Insulin-like growth factor 1/Insulin-like growth factor 1-receptor (IGF-1/IGF-1R) pathway is highly breast cancer subtype context-dependent. Triple-negative breast cancer (TNBC) is an aggressive, highly metastatic cancer showing early recurrence and poor prognosis. High expression of IGF-1 and its receptor IGF-1R, their interaction, autophosphorylation, and activation of intracellular signaling cascades have been significantly associated with TNBC pathophysiology. In the last five to seven years, marvelous work has been done to explore the role of IGF-1/IGF-1R axis in TNBC. In the present review, starting from the general introduction to IGF-1/IGF-1R pathway an up-to-date discussion was focused on its role in TNBC pathophysiology. Further we discussed the up/down stream molecular events of IGF-1/IGF-1R axis, clinical relevance of IGF-1 and IGF-1R levels in TNBC patients, anti-TNBC therapy and possible way-out for IGF-1/IGF-1R axis mediate therapy resistance in TNBC. Combination therapy strategy has been researched to overcome direct IGF-1/IGF-1R pathway inhibition mediated therapy resistance and produced promising results in the management of TNBC. The understanding of up/downstream of the IGF-1/IGF-1R axis provide immense focus on the pathway as a therapeutic target. It is expected within the next decade to determine its potentiality, or lack thereof, for TNBC treatment.

Increased activity reduces the prevalence of woody breast in Ross 708 and Ranger Gold broilers.

Woody or wooden breast (WB) is characterized by hardening and paleness of the Pectoralis major muscle and can affect up to 85% of broilers. We hypothesized that increased locomotor activity would lead to a lower prevalence of WB and increased tibia bone quality, with a greater effect on a faster growing than a slower growing broiler strain. Ross 708 (N = 188) and Ranger Gold (N = 213) broilers were raised in 3.05×3.05 m2 pens in groups of 23 to 24 and 26 to 27, respectively. Target ages for the Ross 708 and Ranger Gold birds were 42 and 56 d. There were 8 pens per strain: 4 assigned to an exercise treatment and 4 unexercised controls. An exercise regimen was applied for 10 min every hour for 6 h during each weekday with the goal of increasing frequency of standing and walking. A perch was placed between the feeder and drinker line in the exercise treatment pens to further promote broiler activity. WB severity was determined by palpation for all birds at the target age. Tibial bone mineral content (BMC) and bone mineral density (BMD) were measured using a dual-energy x-ray absorptiometry. The Fisher's Exact Test was used to determine treatment effects on the prevalence and severity of WB. Both prevalence (Ross 708: 77.5 vs. 90.5% control, P = 0.013; Ranger Gold: 57.9 vs. 76.4% control, P = 0.005) and severity (Ross 708: 12.9 vs. 24.2% control, P = 0.02; Ranger Gold: 4.7 vs. 0.02% control, P = 0.01) were reduced by treatment. The effects of strain, treatment and their interaction on tibial BMC and BMD were analyzed using linear mixed models. Only strain affected BMC (P = 0.003) and BMD (P = 0.03), with Ross 708 broilers having higher BMC (control: 3.246 g ± 0.061; treatment: 3.251 g ± 0.058) and BMD (control: 0.177 g/cm2 ± 0.002; treatment: 0.174 g/cm2 ± 0.002) values compared to Ranger Gold's BMC (control: 2.966 g ± 0.067; treatment: 2.987 g ± 0.064) and BMD (control: 0.168 g/cm2 ± 0.002; treatment: 0.168 g/cm2 ± 0.002) values. However, per unit of final body weight, Ranger Gold birds had a significantly higher BMC (P = 0.006) and BMD (P = 0.01) than Ross 708 broilers. Promoting broiler activity can reduce the prevalence and severity of WB prevalence in fast and slow growing broilers.

Accessing breast cancer care in a protracted conflict: Qualitative exploration of the perspectives of women with breast cancer in northwest Syria.

BACKGROUND: Women with breast cancer in northwest Syria, an area of protracted armed conflict, face multiple intersecting challenges to accessing care which may relate to gender, social structures, and financial constraints. Our aim was to explore the perspectives of women with breast cancer in northwest Syria about the impact of their diagnosis and experiences of accessing care. METHODS: Women who accessed diagnosis or clinical care at the Syrian American Medical Society (SAMS) oncology centre in Idlib city during 2022 were identified from hospital records; they were invited to participate in semi-structured interviews conducted in Arabic by four local female-trained researchers. Participation was voluntary and informed consent was sought. Semi-structured interviews were conducted in August and September 2022 until thematic saturation was reached. Data were audio recorded and transcribed in Arabic before translation and thematic analysis using Nvivo to identify key emerging themes. RESULTS: 22 women with breast cancer were interviewed. Findings were categorised into three themes: 1. Challenges to accessing oncology care in northwest Syria 2. Interactions with healthcare workers 3. The role of community and society. All participants noted the financial strains which the breast cancer diagnosis placed on them and their families. Most also noted the additional strains of travelling long distances, either in northwest Syria or to Turkey, where referral would entail additional costs, bureaucracy or isolation from family or social support. Some participants described social impacts including the expectation that they would continue with household chores and childcare even while ill. Patients reported that strong faith, having children, compassion from healthcare staff and peer support as being important factors for coping with their diagnosis and treatment. CONCLUSION: Though there have been improvements to breast cancer care in northwest Syria, stock-outs and the lack of availability of radiotherapy may still force women to travel to Turkey for further investigations or treatment. Our findings suggest increased support for women with breast cancer as well as their families is required. This work is a starting point for future research on this topic both in northwest Syria and other areas in Syria.

Drug discovery of N-methyl-pyrazole derivatives as potent selective estrogen receptor degrader (SERD) for the treatment of breast cancer.

Nowadays, ERα is considered to be a primary target for the treatment of breast cancer, and selective estrogen receptor degraders (SERDs) are emerging as promising antitumor agents. By analysing ERα-SERDs complexes, the pharmacophore features of SERDs and the crucial protein-ligand interactions were identified. Then, by utilizing the scaffold-hopping and bioisosteres strategy, 23 novel derivatives were designed, synthesized and biologically evaluated. Among these derivatives, A20 exhibited potent ERα binding affinity (IC50 = 24.0 nM), degradation ability (EC50 = 5.3 nM), excellent ER selectivity, and outstanding anti-proliferative effects on MCF-7 cells (IC50 = 0.28 nM). Further biological studies revealed that A20 could degrade ERα through proteasome-mediated pathway, suppress signal transduction of MCF-7 cells, and arrest the cell cycle in G1 phase. Moreover, A20 showed excellent antitumor effect (TGI = 92.98 %, 30 mg kg-1 day-1) in the MCF-7 xenograft model in vivo with good safety and favorable pharmacokinetics (F = 39.6 %), making it a promising candidate for the treatment of breast cancer.

Unlocking the potential of extracellular vesicle circRNAs in breast cancer: From molecular mechanisms to therapeutic horizons.

Breast cancer remains the leading cause of cancer-related morbidity and mortality among women worldwide, underscoring the urgent need for novel diagnostic and therapeutic strategies. This review explores the emerging roles of circular RNAs (circRNAs) within extracellular vesicles (exosomes) in breast cancer. circRNAs, known for their stability and tissue-specific expression, are aberrantly expressed in breast cancer and regulate critical cellular processes such as proliferation, migration, and apoptosis, positioning them as promising biomarkers. Exosomes facilitate intercellular communication by delivering circRNAs, reflecting the physiological and pathological state of their source cells. This review highlights the multifaceted roles of exosomal circRNAs in promoting tumor growth, metastasis, and drug resistance through their modulation of tumor metabolism, the tumor microenvironment, and immune responses. In particular, we emphasize their contributions to chemotherapy resistance and their potential as both diagnostic markers and therapeutic targets. By synthesizing current research, this review provides novel insights into the clinical applications of exosomal circRNAs, offering a foundation for future studies aimed at improving breast cancer management through non-invasive diagnostics and targeted therapies.

Standard chemotherapy impacts on in vitro cellular heterogeneity in spheroids enriched with cancer stem cells (CSCs) derived from triple-negative breast cancer cell line.

Triple-negative breast cancer is a heterogeneous disease with high recurrence and mortality, linked to cancer stem cells (CSCs). Our study characterized distinct cell subpopulations and signaling pathways to explore chemoresistance. We observed cellular heterogeneity among and within the cells regarding phenotyping and drug response. In untreated BT-549 cells, we noted plasticity properties in both CD44+/CD24+/CD146+ hybrid cells and CD44-/CD24+/CD146+ epithelial cells, enabling phenotypic conversion into CD44+/CD24-/CD146- epithelial-mesenchymal transition (EMT)-like like breast CSCs (BCSCs). Additionally, non-BCSCs may give rise to ALDH+ epithelial-like BCSCs. Enriched BCSCs demonstrated the potential to differentiation into CD44-/CD24-/CD146- cells and exhibited self-renewal capabilities. Similar phenotypic plasticity was not observed in untreated Hs 578T and HMT-3522 S1 cells. BT-549 cells were more resistant to paclitaxel/PTX than to doxorubicin/DOX, a phenomenon potentially linked to the presence of CD24+ cells prior to treatment. Under the CSCs-enriched spheroids model, BT-549 demonstrated extreme resistance to DOX, likely due to the enrichment of BCSCs CD44+/CD24-/CD146- and the tumor cells CD44-/CD24-/CD146-. Additionally, DOX treatment induced the enrichment of plastic and chemoresistant cells, further exacerbating resistance mechanisms. BT-549 exhibited high heterogeneity, leading to significant alterations in cell subpopulations under BCSCs enrichment, demonstrating increased phenotypic plasticity during EMT. This phenomenon appears to play a major role in DOX resistance, as indicated by the presence of the refractory cells CD44+/CD24-/CD146- BCSCs EMT-like, CD44-/CD24-/CD146- tumor cells, and elevated STAT3 expression. Gene expression data from BT-549 CSCs-enriched spheroids suggests that ferroptosis may be occurring via autophagic regulation triggered by RAB7A, highlighting this gene as a potential therapeutic target.

Photothermal nanocomposite reactivate "immune-hot" for triple-negative breast cancer treatment via glutamine metabolism reprograming.

Herein, a photothermal nanocomposite PAI@CB839 nanoparticles (NPs) was constructed to perform a heat-immune therapy for triple-negative breast cancer (TNBC). Firstly, a photothermal agent animated IR780 was modified on a mPEG-NH2 using 4,4'-dicarboxylazobenzene as a linker. The synthesized PAI exhibited superior photothermal efficiency of the IR780 even after assembling in water. As a functional carrier, PAI was used to load and deliver the glutaminase inhibitor CB839 to tumor tissue. In the hypoxic environment of tumor cells, the azo bond would break, triggering the release of cargo. Upon irradiation, the outstanding photothermal properties of IR780 resulted in tumor cell damage. This process could promote immunogenic cell death and program tumor to "immune-hot" condition. Concurrently, CB839 strengthened the antitumor immune response by remodulating the immunosuppressive TME through disturbing Glu abnormal metabolism, which further inhibited TNBC growth and metastasis. In conclusion, PAI@CB839 NPs exhibited great antitumor efficiency, which pave a new way for TNBC therapeutic regimen development.