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Automated Quantification of Extranuclear ERα using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR+/HER2? Breast Cancer
摘要： In addition to genomic signaling, Estrogen receptor alpha (ERα) is associated with cell proliferation and survival through extranuclear signaling contributing to endocrine therapy (ET) resistance. However, the relationship between extranuclear ERα and ET resistance has not been extensively studied. We sought to measure extranuclear ERα expression by immunohistochemistry using phosphor-integrated dots (IHC-PIDs) and to assess its predictive value for ET resistance. After quantitative detection of ERα by IHC-PIDs in vitro, we developed “the nearest-neighbor method” to calculate the extranuclear ERα. Furthermore, tissue sections from 65 patients with HR+/HER2- BC were examined by IHC-PIDs, and the total ERα, nuclear ERα, extranuclear ERα PIDs score, and ratio of extranuclear-to-nuclear ERα (ENR) were measured using the novel method. We demonstrate that quanti?cation of ERα using IHC-PIDs exhibited strong correlations to real-time qRT-PCR (r2 = 0.94) and ?ow cytometry (r2 = 0.98). High ERα ENR was signi?cantly associated with poor overall survival (p = 0.048) and disease-free survival (DFS) (p = 0.007). Multivariate analysis revealed that the ERα ENR was an independent prognostic factor for DFS [hazard ratio, 3.8; 95% CI, 1.4–11.8; p = 0.006]. Our automated measurement has high accuracy to localize and assess extranuclear ERα. A high ERα ENR in HR+/HER2- BC indicates decreased likelihood of bene?ting from ET.
关键词： estrogen receptor α,endocrine therapy resistance,breast cancer,prognostic,IHC-PIDs
更新于2025-11-21 11:08:12
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Green Synthesis of Carrier-Free Curcumin Nanodrugs for Light-activated Breast Cancer Photodynamic Therapy
摘要： Photodynamic therapy (PDT) is a promising procedure for breast cancer therapy. Curcumin (Cur), a hydrophobic polyphenol derived from the spice turmeric, has been considered as a potential photosensitizer for PDT with evoked immune response, excellent safety, and low cost. However, the translation of curcumin in clinical cancer therapy suffers from an insufficient therapeutic dose in tumor tissues due to its poor solubility and low bioavailability. In this study, carrier-free curcumin nanodrugs (Cur NDs) were prepared without using any toxic solvents through a facile and green reprecipitation method. Cur NDs exhibited distinct optical properties, light-sensitive drug release behavior, resulting in increased reactive oxygen species (ROS) generation and PDT efficacy on breast cancer cells compared with free Cur. Furthermore, cell apoptosis during Cur-based PDT was concomitant with the activation of the ROS-mediated JNK/caspase-3 signaling pathway. Overall, our carrier-free Cur nanodrugs may be promising candidates for facilitating the efficacy and safety of PDT against breast cancer.
关键词： Carrier-free,Curcumin,Light-responsive drug release,Breast cancer,Photodynamic therapy
更新于2025-11-14 15:26:12
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Synthesizing mammogram from digital breast tomosynthesis
摘要： The purpose of this study is to develop a new method for generating synthesized mammogram (SM) from digital breast tomosynthesis (DBT) and to assess its potential as an adjunct to DBT. We first applied multiscale bilateral filtering to the reconstructed DBT slices to enhance the high-frequency features and reduce noise. A maximum intensity projection (MIP) image was then obtained from the high-frequency components of the DBT slices. A multiscale image fusion method was designed to combine the MIP image and the central DBT projection view into an SM and further enhance the high-frequency features. We conducted a pilot reader study to visually assess the image quality of SM in comparison to full field digital mammograms (FFDM). For each DBT craniocaudal or mediolateral view, a clinical FFDM of the corresponding view was retrospectively collected. Three MQSA radiologists, blinded to the pathological and other clinical information, independently interpreted the SM and the corresponding FFDM side by side marked with the lesion locations. The differences in the BI-RADS assessments of both MCs and masses between SM and FFDM did not achieve statistical significance for all 3 readers. The conspicuity of MCs on SM was superior to that on FFDM and the BI-RADS assessments of MCs were comparable while the conspicuity of masses on SM was degraded and interpretation on SM was less accurate than that on FFDM. The SM may be useful for efficient prescreening of MCs in DBT but the DBT should be used for detection and characterization of masses.
关键词： synthesized mammography (SM),digital breast tomosynthesis (DBT),breast cancer
更新于2025-09-23 15:23:52
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Predicting interval and screen-detected breast cancers from mammographic density defined by different brightness thresholds
摘要： Background: Case–control studies show that mammographic density is a better risk factor when defined at higher than conventional pixel-brightness thresholds. We asked if this applied to interval and/or screen-detected cancers. Method: We conducted a nested case–control study within the prospective Melbourne Collaborative Cohort Study including 168 women with interval and 422 with screen-detected breast cancers, and 498 and 1197 matched controls, respectively. We measured absolute and percent mammographic density using the Cumulus software at the conventional threshold (Cumulus) and two increasingly higher thresholds (Altocumulus and Cirrocumulus, respectively). Measures were transformed and adjusted for age and body mass index (BMI). Using conditional logistic regression and adjusting for BMI by age at mammogram, we estimated risk discrimination by the odds ratio per adjusted standard deviation (OPERA), calculated the area under the receiver operating characteristic curve (AUC) and compared nested models using the likelihood ratio criterion and models with the same number of parameters using the difference in Bayesian information criterion (ΔBIC). Results: For interval cancer, there was very strong evidence that the association was best predicted by Cumulus as a percentage (OPERA = 2.33 (95% confidence interval (CI) 1.85–2.92); all ΔBIC > 14), and the association with BMI was independent of age at mammogram. After adjusting for percent Cumulus, no other measure was associated with risk (all P > 0.1). For screen-detected cancer, however, the associations were strongest for the absolute and percent Cirrocumulus measures (all ΔBIC > 6), and after adjusting for Cirrocumulus, no other measure was associated with risk (all P > 0.07). Conclusion: The amount of brighter areas is the best mammogram-based measure of screen-detected breast cancer risk, while the percentage of the breast covered by white or bright areas is the best mammogram-based measure of interval breast cancer risk, irrespective of BMI. Therefore, there are different features of mammographic images that give clinically important information about different outcomes.
关键词： Masking effect,Interval cancer,Screen-detected,Mammographic density,Australian women,Nested case–control cohort study,Mammography,Breast cancer
更新于2025-09-23 15:23:52
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Measurement of peripheral dose to pelvic region and associated risk for cancer development after breast intraoperative electron radiation therapy
摘要： This study aimed to measure received dose to the pelvic region of patients during breast intraoperative electron radiation therapy (IOERT). Furthermore, we compared the findings with those of external beam radiation therapy. Finally, secondary ovary and uterus cancer risks following breast IOERT were estimated. In the current study, the received dose to the pelvic surface of 18 female patients during breast IOERT boost were measured by thermoluminescent dosimeter (TLD-100) chips. All patients were treated with 12 Gy given in a single fraction. To estimate the dose to the ovary and uterus of the patients, conversion coefficients for depth from surface dose were obtained in a Rando phantom. Given the received dose to the pelvic region of the patients, secondary ovary and uterus cancer risks following breast IOERT were estimated. The received doses to ovary and uterus surface of the patients were 0.260±0.155 mGy to 31.460±6.020 mGy and 0.485±0.122 mGy to 22.387±15.476 mGy, respectively. Corresponding intra-pelvic (ovary and uterus) regional doses were 0.012±0.007 mGy to 1.479±0.283 mGy and 0.027±0.001 mGy to 1.164±0.805 mGy, respectively. Findings demonstrated that the ratio of the received dose by pelvic surface to regional dose during breast IOERT was much less than external beam energies were 135.722±117.331 × 10-6 and 69.958±28.072 × 10-6, and for uterus were 17.342±10.583 × 10-6 and 2.971±3.604 × 10-6, respectively. According to our finding, the use of breast IOERT in pregnant patients can be considered as a safe radiotherapeutic technique, because the received dose to the fetus was lower than 50 mGy. Furthermore, IOERT can efficiently reduce the unnecessary dose to the pelvis region and lowers the risk of a secondary ovary and uterus cancer following breast irradiation.
关键词： Breast cancer,peripheral dose,Radiation therapy,IOERT,Secondary cancer risk,pelvic region
更新于2025-09-23 15:23:52
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Optical Imaging of Triple-Negative Breast Cancer Cells in Xenograft Athymic Mice Using an ICAM-1-Targeting Small-Molecule Probe
摘要： Purpose: The development of early, accurate diagnostic strategies for triple-negative breast cancer (TNBC) remains a significant challenge. Intercellular adhesion molecule-1 (ICAM-1) overexpressed in human TNBC cells is a potential molecular target and biomarker for diagnosis. In this study, small-molecule probe (denoted as γ3-Cy5.5) constructed with a short 17-mer linear peptide (γ3) and near-infrared fluorescence (NIRF) dye cyanine 5.5 (Cy5.5) was used to detect the expression of ICAM-1 in vitro and in vivo, and to diagnose TNBC via NIRF imaging. Procedures: Western blotting and flow cytometric analysis were used for the detection of ICAM-1 expression in MDA-MB-231 and MCF-7 cells. The cytotoxicity of the small-molecule probe γ3-Cy5.5 was detected using the CCK8 assay. The in vitro targeting of the small-molecule probe γ3-Cy5.5 was verified via flow cytometry and a laser scanning confocal microscope. Finally, the targeting of small-molecule probe in vivo and ex vivo was observed by NIRF imaging. Results: Western blotting and flow cytometry demonstrate that ICAM-1 was highly expressed in the MDA-MB-231 TNBC cell line. Laser confocal microscopy and flow cytometry results show that TNBC cells have an increased cellular uptake of γ3-Cy5.5 compared to the control probe γ3S-Cy5.5. With in vivo NIRF, a significantly higher Cy5.5 signal appeared in the tumors of mice administered γ3-Cy5.5 than those treated with γ3S-Cy5.5. The target-to-background ratio observed on the NIRF images was significantly higher in the γ3-Cy5.5 group (10.2, 13.6) compared with the γ3S-Cy5.5 group (4.4, 4.0) at 1 and 2 h, respectively. Conclusions: This is the first report of the use of ICAM-1-specific small-molecule probe for in vivo NIRF optical imaging of TNBC. This method provides a noninvasive and specific strategy for the early diagnosis of TNBC.
关键词： Triple-negative breast cancer,Near-infrared fluorescence imaging,Small-molecule probe,ICAM-1
更新于2025-09-23 15:23:52
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Development of an Aptamer-Conjugated Polyrotaxane-Based Biodegradable Magnetic Resonance Contrast Agent for Tumor-Targeted Imaging
摘要： Gadolinium-based magnetic resonance imaging (MRI) contrast agents with biodegradability, biosafety, and high efficiency are highly desirable for tumor diagnosis. Herein, a biodegradable, AS1411-conjugated, α-cyclodextrin polyrotaxane-based MRI contrast agent (AS1411-G2(DTPA-Gd)-SS-PR) was developed for targeted imaging of cancer. The polyrotaxane-based contrast agent was achieved by the complexation of α-cyclodextrin (α-CD) and a linear poly(ethylene glycol) (PEG) chain containing disulfide linkages at two terminals. The disulfides enable the de-threading of the polyrotaxane into excretable small units due to cleavage of the disulfide linkages by reducing agents such as intracellular glutathione (GSH). Furthermore, the second-generation lysine dendron conjugated with gadolinium chelates and AS1411, a G-quadruplex oligonucleotide that has high binding affinity to nucleolin generally presenting a high level on the surface of tumor cells, coupled to the α-CD via click chemistry. The longitudinal relaxivity of AS1411-G2(DTPA-Gd)-SS-PR (11.7 mM?1 s?1) was two times higher than the clinically used Gd-DTPA (4.16 mM?1 s?1) at 0.5 T. The in vitro degradability was confirmed by incubating with 10 mM 1,4-Dithiothreitol (DTT). Additionally, the cytotoxicity, histological assessment and gadolinium retention studies showed that the prepared polyrotaxane-based contrast agent had a superior biocompatibility and was predominantly cleared renally without long-term accumulation toxicity. Importantly, AS1411-G2(DTPA-Gd)-SS-PR displayed the enhanced performance in MRI of breast cancer cells in vitro as well as a subcutaneous breast tumor in vivo due to the targeting ability of AS1411 aptamer. The enhanced performance was due to efficient multivalent interactions with tumor cells, producing faster accumulation and longer contrast imaging time at the tumor site. This work clearly confirms that the specially designed and fabricated α-CD-based polyrotaxane is a promising contrast agent with excellent contrast imaging performance and biosafety for tumor MR imaging.
关键词： AS1411 aptamer,biodegradability,polyrotaxanes,magnetic resonance imaging,breast cancer targeting
更新于2025-09-23 15:23:52
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Intratumorally Injected Photothermal Agent-Loaded Photodynamic Nanocarriers for Ablation of Orthotopic Melanoma and Breast Cancer
摘要： Traditional chemotherapy of cancers may lead to serious adverse reactions due to little drug distribution in tumors. Here, a combination of photothermal therapy (PTT) and photodynamic therapy (PDT) was used for local treatment of orthotopic melanoma and breast cancer via intratumoral (i.t.) injection of photothermal agent-loaded photodynamic nanocarriers. A hydrophobic derivative of indocyanine green, DCC, was synthesized and entrapped into a pH-sensitive photosensitizer-core copolymer, PDCZP, to form DCC@PDCZP. The nanocarriers showed remarkable fluorescence, high singlet oxygen quantum yields, and strong photothermal effect. Flow cytometry suggested that the nanocarriers were efficiently internalized by cancer cells. Near infrared thermal imaging and fluorescence self-imaging showed that the i.t. injected DCC@PDCZP mainly remained in the tumors but the intravenous (i.v.) nanocarriers were distributed a little. One i.t. injection of DCC@PDCZP was enough to ablate the orthotopic B16-F10 and 4T1 mouse tumors under 830 nm and 660 nm irradiation at 4 hours post-injection. More importantly, no local recurrences were found though scabs were formed at 9 days post-treatment. The major anticancer mechanisms included improvement of cancer cell necrosis due to hyperthermia, inhibition of neovascularization, and enhancement of cell apoptosis. The i.t. injection of PTT/PDT nanoformulations is thus a promising local treatment of superficial tumors.
关键词： zinc phthalocyanine,intratumoral injection,melanoma,indocyanine green,breast cancer,photodynamic therapy,photothermal therapy
更新于2025-09-23 15:23:52
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Nonrigid reconstruction of 3D breast surfaces with a low-cost RGBD camera for surgical planning and aesthetic evaluation
摘要： Accounting for 26% of all new cancer cases worldwide, breast cancer remains the most common form of cancer in women. Although early breast cancer has a favourable long-term prognosis, roughly a third of patients suffer from a suboptimal aesthetic outcome despite breast conserving cancer treatment. Clinical-quality 3D modelling of the breast surface therefore assumes an increasingly important role in advancing treatment planning, prediction and evaluation of breast cosmesis. Yet, existing 3D torso scanners are expensive and either infrastructure-heavy or subject to motion artefacts. In this paper we employ a single consumer-grade RGBD camera with an ICP-based registration approach to jointly align all points from a sequence of depth images non-rigidly. Subtle body deformation due to postural sway and respiration is successfully mitigated leading to a higher geometric accuracy through regularised locally affine transformations. We present results from 6 clinical cases where our method compares well with the gold standard and outperforms a previous approach. We show that our method produces better reconstructions qualitatively by visual assessment and quantitatively by consistently obtaining lower landmark error scores and yielding more accurate breast volume estimates.
关键词： Breast cancer treatment,Nonrigid registration,Depth camera,3D surface reconstruction,Aesthetic evaluation
更新于2025-09-23 15:23:52
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Methylene-Blue-Encapsulated Liposomes as Photodynamic Therapy Nano Agents for Breast Cancer Cells
摘要： Methylene blue (MB) is a widely used dye and photodynamic therapy (PDT) agent that can produce reactive oxygen species (ROS) after light exposure, triggering apoptosis. However, it is hard for the dye to penetrate through the cell membrane, leading to poor cellular uptake; thus, drug carriers, which could enhance the cellular uptake, are a suitable solution. In addition, the defective vessels resulting from fast vessel outgrowth leads to an enhanced permeability and retention (EPR) effect, which gives nanoscale drug carriers a promising potential. In this study, we applied poly(12-(methacryloyloxy)dodecyl phosphorylcholine), a zwitterionic polymer-lipid, to self-assemble into liposomes and encapsulate MB (MB-liposome). Its properties of high stability and fast intracellular uptake were confirmed, and the higher in vitro ROS generation ability of MB-liposomes than that of free MB was also verified. For in vivo tests, we examined the toxicity in mice via tail vein injection. With the features found, MB-liposome has the potential of being an effective PDT nano agent for cancer therapy.
关键词： methylene blue,zwitterion,liposome,photodynamic therapy,breast cancer cell
更新于2025-09-23 15:23:52