Novel Self-Assembled Multifunctional Nanoprobes for Second-Near-Infrared-Fluorescence-Image-Guided Breast Cancer Surgery and Enhanced Radiotherapy Efficacy.

Breast-conserving surgery (BCS) is the predominant treatment approach for initial breast cancer. However, due to a lack of effective methods evaluating BCS margins, local recurrence caused by positive margins remains an issue. Accordingly, radiation therapy (RT) is a common modality in patients with advanced breast cancer. However, while RT also protects normal tissue and enhances tumor bed doses to improve therapeutic effects, current radiosensitizers cannot meet these urgent clinical needs. To address this, a novel self-assembled multifunctional nanoprobe (NP) gadolinium (Gd)-diethylenetriaminepentaacetic acid-human serum albumin (HSA)@indocyanine green-Bevacizumab (NPs-Bev) is synthesized to improve the efficacy of fluorescence-image-guided BCS and RT. Fluorescence image guidance of the second near infrared NP improves complete resection in tumor-bearing mice and accurately discriminates between benign and malignant mammary tissue in transgenic mice. Moreover, targeting tumors with NPs induces more reactive oxygen species under X-ray radiation therapy, which not only increases RT sensitivity, but also reduces tumor progression in mice. Interestingly, self-assembled NPs-Bev using HSA, the magnetic resonance contrast agent and Bevacizumab-targeting vascular growth factor A, which are clinically safe reagents, are safe in vitro and in vivo. Therefore, the novel self-assembled NPs provide a solid precision therapy platform to treat breast cancer.

Application of molecular imaging in immune checkpoints therapy: From response assessment to prognosis prediction.

Recently, immune checkpoint therapy (ICT) represented by programmed cell death1 (PD-1) and its major ligands, programmed death ligand 1 (PD-L1), has achieved significant success. Detection of PD-L1 by immunohistochemistry (IHC) is a classic method to guide the treatment of ICT patients. However, PD-L1 expression in the tumor microenvironment is highly complex. Thus, PD-L1 IHC is inadequate to fully understand the relevance of PD-L1 levels in the whole body and their dynamics to improve therapeutic outcomes. Intriguingly, numerous studies have revealed that molecular imaging technologies could potentially meet this need. Therefore, the purpose of this narrative review is to summarize the preclinical and clinical application of ICT guided by molecular imaging technology, and to explore the future opportunities and practical difficulties of these innovations.

In vivo visualization of fluorescence reflecting CDK4 activity in a breast cancer mouse model.

The CDK4/6-Rb axis is a crucial target of cancer therapy and several selective inhibitors of it have been approved for clinical application. However, current therapeutic efficacy evaluation mostly relies on anatomical imaging, which cannot directly reflect changes in drug targets, leading to a delay in the selection of optimal treatment. In this study, we constructed a novel fluorescent probe, CPP30-Lipo/CDKACT4, for real-time monitoring of CDK4 activity and the therapeutic efficacy of its inhibitor in HR+/HER2- breast cancer. CPP30-Lipo/CDKACT4 exhibited good optical stability and targetability. The signal of the probe in living cells decreased after CDK4 knockdown or palbociclib treatment. Moreover, the fluorescence intensity of the tumors after 7 days of palbociclib treatment was significantly lower than that before treatment, while no significant change in tumor diameter was observed under magnetic resonance imaging. Overall, we developed an innovative fluorescent probe that can monitor CDK4 activity and the early therapeutic response to CDK4 inhibitors in living cells and in vivo. It may provide a new strategy for evaluating antitumor therapeutic efficacy in a clinical context and for drug development.

Fabrication of tumor targeting rare-earth nanocrystals for real-time NIR-IIb fluorescence imaging-guided breast cancer precise surgery.

The near-infrared fluorescence imaging has been integrated into the operating room to guide tumor resection, potentially reducing the positive margin rates in breast-conserving surgery (BCS). Relative to the widely used first near-infrared fluorescence imaging, imaging in the second near-infrared (NIR-II) region possesses higher contrast and deeper tissue penetration, particularly in the NIR-IIb window, offering many new opportunities for imaging-guided BCS. Here, we fabricated the c(RGDfC) functionalized erbium-based rare-earth nanoparticles (ErNPs@cRGD) with superior optical property in NIR-IIb region. Owing to deeper tissue penetration and efficient tumor targeting, ErNPs@cRGD-based NIR-IIb fluorescence imaging achieved enhanced signal-to-background ratios in tumor visualization, which was able to guide more complete tumor resection, identify multiple microtumors and distinguish malignant lesions from normal tissues in various mice models. Based on these, this NIR-IIb imaging strategy for surgical navigation can significantly reduce positive margin rates and improve prognosis, laying a foundation for the clinical resection of breast cancer.

Development and Preclinical Evaluation of a Near-Infrared Fluorescence Probe Based on Tailored Hepatitis B Core Particles for Imaging-Guided Surgery in Breast Cancer.

Purpose: Tumor-free surgical margin is crucial but challenging in breast-conserving surgery (BCS). Fluorescence imaging is a promising strategy for surgical navigation that can reliably assist the surgeon with visualization Of the tumor in real-time. Notably, finding an optimized fluorescent probe has been a challenging research topic. Herein, we developed a novel near-infrared (NIR) fluorescent probe based on tailored Hepatitis B Core virus-like protein (HBc VLP) and presented the preclinical imaging-guided surgery. Methods: The RGD-HBc160 VLP was synthesized by genetic engineering followed encapsulation of ICG via disassembly-reassembly. The applicability of the probe was tested for cell and tissue binding capacities through cell-based plate assays, xenograft mice model, and MMTV-PyVT mammary tumor transgenic mice. Subsequently, the efficacy of RGD-HBc160/ICG-guided surgery was evaluated in an infiltrative tumor-bearing mouse model. The protein-induced body's immune response was further assessed. Results: The prepared RGD-HBc160/ICG showed outstanding integrin αvß3 targeting ability in vitro and in vivo. After intravenous administration of probe, the fluorescence guidance facilitated more complete tumor resection and improved overall survival Of the infiltrative tumor-bearing mice. The probe also showed the excellent capability to differentiate between benign and malignant breast tissues in the mammary tumor transgenic mice. Interestingly, the ingenious tailoring of HBc VLP could not only endow its tumor-targeting ability towards integrin αvß3 but also significantly reduce the humoral and cellular immune response. Conclusion: The RGD-HBc160/ICG holds promise as an effective tool to delineate tumor margin. These results have translational potential to achieve margin-negative resection and improve the stratification of patients for a potentially curative.

Biodegradable Nanoprobe for NIR-II Fluorescence Image-Guided Surgery and Enhanced Breast Cancer Radiotherapy Efficacy.

Positive resection margin frequently exists in breast-conserving treatment (BCT) of early-stage breast cancer, and insufficient therapeutic efficacy is common during radiotherapy (RT) in advanced breast cancer patients. Moreover, a multimodal nanotherapy platform is urgently required for precision cancer medicine. Therefore, a biodegradable cyclic RGD pentapeptide/hollow virus-like gadolinium (Gd)-based indocyanine green (R&HV-Gd@ICG) nanoprobe is developed to improve fluorescence image-guided surgery and breast cancer RT efficacy. R&HV-Gd exhibits remarkably improved aqueous stability, tumor retention, and target specificity of ICG, and achieves outstanding magnetic resonance/second near-infrared (NIR-II) window multimodal imaging in vivo. The nanoprobe-based NIR-II fluorescence image guidance facilitates complete tumor resection, improves the overall mouse survival rate, and effectively discriminates between benign and malignant breast tissues in spontaneous breast cancer transgenic mice (area under the curve = 0.978; 95% confidence interval: 0.952, 1.0). Moreover, introducing the nanoprobe to tumors generated more reactive oxygen species under X-ray irradiation, improved RT sensitivity, and reduced mouse tumor progression. Notably, the nanoprobe is biodegradable in vivo and exhibits accelerated bodily clearance, which is expected to reduce the potential long-term inorganic nanoparticle toxicity. Overall, the nanoprobe provides a basis for developing precision breast cancer treatment strategies.

Surgical Navigation for Malignancies Guided by Near-Infrared-II Fluorescence Imaging.

Near-infrared (NIR) fluorescence imaging is an emerging noninvasive imaging modality, with unique advantages in guiding tumor resection surgery, thanks to its high sensitivity and instantaneity. In the past decade, studies on the conventional NIR window (NIR-I, 750-900 nm) have gradually focused on the second NIR window (NIR-II, 1000-1700 nm). With its reduced light scattering, photon absorption, and auto-fluorescence qualities, NIR-II fluorescence imaging significantly improves penetration depths and signal-to-noise ratios in bio-imaging. Recently, several studies have applied NIR-II imaging to navigating cancer surgery, including localizing cancers, assessing surgical margins, tracing lymph nodes, and mapping important anatomical structures. These studies have exemplified the significant prospects of this new approach. In this review, several NIR-II fluorescence agents and some of the complex applications for guiding cancer surgeries are summarized. Future prospects and the challenges of clinical translation are also discussed.

Mutant p53 and Twist1 Co-Expression Predicts Poor Prognosis and Is an Independent Prognostic Factor in Breast Cancer.

PURPOSE: The basic helix-loop-helix transcription factor (bHLH) transcription factor Twist1 plays a key role in embryonic development and tumorigenesis. p53 is a frequently mutated tumor suppressor in cancer. Both proteins play a key and significant role in breast cancer tumorigenesis. However, the regulatory mechanism and clinical significance of their co-expression in this disease remain unclear. The purpose of this study was to analyze the expression patterns of p53 and Twist1 and determine their association with patient prognosis in breast cancer. We also investigated whether their co-expression could be a potential marker for predicting patient prognosis in this disease. METHODS: Twist1 and mutant p53 expression in 408 breast cancer patient samples were evaluated by immunohistochemistry. Kaplan-Meier Plotter was used to analyze the correlation between co-expression of Twist1 and wild-type or mutant p53 and prognosis for recurrence-free survival (RFS) and overall survival (OS). Univariate analysis, multivariate analysis, and nomograms were used to explore the independent prognostic factors in disease-free survival (DFS) and OS in this cohort. RESULTS: Of the 408 patients enrolled, 237 (58%) had high mutant p53 expression. Two-hundred twenty patients (53.9%) stained positive for Twist1, and 188 cases were Twist1-negative. Furthermore, patients that co-expressed Twist1 and mutant p53 (T+P+) had significantly advanced-stage breast cancer [stage III, 61/89 T+P+ (68.5%) vs. 28/89 T-P- (31.5%); stage II, 63/104 T+P+ (60.6%)vs. 41/104 T-P- (39.4%)]. Co-expression was negatively related to early clinical stage (i.e., stages 0 and I; P = 0.039). T+P+ breast cancer patients also had worse DFS (95% CI = 1.217-7.499, P = 0.017) and OS (95% CI = 1.009-9.272, P = 0.048). Elevated Twist1 and mutant p53 expression predicted shorter RFS in basal-like patients. Univariate and multivariate analysis identified three variables (i.e., lymph node involvement, larger tumor, and T+P+) as independent prognostic factors for DFS. Lymph node involvement and T+P+ were also independent factors for OS in this cohort. The total risk scores and nomograms were reliable for predicting DFS and OS in breast cancer patients. CONCLUSIONS: Our results revealed that co-expression of mutant p53 and Twist1 was associated with advanced clinical stage, triple negative breast cancer (TNBC) subtype, distant metastasis, and shorter DFS and OS in breast cancer patients. Furthermore, lymph nodes status and co-expression of Twist1 and mutant p53 were classified as independent factors for DFS and OS in this cohort. Co-evaluation of mutant p53 and Twist1 might be an appropriate tool for predicting breast cancer patient outcome.

Notch3 inhibits cell proliferation and tumorigenesis and predicts better prognosis in breast cancer through transactivating PTEN.

Notch receptors (Notch1-4) play critical roles in tumorigenesis and metastasis of malignant tumors, including breast cancer. Although abnormal Notch activation is related to various tumors, the importance of single receptors and their mechanism of activation in distinct breast cancer subtypes are still unclear. Previous studies by our group demonstrated that Notch3 may inhibit the emergence and progression of breast cancer. PTEN is a potent tumor suppressor, and its loss of function is sufficient to promote the occurrence and progression of tumors. Intriguingly, numerous studies have revealed that Notch1 is involved in the regulation of PTEN through its binding to CBF-1, a Notch transcription factor, and the PTEN promoter. In this study, we found that Notch3 and PTEN levels correlated with the luminal phenotype in breast cancer cell lines. Furthermore, we demonstrated that Notch3 transactivated PTEN by binding CSL-binding elements in the PTEN promoter and, at least in part, inhibiting the PTEN downstream AKT-mTOR pathway. Notably, Notch3 knockdown downregulated PTEN and promoted cell proliferation and tumorigenesis. In contrast, overexpression of the Notch3 intracellular domain upregulated PTEN and inhibited cell proliferation and tumorigenesis in vitro and in vivo. Moreover, inhibition or overexpression of PTEN partially reversed the promotion or inhibition of cell proliferation induced by Notch3 alterations. In general, Notch3 expression positively correlated with elevated expression of PTEN, ER, lower Ki-67 index, and incidence of involved node status and predicted better recurrence-free survival in breast cancer patients. Therefore, our findings demonstrate that Notch3 inhibits breast cancer proliferation and suppresses tumorigenesis by transactivating PTEN expression.

[Cadmium adsorption by biochar prepared from pyrolysis of silk waste at different temperatures]. / 不同炭化温度制备的蚕丝被废弃物生物炭对重金属Cd2+的吸附性能.

In this study, biochars (BC300, BC500 and BC700) were produced from silk waste through pyrolysis under oxygen-limited condition at 300, 500 and 700 ℃, respectively. The physicochemical properties of biochar were detected by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometer (XRD) and specific surface area analyzer. The Cd2+ adsorption capacities of biochars were investigated. Results showed that BET surface area, pH, and ash were increased with the increases of pyrolysis temperature. SEM images showed that the surfaces of biochars were rough and irregular. XRD and FT-IR results showed that all the silk waste biochars obtained at different temperatures contained calcite. pH had limited influence on the removal efficiency of biochar for Cd2+. Langmuir isotherm fitted the experimental data quite well. The Langmuir monolayer adsorption capacity of BC300, BC500, and BC700 were 25.61, 52.41, and 91.07 mg·g-1, respectively. The adsorption of Cd2+ onto the biochars obeyed a pseudo second-order kinetic model, with the BC700 showing the best removal efficiency. Further-more, the effects of the ionic strength and coexisting cations on Cd2+ removal were investigated. The results showed that the removal of Cd2+ was decreased with the increases of NaCl. Among the coexisting cations, the removal of Cd2+ was decreased by Ca2+ and Mg2+, while K+ had limited effect on the removal of Cd2+. In conclusion, the biochar derived from silk waste pyrolysis is a potential attractive adsorbent for the removal of Cd2+ from water.