An experimental-analytical scale-linking study on the crack-bridging mechanisms in different types of SHCC in dependence on fiber orientation

A scale-linking, experimental study complemented by an analytical model was carried out to investigate the influence of fiber orientation on the crack-opening behavior of strain-hardening cement-based composites (SHCC). Three SHCC compositions were investigated with polyvinyl alcohol (PVA) and ultra-high molecular weight polyethylene (UHMWPE) fibers in combination with normal- and high-strength matrices. The micromechanical experiments with fiber inclinations of 0◦, 30◦, 45◦, and 60◦ involved fiber embedment in plain and fiber-reinforced specimens. The experimentally derived micromechanical parameters were input into an analytical crack-bridging model to assess the upscaling accuracy of the micromechanical results by comparing the predicted crack-bridging laws to the single-crack opening behavior of equivalent miniature SHCC specimens with controlled fiber orientation. This study yields new insights into the effect of fiber orientation on the crackbridging properties of different types of SHCC, assesses the link between micromechanical and composite scale properties, offers a solid experimental basis for refining the analytical models, and developing anisotropic materials models for SHCC in dependence on fiber orientation

[89Zr]-Pertuzumab PET Imaging Reveals Paclitaxel Treatment Efficacy Is Positively Correlated with HER2 Expression in Human Breast Cancer Xenograft Mouse Models

Paclitaxel (PTX) treatment efficacy varies in breast cancer, yet the underlying mechanism for variable response remains unclear. This study evaluates whether human epidermal growth factor receptor 2 (HER2) expression level utilizing advanced molecular positron emission tomography (PET) imaging is correlated with PTX treatment efficacy in preclinical mouse models of HER2+ breast cancer. HER2 positive (BT474, MDA-MB-361), or HER2 negative (MDA-MB-231) breast cancer cells were subcutaneously injected into athymic nude mice and PTX (15 mg/kg) was administrated. In vivo HER2 expression was quantified through [89Zr]-pertuzumab PET/CT imaging. PTX treatment response was quantified by [18F]-fluorodeoxyglucose ([18F]-FDG) PET/CT imaging. Spearman’s correlation, Kendall’s tau, Kolmogorov–Smirnov test, and ANOVA were used for statistical analysis. [89Zr]-pertuzumab mean standard uptake values (SUVmean) of BT474 tumors were 4.9 ± 1.5, MDA-MB-361 tumors were 1.4 ± 0.2, and MDA-MB-231 (HER2−) tumors were 1.1 ± 0.4. [18F]-FDG SUVmean changes were negatively correlated with [89Zr]-pertuzumab SUVmean (r = −0.5887, p = 0.0030). The baseline [18F]-FDG SUVmean was negatively correlated with initial [89Zr]-pertuzumab SUVmean (r = −0.6852, p = 0.0002). This study shows PTX treatment efficacy is positively correlated with HER2 expression level in human breast cancer mouse models. Molecular imaging provides a non-invasive approach to quantify biological interactions, which will help in identifying chemotherapy responders and potentially enhance clinical decision-making

Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer

DNA damage repair and tumor hypoxia contribute to intratumoral cellular and molecular heterogeneity and affect radiation response. The goal of this study is to investigate anti-HER2-induced radiosensitization of the tumor microenvironment to enhance fractionated radiotherapy in models of HER2+ breast cancer. This is monitored through in vitro and in vivo studies of phosphorylated γ-H2AX, [18F]-fluoromisonidazole (FMISO)-PET, and transcriptomic analysis. In vitro, HER2+ breast cancer cell lines were treated with trastuzumab prior to radiation and DNA double-strand breaks (DSB) were quantified. In vivo, HER2+ human cell line or patient-derived xenograft models were treated with trastuzumab, fractionated radiation, or a combination and monitored longitudinally with [18F]-FMISO-PET. In vitro DSB analysis revealed that trastuzumab administered prior to fractionated radiation increased DSB. In vivo, trastuzumab prior to fractionated radiation significantly reduced hypoxia, as detected through decreased [18F]-FMISO SUV, synergistically improving long-term tumor response. Significant changes in IL-2, IFN-gamma, and THBS-4 were observed in combination-treated tumors. Trastuzumab prior to fractionated radiation synergistically increases radiotherapy in vitro and in vivo in HER2+ breast cancer which is independent of anti-HER2 response alone. Modulation of the tumor microenvironment, through increased tumor oxygenation and decreased DNA damage response, can be translated to other cancers with first-line radiation therapy

Hyperintensity of integrin-targeted fluorescence agent IntegriSense750 accurately predicts flap necrosis compared to Indocyanine green

BackgroundFlap necrosis is a feared complication of reconstructive surgery. Current methods of prediction using Indocyanine green (ICG) lack specificity. IntegriSense750 is a fluorescence agent that binds sites of vascular remodeling. We hypothesized that IntegriSense750 better predicts flap compromise compared to ICG.MethodsFifteen mice underwent lateral thoracic artery axial flap harvest. Mice received an injection of ICG (n = 7) or IntegriSense750 (n = 8) daily from postoperative days (POD) 0-3 and were imaged daily. Mean signal-to-background ratios quantified the change in fluorescence as necrosis progressed.ResultsMean signal-to-background ratio was significantly higher for IntegriSense750 compared to ICG on POD0 (1.47 ± 0.17 vs. 0.86 ± 0.21, p = 0.01) and daily through POD3 (2.12 ± 0.70 vs. 0.96 ± 0.29, p ConclusionsIntegriSense750 demonstrates increased signal-to-background ratio at areas of flap distress compared to ICG which may increase identification of flap necrosis and improve patient outcomes

Dual anti-HER2/EGFR inhibition synergistically increases therapeutic effects and alters tumor oxygenation in HNSCC

Abstract Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and hypoxia are associated with radioresistance. The goal of this study is to study the synergy of anti-HER2, trastuzumab, and anti-EGFR, cetuximab, and characterize the tumor microenvironment components that may lead to increased radiation sensitivity with dual anti-HER2/EGFR therapy in head and neck squamous cell carcinoma (HNSCC). Positron emission tomography (PET) imaging ([89Zr]-panitumumab and [89Zr]-pertuzumab) was used to characterize EGFR and HER2 in HNSCC cell line tumors. HNSCC cells were treated with trastuzumab, cetuximab, or combination followed by radiation to assess for viability and radiosensitivity (colony forming assay, immunofluorescence, and flow cytometry). In vivo, [18F]-FMISO-PET imaging was used to quantify changes in oxygenation during treatment. Bliss Test of Synergy was used to identify combination treatment synergy. Quantifying EGFR and HER2 receptor expression revealed a 50% increase in heterogeneity of HER2 relative to EGFR. In vitro, dual trastuzumab-cetuximab therapy shows significant decreases in DNA damage response and increased response to radiation therapy (p < 0.05). In vivo, tumors treated with dual anti-HER2/EGFR demonstrated decreased tumor hypoxia, when compared to single agent therapies. Dual trastuzumab-cetuximab demonstrates synergy and can affect tumor oxygenation in HNSCC. Combination trastuzumab-cetuximab modulates the tumor microenvironment through reductions in tumor hypoxia and induces sustained treatment synergy