Bispecific radioimmunoconjugates exploit receptor heterogeneity for positron emission tomography of tumors expressing HER2 and/or EGFR.

HER2 heterogeneity is a challenge for molecular imaging or treating HER2-positive breast cancer (BC). EGFR is coexpressed in some tumors exhibiting HER2 heterogeneity. Bispecific radioimmunoconjugates (bsRICs) that bind HER2 and EGFR were constructed by linking trastuzumab Fab through polyethyleneglycol (PEG) to EGF.

Ultrasound-stimulated microbubble radiation enhancement of tumors: Single-dose and fractionated treatment evaluation.

The use of ultrasound-stimulated microbubble therapy has successfully been used to target tumor vasculature and enhance the effects of radiation therapy in tumor xenografts in mice. Here, we further investigate this treatment using larger, more clinically relevant tumor models. New Zealand white rabbits bearing prostate tumor (PC3) xenografts received a single treatment of either ultrasound-stimulated microbubbles (USMB), ionizing radiation (XRT; 8Gy), or a combination of both treatments (USMB+XRT).

Effect of Treatment Sequencing on the Tumor Response to Combined Treatment With Ultrasound-Stimulated Microbubbles and Radiotherapy.

Objectives: To investigate whether timing and sequencing of ultrasound-stimulated microbubbles (USMBs) and external beam radiotherapy (XRT) affect the treatment response in a preclinical prostate cancer model.

Methods: Prostate cancer xenografts were treated with ultrasound-stimulated lipid microspheres before and after 8-Gy XRT. Treatments were separated by 0, 3, 6, 12, and 24 hours, with 5 tumors per group.

Role of Acid Sphingomyelinase and Ceramide in Mechano-Acoustic Enhancement of Tumor Radiation Responses.

Background: High-dose radiotherapy (>8-10 Gy) causes rapid endothelial cell death via acid sphingomyelinase (ASMase)-induced ceramide production, resulting in biologically significant enhancement of tumor responses. To further augment or solicit similar effects at low radiation doses, we used genetic and chemical approaches to evaluate mechano-acoustic activation of the ASMase-ceramide pathway by ultrasound-stimulated microbubbles (USMB).

Methods: Experiments were carried out in wild-type and acid sphingomyelinase (asmase) knockout mice implanted with fibrosarcoma xenografts.

Microbubble-based enhancement of radiation effect: Role of cell membrane ceramide metabolism.

Ultrasound (US) stimulated microbubbles (MB) is a new treatment approach that sensitizes cancer cells to radiation (XRT). The molecular pathways in this response remain unelucidated, however, previous data has supported a role for cell membrane-metabolism related pathways including an up regulation of UDP glycosyltransferase 8 (UGT8), which catalyzes the transfer of galactose to ceramide, a lipid that is associated with the induction of apoptotic signalling. In this study, the role of UGT8 in responses of prostate tumours to ultrasound-stimulated microbubble radiation enhancement therapy is investigated.

Erratum: Breast tumor response to ultrasound mediated excitation of microbubbles and radiation therapy in vivo.

[This corrects the article DOI: 10.18632/oncoscience.299.

Effect of chromatin structure on quantitative ultrasound parameters.

High-frequency ultrasound (~20 MHz) techniques were investigated using in vitro and ex vivo models to determine whether alterations in chromatin structure are responsible for ultrasound backscatter changes in biological samples. Acute myeloid leukemia (AML) cells and their isolated nuclei were exposed to various chromatin altering treatments. These included 10 different ionic environments, DNA cleaving and unfolding agents, as well as DNA condensing agents.

Quantitative ultrasound imaging of therapy response in bladder cancer in vivo.

Background And Aims: Quantitative ultrasound (QUS) was investigated to monitor bladder cancer treatment response in vivo and to evaluate tumor cell death from combined treatments using ultrasound-stimulated microbubbles and radiation therapy.

Methods: Tumor-bearing mice (n=45), with bladder cancer xenografts (HT- 1376) were exposed to 9 treatment conditions consisting of variable concentrations of ultrasound-stimulated Definity microbubbles [nil, low (1%), high (3%)], combined with single fractionated doses of radiation (0 Gy, 2 Gy, 8 Gy). High frequency (25 MHz) ultrasound was used to collect the raw radiofrequency (RF) data of the backscatter signal from tumors prior to, and 24 hours after treatment in order to obtain QUS parameters.

Breast tumor response to ultrasound mediated excitation of microbubbles and radiation therapy in vivo.

Acoustically stimulated microbubbles have been demonstrated to perturb endothelial cells of the vasculature resulting in biological effects. In the present study, vascular and tumor response to ultrasound-stimulated microbubble and radiation treatment was investigated in vivo to identify effects on the blood vessel endothelium. Mice bearing breast cancer tumors (MDA-MB-231) were exposed to ultrasound after intravenous injection of microbubbles at different concentrations, and radiation at different doses (0, 2, and 8 Gy).

Multiparametric monitoring of chemotherapy treatment response in locally advanced breast cancer using quantitative ultrasound and diffuse optical spectroscopy.

Purpose: This study evaluated pathological response to neoadjuvant chemotherapy using quantitative ultrasound (QUS) and diffuse optical spectroscopy imaging (DOSI) biomarkers in locally advanced breast cancer (LABC).

Materials And Methods: The institution's ethics review board approved this study. Subjects (n = 22) gave written informed consent prior to participating.

Ultrasound-stimulated microbubble enhancement of radiation treatments: endothelial cell function and mechanism.

Endothelial cell death caused by novel microbubble-enhanced ultrasound cancer therapy leads to secondary tumour cell death. In order to characterize and optimize these treatments, the molecular mechanisms resulting from the interaction with endothelial cells were investigated here. Endothelial cells (HUVEC) were treated with ultrasound-stimulated microbubbles (US/MB), radiation (XRT), or a combination of US/MB+XRT.

Quantification of Ultrasonic Scattering Properties of In Vivo Tumor Cell Death in Mouse Models of Breast Cancer.

Introduction: Quantitative ultrasound parameters based on form factor models were investigated as potential biomarkers of cell death in breast tumor (MDA-231) xenografts treated with chemotherapy.

Methods: Ultrasound backscatter radiofrequency data were acquired from MDA-231 breast cancer tumor-bearing mice (n = 20) before and after the administration of chemotherapy drugs at two ultrasound frequencies: 7 MHz and 20 MHz. Radiofrequency spectral analysis involved estimating the backscatter coefficient from regions of interest in the center of the tumor, to which form factor models were fitted, resulting in estimates of average scatterer diameter and average acoustic concentration (AAC).

Quantitative ultrasound characterization of tumor cell death: ultrasound-stimulated microbubbles for radiation enhancement.

The aim of this study was to assess the efficacy of quantitative ultrasound imaging in characterizing cancer cell death caused by enhanced radiation treatments. This investigation focused on developing this ultrasound modality as an imaging-based non-invasive method that can be used to monitor therapeutic ultrasound and radiation effects. High-frequency (25 MHz) ultrasound was used to image tumor responses caused by ultrasound-stimulated microbubbles in combination with radiation.

Cellular characterization of ultrasound-stimulated microbubble radiation enhancement in a prostate cancer xenograft model.

Tumor radiation resistance poses a major obstacle in achieving an optimal outcome in radiation therapy. In the current study, we characterize a novel therapeutic approach that combines ultrasound-driven microbubbles with radiation to increase treatment responses in a prostate cancer xenograft model in mice. Tumor response to ultrasound-driven microbubbles and radiation was assessed 24 hours after treatment, which consisted of radiation treatments alone (2 Gy or 8 Gy) or ultrasound-stimulated microbubbles only, or a combination of radiation and ultrasound-stimulated microbubbles.

Sunitinib effects on the radiation response of endothelial and breast tumor cells.

Background: Endothelial cells are suggested regulators of tumor response to radiation. Anti-vascular targeting agents can enhance tumor response by targeting endothelial cells. Here, we have conducted experiments in vitro to discern the effects of radiation combined with the anti-angiogenic Sunitinib on endothelial (HUVEC) and tumor (MDA-MB-231) cells, and further compared findings to results obtained in vivo.

Ultrasound-mediated microbubble enhancement of radiation therapy studied using three-dimensional high-frequency power Doppler ultrasound.

Tumor responses to high-dose (>8 Gy) radiation therapy are tightly connected to endothelial cell death. In the study described here, we investigated whether ultrasound-activated microbubbles can locally enhance tumor response to radiation treatments of 2 and 8 Gy by mechanically perturbing the endothelial lining of tumors. We evaluated vascular changes resulting from combined microbubble and radiation treatments using high-frequency 3-D power Doppler ultrasound in a breast cancer xenograft model.

Low-frequency quantitative ultrasound imaging of cell death in vivo.

Purpose: Currently, no clinical imaging modality is used routinely to assess tumor response to cancer therapies within hours to days of the delivery of treatment. Here, the authors demonstrate the efficacy of ultrasound at a clinically relevant frequency to quantitatively detect changes in tumors in response to cancer therapies using preclinical mouse models.

Methods: Conventional low-frequency and corresponding high-frequency ultrasound (ranging from 4 to 28 MHz) were used along with quantitative spectroscopic and signal envelope statistical analyses on data obtained from xenograft tumors treated with chemotherapy, x-ray radiation, as well as a novel vascular targeting microbubble therapy.

Conventional frequency ultrasonic biomarkers of cancer treatment response in vivo.

Background: Conventional frequency quantitative ultrasound in conjunction with textural analysis techniques was investigated to monitor noninvasively the effects of cancer therapies in an in vivo preclinical model.

Methods: Conventional low-frequency (∼7 MHz) and high-frequency (∼20 MHz) ultrasound was used with spectral analysis, coupled with textural analysis on spectral parametric maps, obtained from xenograft tumor-bearing animals (n = 20) treated with chemotherapy to extract noninvasive biomarkers of treatment response.

Results: Results indicated statistically significant differences in quantitative ultrasound-based biomarkers in both low- and high-frequency ranges between untreated and treated tumors 12 to 24 hours after treatment.

Effects of biophysical parameters in enhancing radiation responses of prostate tumors with ultrasound-stimulated microbubbles.

We show here that ultrasound-stimulated microbubbles can enhance cell death within tumors when combined with radiation. The aim of this study was to investigate how different ultrasound parameters, different microbubble concentrations and different radiation doses interact to enhance cell death. Prostate xenograft tumors (PC-3) in severe combined immunodeficiency mice were subjected to ultrasound treatment at various peak negative pressures (250, 570 and 750 kPa) at a center frequency of 500 kHz, different microbubble concentrations (8, 80 and 1000 μL/kg) and different radiation doses (0, 2 and 8 Gy).

Bioeffects of ultrasound-stimulated microbubbles on endothelial cells: gene expression changes associated with radiation enhancement in vitro.

Ultrasound can be used to target endothelial cells in cancer therapy where the destruction of vasculature leads to tumor cell death. Here, we demonstrate ultrasound bioeffects in which the levels of genes in endothelial cells can be significantly altered by ultrasound-stimulated microbubble exposure. These were compared with established effects of radiation on endothelial cells at a gene level.

Tumor radiation response enhancement by acoustical stimulation of the vasculature.

We have discovered that ultrasound-mediated microbubble vascular disruption can enhance tumor responses to radiation in vivo. We demonstrate this effect using a human PC3 prostate cancer xenograft model. Results indicate a synergistic effect in vivo with combined single treatments of ultrasound-stimulated microbubble vascular perturbation and radiation inducing an over 10-fold greater cell kill with combined treatments.

Selection of surfactants for cell lysis in chemical cytometry to study protein-DNA interactions.

Protein-DNA interactions play a defining role in many cellular processes. Studying such interactions at the single-cell level is important and challenging. Here we make the first step toward achieving this goal with chemical cytometry.

Calibration-free quantitative analysis of mRNA.

Here we introduce a method for accurate and sensitive quantitative analysis of mRNA, which does not require calibration with mRNA. The method uses a fluorescently labeled hybridization probe as a reference standard. It involves the following: (i) annealing mRNA to the excess of the fluorescently labeled ssDNA hybridization probe, (ii) separation of the mRNA-probe hybrid from the excess of the probe by gel-free capillary electrophoresis mediated by ssDNA-binding protein, (iii) fluorescence detection of the hybrid and the excess probe, and (iv) quantification of mRNA using a simple algebraic formula.

Desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors facilitates use-dependent inhibition by pentobarbital.

Although the mechanisms underlying the use-dependent inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) by barbiturates are not well understood, it has generally been assumed to involve open channel block. We examined the properties of the inhibition of AMPARs by the barbiturate pentobarbital (PB) in acutely isolated and cultured hippocampal neurons. PB caused a use- and concentration-dependent inhibition (IC50 = 20.

Co-stimulation of mGluR5 and N-methyl-D-aspartate receptors is required for potentiation of excitatory synaptic transmission in hippocampal neurons.

In the central nervous system, excitatory synaptic transmission is mediated by the neurotransmitter glutamate and its receptors. Interestingly, stimulation of group I metabotropic glutamate receptors (mGluRs) can either enhance or depress synaptic transmission at CA1 hippocampal synapses. Here we report that co-activation of mGluR5, a member of the group I mGluR family, and N-methyl-d-aspartate receptors (NMDARs) potentiates NMDAR currents and induces a long lasting enhancement of excitatory synaptic transmission in primary cultured hippocampal neurons.