Novel Technology Enables Diagnostic Ultrasound Machine to Treat Hepatocellular Carcinoma in Mice

An off-the-shelf diagnostic transducer (ULTRASONIX C5-2) was modified with custom-built circuitry to enable the transducer to produce therapeutic ultrasound in order to ablate hepatocellular carcinomas grown in immunodeficient athymic nude mice (25-35 g; Charles River Laboratories, Wilmington, MA, USA). The therapeutic antivascular ultrasound (AVUS) produced by the off-the-shelf abdominal transducer was unfocused, continuous 2.8MHz ultrasound targeting contrast-enhancing perflutren lipid microbubbles within tumor vasculature. Previous research with a dedicated physiotherapy ultrasound machine (D150 Plus, Dynatronics Corp., Salt Lake City, UT, USA) targeting similar hepatocellular carcinomas showed disrupted tumor neovasculature and irreparable dilation of tumor capillaries with subsequent intercellular edema and hemorrhage.1-3 In this study, the echointensity, peak enhancement (PE), perfusion index (PI), and area under curve (AUC) were measured using non-linear contrast B-mode images acquired before and after the sham or AVUS treatment. These measurements all showed the AVUS produced by the diagnostic transducer markedly decreased tumor blood flow (P \u3c 0.001). In addition, tumor temperature measurement in the live mice showed that AVUS treatment markedly increased tumor temperature with a thermal dose (CEM43) delivered by ultrasound treatment of 124.02 min versus sham of 0 min. Finally, histochemical staining of the tumor samples taken after AVUS treatment revealed several hemorrhagic pools in tumors while the sham-treated tumors lack such hemorrhagic pools. This study demonstrates diagnostic transducers can be enabled to produce AVUS with the ability to target mural hepatocellular carcinomas

Epidermal Growth Factor Receptor Inhibition Modulates the Microenvironment by Vascular Normalization to Improve Chemotherapy and Radiotherapy Efficacy

Background: Epidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-a (HIF-1a) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity. Methodology/Principal Findings: Erlotinib treatment of human tumor cells in vitro and mice bearing xenografts in vivo led to decreased HIF-1a and VEGF expression. Treatment altered xenograft vessel morphology assessed by confocal microscopy (following tomato lectin injection) and decreased vessel permeability (measured by Evan’s blue extravasation), suggesting vascular normalization. Erlotinib increased tumor blood flow measured by Power Doppler ultrasound and decreased hypoxia measured by EF5 immunohistochemistry and tumor O2 saturation measured by optical spectroscopy. Predictin

Mutation detection analysis of a region of 16S-like ribosomal RNA gene of Entamoeba histolytica, Entamoeba dispar and Entamoeba moshkovskii

<p>Abstract</p> <p>Background</p> <p>The level of intra-species genetic variation in <it>Entamoeba histolytica, Entamoeba dispar </it>and <it>Entamoeba moshkovskii </it>populations in a localized geographic area, like Puducherry, India, remains unknown.</p> <p>Methods</p> <p>In the present study the existence of genetic variation in the nested multiplex polymerase chain reaction (NM-PCR) amplified region of the 16S-like ribosomal RNA genes of <it>E. histolytica, E. dispar </it>and <it>E. moshkovskii </it>was investigated by riboprinting and single strand conformation polymorphism (SSCP) analysis.</p> <p>Results</p> <p>We found that 70 stool specimens were positive for <it>E. histolytica</it>, 171 stool specimens were positive for <it>E. dispar</it>, and 37 stool specimens were positive for <it>E. moshkovskii </it>by NM-PCR. Ninety liver abscess pus specimens, 21 urine specimens, and 8 saliva specimens were positive for <it>E. histolytica </it>by NM-PCR. Riboprinting analysis detected a mutation in the PCR product of only one <it>E. histolytica </it>isolate from a stool specimen. However, SSCP analysis detected mutations in the PCR products of five <it>E. histolytica </it>isolates and three <it>E. moshkovskii </it>isolates from stool specimens, and one <it>E. histolytica </it>isolate from a saliva specimen. The mutations detected by riboprinting and SSCP analysis were confirmed by sequencing. All the nucleotide sequences showing mutations in this study have already been deposited into the NCBI GenBank database under accession numbers [GenBank: <ext-link ext-link-type="gen" ext-link-id="EF682200">EF682200</ext-link> to GenBank: <ext-link ext-link-type="gen" ext-link-id="EF682208">EF682208</ext-link>].</p> <p>Conclusion</p> <p>The present study has revealed the subsistence of mutations in the ribosomal RNA genes of <it>E. histolytica </it>and <it>E. moshkovskii</it>, which points towards the existence of intra-species genetic variation in <it>E. histolytica </it>and <it>E. moshkovskii </it>isolates infecting humans.</p

2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2′-O-Methyl (2′-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2′-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types

Dynamic contrast-enhanced MRI and Doppler sonography in patients with squamous cell carcinoma of head and neck treated with induction chemotherapy.

In view of the inherent limitations associated with performing dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) in clinical settings, current study was designed to provide a proof of principle that Doppler sonography and DCE-MRI derived perfusion parameters yield similar hemodynamic information from metastatic lymph nodes in squamous cell carcinomas of head and neck (HNSCCs). Strong positive correlations between volume fraction of plasma space in tissues (Vp ) and blood volume (r = 0.72, p = 0.02) and between Vp and %area perfused (r = 0.65, p = 0.04) were observed. Additionally, a moderate positive correlation trending towards significance was obtained between volume transfer constant (Ktrans ) and %area perfused (r = 0.49, p = 0.09)