Improve Cancer Diagnostics Research Articles

High intensity focused ultrasound-induced bubbles stimulate the release of nucleic acid cancer biomarkers

Prostate biopsy for prostate cancer (PCa) is invasive with associated morbidity and several diagnostic limitations, suggesting the need for a new approach. Recently, several nucleic acid cancer biomarkers (e.g., microRNA and mutant DNA) have been identified and shown promise for improving cancer diagnostics. However, the abundance of these biomarker classes in the circulation is low, impeding reliable detection and adoption into clinical practice. In order to stimulate the release of these intracellular biomarkers, the exposures optimized for mechanical disruption of cells may be desirable. Here, two approaches based on HIFU-induced bubble activity were tested for their ability to stimulate release of cancer-associated microRNAs in a heterotopic syngeneic rat prostate cancer model. In the first approach, tumor tissue was locally liquefied with boiling histotripsy (BH) - a HIFU technique utilizing millisecond-long pulses to create boiling bubbles via rapid shockwave heating. The interaction of shocks with the ensuing vapor cavity fractionates tissue with negligible thermal effect. In the second approach HIFU-induced inertial cavitation was used for permeabilization of tumor tissue and vasculature.

Hepatitis B: The view from West Africa

The Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) study began in 2011 in The Gambia, Senegal and Nigeria. The study aims to reduce the risk of hepatocellular carcinoma (HCC) in West Africa through the suppression of the Hepatitis B virus (HBV). The biological samples collected allow for the detection of novel liver cancer biomarkers in the hope of improving the diagnostic ability of early disease states. The PROLIFICA platform hopes to improve cancer diagnostics whilst simultaneously providing the training, skills and infrastructure necessary to develop the quality of liver cancer care in West Africa.

Complete parameterization of temporally and spectrally resolved laser induced fluorescence data with applications in bio-photonics

We present a set of spectrally and temporally resolved clinical fluorescence data—with two separate excitation wavelengths—that was recorded in vivo. We demonstrate that data in the spectral and temporal domains are in certain ways coupled and provide a method for integrated and effective parameterization of spectrally and temporally resolved fluorescence (i.e., time-resolved emission spectra). This parameterization is based on linear algebra, matrix formulation and system identification. We demonstrate how to empirically extract single exponentially decaying components and provide rectified emission spectra without prior knowledge. We investigate the potential for improved cancer diagnostics according to the reduced parameters along the various domains. In this case, in terms of cancer diagnostics, we were unable to identify any benefits of simultaneously measuring both the temporal and spectral properties of the observed fluorescence. However, we note that this may be explained by an important experimental bias present in many studies of optical cancer diagnostics, namely, that, in general, suspected lesions always differ visually from the neighboring healthy tissue.

High intensity focused ultrasound-induced bubbles stimulate the release of nucleic acid cancer biomarkers

Recently, several nucleic acid cancer biomarkers, e.g., microRNA and mutant DNA, have been identified and shown promise for improving cancer diagnostics. However, the abundance of these biomarker classes in the circulation is low, impeding reliable detection and adoption into clinical practice. Here, the ability of HIFU-induced bubbles to stimulate release of cancer-associated microRNAs by tissue fractionation or permeabilization was investigated in a heterotopic syngeneic rat prostate cancer model. A 1.5 MHz HIFU transducer was used to either mechanically fractionate subcutaneous tumor with boiling histotripsy (BH) (~20 kW/cm2, 10 ms pulses, and duty factor 0.01) or to permeabilize tumor tissue with inertial cavitation activity (p- = 16 MPa, 1 ms pulses, duty factor 0.001). Blood was collected immediately prior to and serially up to 24-hours after treatments. Plasma concentrations of microRNAs were measured by quantitative RT-PCR. Both exposures resulted in a rapid (within 15 min), short (≤3 h) and dramatic (over ten-fold) increase in relative plasma concentrations of tumor-associated microRNAs, Histologic examination of excised tumor confirmed complete fractionation of targeted tumor by BH and localized areas of intraparenchymal hemorrhage and tissue disruption by cavitation-based treatment. These data suggest a clinically useful application of HIFU-induced bubbles for non-invasive molecular biopsy. [Grant support: NIH 1K01EB015745, R01CA154451, R01DK085714.]

An empirical assay for assessing genomic sensitivity and for improving cancer diagnostics.

Detection tests have been developed for many cancers, but there is no single test to identify cancer in general. We have developed such an assay. In this modified patented Comet assay, we investigated lymphocytes of 208 individuals: 20 melanoma, 34 colon cancer, 4 lung cancer patients, 18 suspect melanoma, 28 polyposis, 10 COPD patients and 94 healthy volunteers. The natural logarithm of the Olive tail moment was plotted for exposure to UVA through different agar depths for each of the above groups and analyzed using a repeated measures regression model. Response patterns for cancer patients formed a plateau after treating with UVA where intensity varied with different agar depths. In comparison, response patterns for healthy individuals returned towards control values and for pre/suspected cancers, were intermediate with less of a plateau. All cancers tested exhibited comparable responses. Analyses of Receiver Operating Characteristic curves, of mean log Olive tail moments, for all cancers plus pre/suspected-cancer versus controls gave a value for the area under the curve of 0.87; for cancer versus pre/suspected-cancer plus controls the value was 0.89; and for cancer alone versus controls alone (excluding pre/suspected-cancer), the value was 0.93. By varying the threshold for test positivity, its sensitivity or specificity can approach 100% whilst maintaining acceptable complementary measures. Evidence presented indicates that this modified assay shows promise as both a stand-alone test and as a possible adjunct to other investigative procedures, as part of detection programs for a range of cancers.

Reasonable design of antibody mimetics for targeting glioma and small cell lung cancer

According to the recent research available from the American Cancer Society, cancer is the second leading cause of death in the USA. Many kinds of chemotherapeutic agents have been shown to be effective against tumor cells. Unfortunately, most of them also kill normal cells. Because native antibodies and antibody fragments find it hard to penetrate solid tumors, most approaches have focused on developing antibody mimetics. Therefore, we wanted to design more reasonable antibody mimetics, containing three regions, for targeting glioma and small cell lung cancer, and supposed that these mimetic-toxin immunotoxins could specifically kill targeting tumors. VLCDR1 and VHCDR3, together with five amino acid residues on both sides of the complementarity-determining regions, through a cognate framework region (VHFR2) yielded mimetics of BT32/A6 (United States Patent number: 5639863) and TB2A36C3 (United States Patent number: 5744585). When genetically fused, the mimetic with the first 388 amino acid residues of diphtheria toxin, Escherichia coli strain, BL21 (ED3), was used for expression of soluble immunotoxins DT-BT and DT-TB. The killing activities of our fusion proteins were examined in vitro. DT-BT and DT-TB could not kill Raji up to the maximal concentration tested (10⁻⁷ mol/l) in vitro. In contrast, at concentrations ≥ 10⁻⁸ mol/l, DT-BT and DT-TB killed 90% of U-87 MG cells and small cell lung cancer in vitro, respectively. The killing activities of our fusion proteins hinted that 5aa-VLCDR1-5aa-VHFR2-5aa-VHCDR3-5aa mimetics maintained the synergic interactions and high affinity of parent antibodies. Such mimetics may hold promise for markedly improving cancer diagnostics and therapeutics, especially as the small size of the mimetics may confer other useful properties, such as enhanced intracellular delivery.

Comparison of tumor blood perfusion assessed by dynamic contrast‐enhanced MRI with tumor blood supply assessed by invasive imaging

To evaluate the potential of Gd-DTPA-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for providing high-resolution tumor blood perfusion images. Xenografted tumors from two amelanotic human melanoma lines (A-07 and R-18) were used as preclinical models of human cancer. DCE-MRI was performed at a voxel size of 0.5 x 0.2 x 2.0 mm(3) with the use of spoiled gradient recalled sequences. We produced tumor images of E . F (where E is the initial extraction fraction, and F is perfusion) by subjecting the DCE-MRI data to Kety analysis, and then compared those images with images of tumor blood supply. We obtained high-resolution tumor blood supply images using the Bioscope silicon strip detector system to measure the uptake of Na(99m)TcO(4) in histological preparations. We assessed the global blood supply by measuring the tumor uptake of three freely diffusible blood flow tracers: (86)RbCl, [(14)C]IAP, and Na(99m)TcO(4). E . F was found to mirror the blood supply well in A-07 and R-18 tumors. The mean E . F differed between the A-07 and R-18 tumors by a factor of approximately 1.6, and this difference was similar to the difference in the global blood supply. The intratumor heterogeneity in E . F was significant for tumors of both lines, and this heterogeneity was similar to the intratumor heterogeneity in the blood supply. The intratumor heterogeneity in the blood supply differed slightly between the A-07 and R-18 tumors, and even this difference was mirrored by the E . F images. E . F images of xenografted tumors reflect blood perfusion. This implies that E . F may be a useful parameter for improving cancer diagnostics and individualizing cancer treatment. This possibility deserves to be investigated thoroughly in clinical studies.