Prognostic impact of mRNA levels of osteopontin splice variants in soft tissue sarcoma patients

<p>Abstract</p> <p>Background</p> <p>It is well known that osteopontin (OPN) plays an important role in tumor progression and that a high OPN expression level in several tumor entities correlates with poor prognosis in cancer patients. However, little is known about the prognostic relevance of the OPN mRNA splice variants.</p> <p>Methods</p> <p>We analyzed the mRNA expression levels of different OPN splice variants in tumor tissue of 124 soft tissue sarcoma (STS) patients. Quantitative real-time PCR (qRT-PCR) was used to analyze the mRNA expression level of three OPN splice variants (OPN-a, -b and -c).</p> <p>Results</p> <p>The multivariate Cox's proportional hazard regression model revealed that high mRNA expression levels of OPN splice variants are significantly associated with poor prognosis in STS patients (n = 124). Women (n = 68) with high mRNA expression levels of OPN-a and OPN-b have an especially elevated risk of tumor-related death (OPN-a: RR = 3.0, P = 0.01, CI = 1.3-6.8; OPN-b: RR = 3.4, P = 0.01, CI = 1.4-8.2). In particular, we found that high mRNA expression levels of OPN-b and OPN-c correlated with a high risk of tumor-related death in STS patients that received radiotherapy (n = 52; OPN-b: RR = 10.3, P < 0.01, CI = 2.0-53.7; OPN-c: RR = 11.4, P < 0.01, CI = 2.2-59.3).</p> <p>Conclusion</p> <p>Our study shows that elevated mRNA expression levels of OPN splice variants are negative prognostic and predictive markers for STS patients. Further studies are needed to clarify the impact of the OPN splice variants on prognosis.</p

A novel splice variant of the stem cell marker LGR5/GPR49 is correlated with the risk of tumor-related death in soft-tissue sarcoma patients

<p>Abstract</p> <p>Background</p> <p>The human leucine-rich, repeat-containing G protein-coupled receptor (LGR) 5, also called GPR49, is a marker of stem cells in adult intestinal epithelium, stomach and hair follicles. LGR5/GPR49 is overexpressed in tumors of the colon, ovary and liver and in basal cell carcinomas. Moreover, an expression in skeletal muscle tissues was also detected. However, there has been no investigation regarding the expression and function of LGR5/GPR49 in soft-tissue sarcomas (STS) yet.</p> <p>Methods</p> <p>Seventy-seven frozen tumor samples from adult STS patients were studied using quantitative real-time TaqMan™ PCR analysis. The mRNA levels of wild type <it>LGR5/GPR49 </it>and a newly identified splice variant of <it>LGR5/GPR49 </it>lacking exon 5 (that we called <it>GPR49Δ5</it>) were quantified.</p> <p>Results</p> <p>A low mRNA expression level of <it>GPR49Δ5</it>, but not wild type <it>LGR5/GPR49</it>, was significantly correlated with a poor prognosis for the disease-associated survival of STS patients (RR = 2.6; P = 0.026; multivariate Cox's regression hazard analysis). Furthermore, a low mRNA expression level of <it>GPR49Δ5 </it>was associated with a shorter recurrence-free survival (P = 0.043). However, tumor onset in patients with a lower expression level of <it>GPR49Δ5 </it>mRNA occurred 7.5 years later (P = 0.04) than in patients with a higher tumor level of <it>GPR49Δ5 </it>mRNA.</p> <p>Conclusion</p> <p>An attenuated mRNA level of the newly identified transcript variant <it>GPR49Δ5 </it>is a negative prognostic marker for disease-associated and recurrence-free survival in STS patients. Additionally, a lower <it>GPR49Δ5 </it>mRNA level is associated with a later age of tumor onset. A putative role of <it>GPR49Δ5 </it>expression in tumorigenesis and tumor progression of soft tissue sarcomas is suggested.</p

Applicability of Capacitive Micromachined Ultrasonic Transducers for the detection of proton-induced thermoacoustic waves

This study investigates the application of broadband capacitive micromachined ultrasonic transducers (CMUT) to ionoacoustics (i.e., the thermoacoustic emissions induced by the energy deposition of ion beam) over a wide frequency range from hundreds of kHz to a few MHz. A water tank was irradiated by a 20 MeV pulsed proton beam. The frequency and amplitude of the ionoacoustic waves were modulated by adding material before to penetrate into the water tank to change the beam energy and its spatial dimensions. The measurements were performed with a 12 MHz CMUT prototype and compared to ones obtained from commercial 3.5 MHz piezoeletric transducer as well as to in silico studies employing the k-Wave Matlab toolbox in combination with FLUKA Monte Carlo simulations to derive the dose (i.e., energy deposition per mass) and initial pressure distribution. Comparison of the experimental and in silico results show that the CMUT bandwidth is wide enough to measure the signal without any degradation or attenuation of the frequency content in the investigated frequency range, thus ensuring accurate reconstruction of the dose distribution and potential bi-modality system for the co-registration of ionoacoustic and ultrasound imaging

On the robustness of multilateration of ionoacoustic signals for localization of the Bragg peak at pre-clinical proton beam energies in water

Objectives. The energy deposited in a medium by a pulsed proton beam results in the emission of thermoacoustic waves, also called ionoacoustics (IA). The proton beam stopping position (Bragg peak) can be retrieved from a time-of-flight analysis (ToF) of IA signals acquired at different sensor locations (multilateration). This work aimed to assess the robustness of multilateration methods in proton beams at pre-clinical energies for the development of a small animal irradiator. Approach. The accuracy of multilateration performed using different algorithms; namely, time of arrival and time difference of arrival, was investigated in-silico for ideal point sources in the presence of realistic uncertainties on the ToF estimation and ionoacoustic signals generated by a 20 MeV pulsed proton beam stopped in a homogeneous water phantom. The localisation accuracy was further investigated experimentally based on two different measurements with pulsed monoenergetic proton beams at energies of 20 and 22 MeV. Main results. It was found that the localisation accuracy mainly depends on the position of the acoustic detectors relative to the proton beam due to spatial variation of the error on the ToF estimation. By optimally positioning the sensors to reduce the ToF error, the Bragg peak could be located in-silico with an accuracy better than 90 μm (2 error). Localisation errors going up to 1 mm were observed experimentally due to inaccurate knowledge of the sensor positions and noisy ionoacoustic signals. Significance. This study gives a first overview of the implementation of different multilateration methods for ionoacoustics-based Bragg peak localisation in two- and three-dimensions at pre-clinical energies. Different sources of uncertainty were investigated, and their impact on the localisation accuracy was quantified in-silico and experimentally

CD44 SNPrs187115: A Novel Biomarker Signature that Predicts Survival in Resectable Pancreatic Ductal Adenocarcinoma

Purpose: Although pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor, like other common cancers, it displays a wide range of biology. However, at present, there are no reliable tests to predict patients' cancer-specific outcomes and guide personalized treatment decisions. In this study, we aim to identify such biomarkers in resectable PDAC by studying SNPs in the CD44 gene, which drives the progression of pancreatic cancer. Experimental Design: A total of 348 PDAC patients from three independent cohorts [Switzerland, Germany, The Cancer Genome Atlas (TCGA)] who underwent pancreatic resection are included in the study. Information on the haplotype structure of the CD44 gene is obtained using 1000 Genomes Project data, and the genotypes of the respective tagging SNPs are determined. Cox proportional hazards models are utilized to analyze the impact of SNP genotype on patients' survival. Results: We identify an SNP in the CD44 gene (SNPrs187115) that independently associates with allelic differences in prognosis in all study cohorts. Specifically, in 121 Swiss patients, we observe an up to 2.38-fold (P = 0.020) difference in tumor-related death between the genotypes of SNPrs187115. We validate those results in both the German (HR = 2.32, P = 0.044, 101 patients) and the TCGA cohort (HR = 2.36, P = 0.044, 126 patients). Conclusions: CD44 SNPrs187115 can serve as a novel biomarker readily available at the time of PDAC diagnosis that identifies patients at risk for faster tumor progression and guide personalized treatment decisions. It has the potential to significantly expand the pool of patients that would benefit from tumor resection

I-BEAT: New ultrasonic method for single bunch measurement of ion energy distribution

The shape of a wave carries all information about the spatial and temporal structure of its source, given that the medium and its properties are known. Most modern imaging methods seek to utilize this nature of waves originating from Huygens' principle. We discuss the retrieval of the complete kinetic energy distribution from the acoustic trace that is recorded when a short ion bunch deposits its energy in water. This novel method, which we refer to as Ion-Bunch Energy Acoustic Tracing (I-BEAT), is a generalization of the ionoacoustic approach. Featuring compactness, simple operation, indestructibility and high dynamic ranges in energy and intensity, I-BEAT is a promising approach to meet the needs of petawatt-class laser-based ion accelerators. With its capability of completely monitoring a single, focused proton bunch with prompt readout it, is expected to have particular impact for experiments and applications using ultrashort ion bunches in high flux regimes. We demonstrate its functionality using it with two laser-driven ion sources for quantitative determination of the kinetic energy distribution of single, focused proton bunches.Comment: Paper: 17 Pages, 3 figures Supplementary Material 16 pages, 7 figure