Quantitative parameters in dynamic contrast-enhanced magnetic resonance imaging for the detection and characterization of prostate cancer

Objectives: to assess the diagnostic accuracy of quantitative parameters of DCE-MRI in multi-parametric MRI (mpMRI) in comparison to the histopathology (including Gleason grade) of prostate cancer.Patients and methods: 150 men with suspected prostate cancer (abnormal digital rectum examination and or elevated prostate-specific antigen) received pre-biopsy 3T mpMRI and were recruited into peer-reviewed, protocol-based prospective study. The DCE-MRI quantitative parameters (Ktrans (influx transfer constant) and kep (efflux rate constant)) of the cancerous and normal areas were recorded using four different kinetic models employing Olea Sphere (Olea Medical, La Ciotat, France). The correlation between these parameters and the histopathology of the lesions (biopsy and in a sub-cohort 41 radical prostatectomy specimen) was assessed.Results: The quantitative parameters showed a significant difference between non-cancerous (benign) and cancerous lesions (Gleason score≥3+3) in the prostate gland. The cut-off values for prostate cancer differentiation were: Ktrans (0.205 min-1) and kep (0.665 min-1) in the extended Tofts model (ET) and Ktrans(0.205 min-1 and kep (0.63 min-1) in the Lawrence and Lee delay (LD) models respectively. The mean Ktrans value also showed a difference between low-grade cancer (Gleason score=3+3) and high-grade cancer (Gleason score ≥ 3+4). With the addition of DCE-MRI quantitative parameters, the sensitivity of the PIRAD scoring system was increased from 56.6% to 92.1% (Ktrans_ET), 93.1% (kep_ET), 91.0%, (Ktrans_LD) and 89.4% (kep_LD).Conclusion: Quantitative DCE-MRI parameters improved the diagnostic performance of conventional MRI in distinguishing normal and prostate cancers, including characterization of grade of cancers. The ET and LD models in post-image processing analysis provided better cut-off values for prostate cancer differentiation than the other quantitative DCE-MRI parameters

Physicochemical analysis of rotavirus segment 11 supports a 'modified panhandle' structure and not the predicted alternative tRNA-like structure (TRLS)

.Rotaviruses are a major cause of acute gastroenteritis, which is often fatal in infants. The viral genome consists of 11 double-stranded RNA segments, but little is known about their cis-acting sequences and structural elements. Covariation studies and phylogenetic analysis exploring the potential structure of RNA11 of rotaviruses suggested that, besides the previously predicted "modified panhandle" structure, the 5' and 3' termini of one of the isoforms of the bovine rotavirus UKtc strain may interact to form a tRNA-like structure (TRLS). Such TRLSs have been identified in RNAs of plant viruses, where they are important for enhancing replication and packaging. However, using tRNA mimicry assays (in vitro aminoacylation and 3'- adenylation), we found no biochemical evidence for tRNA-like functions of RNA11. Capping, synthetic 3' adenylation and manipulation of divalent cation concentrations did not change this finding. NMR studies on a 5'- and 3'-deletion construct of RNA11 containing the putative intra-strand complementary sequences supported a predominant panhandle structure and did not conform to a cloverleaf fold despite the strong evidence for a predicted structure in this conserved region of the viral RNA. Additional viral or cellular factors may be needed to stabilise it into a form with tRNA-like properties

Aqueous foam stabilized by tricephalic Amphiphilic surfactants

Aqueous foams can be described as a close packing of gas bubbles stabilized by surface active molecules. Their complex and diverse properties make them attractive for many chemical and physical applications where foaming, emulsifying or coating processes are needed. The recent synthesis of multi-cephalic and multi-tailed amphiphilic molecules have reportedly enhanced their antibacterial activity in connection with tail length and nature of the head group. This report covers the foamability of two triple head, double tail cationic surfactants (M-1,14,14, M-P,14,14) and a triple head single tail cationic surfactant (M-1,1,14) and compares them with commercially available single headed, single tailed anionic and cationic surfactants (SDS, CTAB and DTAB). Additionally, a longer tailed variant (M-1,16,16) was also tested. The results show that bubble rupture rate decreases with the length of the carbon chain, irrespective of head structure. For the longer tailed variant (M-1,16,16) foam was difficult to produce leaving it untestable. The growth rate of bubbles with short tailed surfactants (SDS) and longer, single tailed tricationic surfactants (M-1,1,14) was shown to be twice as high as those with longer tailed surfactants (CTAB, M-P,14,14, M-1,14,14). This fact was related to the size variation of bubbles, where the foams made with short tail surfactants exhibited higher polydispersity than those with short tails. This suggests that foams with tricationic amphiphilics are closely linked to their tail length and generally insensitive to their head structure

Response Monitoring with [18F]FLT PET and Diffusion-Weighted MRI After Cytotoxic 5-FU Treatment in an Experimental Rat Model for Colorectal Liver Metastases.

PURPOSE: The aim of the study was to investigate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) and 3'-dexoy-3'-[(¹⁸)F]fluorothymidine ([(¹⁸)F]FLT) positron emission tomography (PET) as early biomarkers of treatment response of 5-fluorouracil (5-FU) in a syngeneic rat model of colorectal cancer liver metastases. PROCEDURES: Wag/Rij rats with intrahepatic syngeneic CC531 tumors were treated with 5-FU (15, 30, or 60 mg/kg in weekly intervals). Before treatment and at days 1, 3, 7, and 14 after treatment rats underwent DW-MRI and [(¹⁸)F]FLT PET. Tumors were analyzed immunohistochemically for Ki67, TK1, and ENT1 expression. RESULTS: 5-FU inhibited the growth of CC531 tumors in a dose-dependent manner. Immunohistochemical analysis did not show significant changes in Ki67, TK1, and ENT1 expression. However, [(¹⁸)F]FLT SUV_mean and SUV_max were significantly increased at days 4 and 7 after treatment with 5-FU (60 mg/kg) and returned to baseline at day 14 (SUV_max at days -1, 4, 7, and 14 was 1.1 ± 0.1, 2.3 ± 0.5, 2.3 ± 0.6, and 1.5 ± 0.4, respectively). No changes in [(¹⁸)F]FLT uptake were observed in the nontreated animals. Furthermore, the apparent diffusion coefficient (ADCmean) did not change in 5-FU-treated rats compared to untreated rats. CONCLUSION: This study suggests that 5-FU treatment induces a flare in [(¹⁸)F]FLT uptake of responsive CC531 tumors in the liver, while the ADC_mean did not change significantly. Future studies in larger groups are warranted to further investigate whether [(¹⁸)F]FLT PET can discriminate between disease progression and treatment response.The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement number 115151, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution

Effects of Dual Targeting of Tumor Cells and Stroma in Human Glioblastoma Xenografts with a Tyrosine Kinase Inhibitor against c-MET and VEGFR2

Contains fulltext : 118357.pdf (publisher's version ) (Open Access)Anti-angiogenic treatment of glioblastoma with Vascular Endothelial Growth Factor (VEGF)- or VEGF Receptor 2 (VEGFR2) inhibitors normalizes tumor vessels, resulting in a profound radiologic response and improved quality of life. This approach however does not halt tumor progression by diffuse infiltration, as this phenotype is less angiogenesis dependent. Combined inhibition of angiogenesis and diffuse infiltrative growth would therefore be a more effective treatment approach in these tumors. The HGF/c-MET axis is important in both angiogenesis and cell migration in several tumor types including glioma. We therefore analyzed the effects of the c-MET- and VEGFR2 tyrosine kinase inhibitor cabozantinib (XL184, Exelixis) on c-MET positive orthotopic E98 glioblastoma xenografts, which routinely present with angiogenesis-dependent areas of tumor growth, as well as diffuse infiltrative growth. In cultures of E98 cells, cabozantinib effectively inhibited c-MET phosphorylation, concomitant with inhibitory effects on AKT and ERK1/2 phosphorylation, and cell proliferation and migration. VEGFR2 activation in endothelial cells was also effectively inhibited . Treatment of BALB/c nu/nu mice carrying orthotopic E98 xenografts resulted in a significant increase in overall survival. Cabozantinib effectively inhibited angiogenesis, resulting in increased hypoxia in angiogenesis-dependent tumor areas, and induced vessel normalization. Yet, tumors ultimately escaped cabozantinib therapy by diffuse infiltrative outgrowth via vessel co-option. Of importance, in contrast to the results from experiments, blockade of c-MET activation was incomplete, possibly due to multiple factors including restoration of the blood-brain barrier resulting from cabozantinib-induced VEGFR2 inhibition. In conclusion, cabozantinib is a promising therapy for c-MET positive glioma, but improving delivery of the drug to the tumor and/or the surrounding tissue may be needed for full activity