On April 11, 2016, Cancer Research UK reported that the first cancer patient in Europe has been scanned with a revolutionary imaging technique that could enable doctors to see whether a drug is working within a day or two of starting treatment (Press release, Cancer Research UK, APR 10, 2016, View Source [SID:1234510639]).

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The patient is the first to take part in a new metabolic imaging trial* of patients across a wide range of cancer types to be carried out by Cancer Research UK-funded scientists at Addenbrooke’s Hospital, part of Cambridge University Hospitals. The study, which is funded by a Wellcome Trust Strategic Award, could show whether patients can stop taking drugs that aren’t working for them, try different ones and receive the best treatment for their cancer as quickly as possible.

The rapid scan will allow doctors to map out molecular changes in patients, opening up potential new ways to detect cancer and monitor the effects of treatment.

The technique uses a breakdown product of glucose called pyruvate. The pyruvate is labelled with a non-radioactive form of carbon, called carbon 13 (C-13) which makes it 10,000 times more likely to be detected in a magnetic resonance imaging (MRI) scan. Pyruvate is injected into the patient and tracked as the molecule moves around the body and enters cells. The scan monitors how quickly cancer cells break pyruvate down – a measure of how active the cells are that tells doctors whether or not a drug has been effective at killing them.

Professor Kevin Brindle, co-lead based at the Cancer Research UK Cambridge Institute, said: "We’re very excited to be the first group outside North America, and the third group world-wide, to test this with patients and we hope that it will soon help improve treatment by putting to an end patients being given treatments that aren’t working for them. Each person’s cancer is different and this technique could help us tailor a patient’s treatment more quickly than before."

Dr Ferdia Gallagher, co-lead also funded by Cancer Research UK and based at the Department of Radiology at the University of Cambridge**, said: "It’s fantastic that we can now try this technique in patients. We hope this will progress the way cancer treatment is given and make therapy more effective for patients in the future. This new technique could potentially mean that doctors will find out much more quickly if a treatment is working for their patient instead of waiting to see if a tumour shrinks."

Dr Emma Smith, Cancer Research UK’s science information manager, said: "Finding out early on whether cancer is responding to therapy could save patients months of treatment that isn’t working for them. The next steps for this study will be collecting and analysing the results to find out if this imaging technology provides an accurate early snapshot of how well drugs destroy tumours."

In gastric cancer (GC), the main subtypes (diffuse and intestinal types) differ in pathological characteristics, with diffuse GC exhibiting early disseminative and invasive behaviour. A distinctive feature of diffuse GC is loss of intercellular adhesion. Although widely attributed to mutations in the CDH1 gene encoding E-cadherin, a significant percentage of diffuse GC do not harbor CDH1 mutations. We found that the expression of the actin-modulating cytoskeletal protein, gelsolin, is significantly higher in diffuse-type compared to intestinal-type GCs, using immunohistochemical and microarray analysis. Furthermore, in GCs with wild-type CDH1, gelsolin expression correlated inversely with CDH1 gene expression. Downregulating gelsolin using siRNA in GC cells enhanced intercellular adhesion and E-cadherin expression, and reduced invasive capacity. Interestingly, hepatocyte growth factor (HGF) induced increased gelsolin expression, and gelsolin was essential for HGF-medicated cell scattering and E-cadherin transcriptional repression through Snail, Twist and Zeb2. The HGF-dependent effect on E-cadherin was found to be mediated by interactions between gelsolin and PI3K-Akt signaling. This study reveals for the first time a function of gelsolin in the HGF/cMet oncogenic pathway, which leads to E-cadherin repression and cell scattering in gastric cancer. Our study highlights gelsolin as an important pro-disseminative factor contributing to the aggressive phenotype of diffuse GC.

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During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.
Copyright © 2016. Published by Elsevier Ltd.

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Immunotherapy is rapidly evolving as an effective treatment option for many cancers. With the emerging fields of cancer vaccines and adoptive cell transfer therapies, there is an increasing demand for high-throughput in vitro cytotoxicity assays that efficiently analyze immune effector functions. The gold standard (51)Cr-release assay is very accurate but has the major disadvantage of being radioactive. We reveal the development of a versatile and nonradioactive firefly luciferase in vitro transcribed (IVT) RNA-based assay. Demonstrating high efficiency, consistency, and excellent target cell viability, our optimized luciferase IVT RNA is used to transfect dividing and nondividing primary antigen presenting cells. Together with the long-lasting expression and minimal background, the direct measurement of intracellular luciferase activity of living cells allows for the monitoring of killing kinetics and displays paramount sensitivity. The ability to cotransfect the IVT RNA of the luciferase reporter and the antigen of interest into the antigen presenting cells and its simple read-out procedure render the assay high-throughput in nature. Results generated were comparable to the (51)Cr release and further confirmed the assay’s ability to measure antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The assay’s combined simplicity, practicality, and efficiency tailor it for the analysis of antigen-specific cellular and humoral effector functions during the development of novel immunotherapies.

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Pharmacokinetic properties of oligonucleotides are largely driven by chemistry of the backbone and thus are sequence independent within a chemical class. Tissue bioavailability (% of administered dose) is assisted by plasma protein binding that limits glomerular filtration and ultimate urinary excretion of oligonucleotides. The substitution of one non-bridging oxygen with the more hydrophobic sulfur atom (phosphorothioate) increases both plasma stability and plasma protein binding and thus, ultimately, tissue bioavailability. Additional modifications of the sugar at the 2′ position, increase RNA binding affinity and significantly increase potency, tissue half-life and prolong RNA inhibitory activity. Oligonucleotides modified in this manner consistently exhibit the highest tissue bioavailability (>90%). Systemic biodistribution is broad, and organs typically with highest concentrations are liver and kidney followed by bone marrow, adipocytes, and lymph nodes. Cell uptake is predominantly mediated by endocytosis. Both size and charge for most oligonucleotides prevents distribution across the blood brain barrier. However, modified single-strand oligonucleotides administered by intrathecal injection into the CSF distribute broadly in the CNS. The majority of intracellular oligonucleotide distribution following systemic or local administration occurs rapidly in just a few hours following administration and is facilitated by rapid endocytotic uptake mechanisms. Further understanding of the intracellular trafficking of oligonucleotides may provide further enhancements in design and ultimate potency of antisense oligonucleotides in the future.
Copyright © 2015. Published by Elsevier B.V.

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