Preclinical Applications of 3'-Deoxy-3'-[18F]Fluorothymidine in Oncology - A Systematic Review

The positron emission tomography (PET) tracer 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) has been proposed to measure cell proliferation non-invasively in vivo. Hence, it should provide valuable information for response assessment to tumor therapies. To date, [18F]FLT uptake has found limited use as a response biomarker in clinical trials in part because a better understanding is needed of the determinants of [18F]FLT uptake and therapy-induced changes of its retention in the tumor. In this systematic review of preclinical [18F]FLT studies, comprising 174 reports, we identify the factors governing [18F]FLT uptake in tumors, among which thymidine kinase 1 plays a primary role. The majority of publications (83 %) report that decreased [18F]FLT uptake reflects the effects of anticancer therapies. 144 times [18F]FLT uptake was related to changes in proliferation as determined by ex vivo analyses. Of these approaches, 77 % describe a positive relation, implying a good concordance of tracer accumulation and tumor biology. These preclinical data indicate that [18F]FLT uptake holds promise as an imaging biomarker for response assessment in clinical studies. Understanding of the parameters which influence cellular [18F]FLT uptake and retention as well as the mechanism of changes induced by therapy is essential for successful implementation of this PET tracer. Hence, our systematic review provides the background for the use of [18F]FLT in future clinical studies

Imaging tumour hypoxia with positron emission tomography.

Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers.Cancer Research UK (CRUK) funded the National Cancer Research Institute (NCRI) PET Research Working party to organise a meeting to discuss imaging cancer with hypoxia tracers and Positron Emission Tomography. IF was funded by CRUK and is also supported by the Chief Scientific Office. ALH is supported by CRUK and the Breast Cancer Research Foundation. RM is funded by NIHR Cambridge Biomedical Research Centre.This is the accepted manuscript. The final version is available from Nature Publishing at http://www.nature.com/bjc/journal/vaop/ncurrent/full/bjc2014610a.html

Routine gastric residual volume measurement and energy target achievement in the PICU: A comparison study

Critically ill children frequently fail to achieve adequate energy intake and some care practices, such as the measurement of gastric residual volume (GRV) may contribute to this problem. We compared outcomes in two similar European Pediatric Intensive Care Units (PICUs): one which routinely measures GRV (PICU-GRV) to one unit that does not (PICU-noGRV). An observational pilot comparison study was undertaken. 87 children were included in the study, 42 (PICU-GRV) and 45 (PICU-noGRV). There were no significant differences in the percentage of energy targets achieved in the first four days of PICU admission although PICU-noGRV showed more consistent delivery of median (and IQR) energy targets, and less under and over feeding for PICU-GRV and PICU-noGRV Day 1 37 (14-72) vs 44 (0-100); Day 2 97 (53-126) vs 100 (100-100), Day 3 84 (45-112) vs 100 (100-100) , Day 4 101 (63-124) vs 100 (100-100). The incidence of vomiting was higher in PICU-GRV. No necrotising enterocolitis was confirmed in either unit and ventilator acquired pneumonia rates were not significantly different (7.01 vs 12 5.31 per 1000 ventilator days; p=0.70) between PICU-GRV and PICU-noGRV units. Conclusions: The practice of routine gastric residual measurement did not significantly impair energy targets in the first four days of PICU admission. However, not measuring GRV did not increase vomiting, ventilator acquired pneumonia or necrotising enterocolitis, which is the main reason clinicians cite for measuring GRV. What is known?•The practice of routinely measuring gastric residual volume is widespread in critical care units•This practice is increasingly being questioned in critically ill patients, both as a practice that increases •the likelihood of delivering inadequate enteral nutrition amounts and as a tool to assess feeding tolerance What is new? •Not routinely measuring gastric residual volume did not increase adverse events of ventilator acquired pneumonia, necrotising enterocolitis or vomiting •In the first four days of PICU stay, energy target achievement was not significantly different, but the rates of under and over feeding were higher in the routine GRV measurement uni

Analysis of protein carbonylation - pitfalls and promise in commonly used methods

Abstract Oxidation of proteins has received a lot of attention in the last decades due to the fact that they have been shown to accumulate and to be implicated in the progression and the patho-physiology of several diseases such as Alzheimer, coronary heart diseases, etc. This has also resulted in the fact that research scientist became more eager to be able to measure accurately the level of oxidized protein in biological materials, and to determine the precise site of the oxidative attack on the protein, in order to get insights into the molecular mechanisms involved in the progression of diseases. Several methods for measuring protein carbonylation have been implemented in different laboratories around the world. However, to date no methods prevail as the most accurate, reliable and robust. The present paper aims at giving an overview of the common methods used to determine protein carbonylation in biological material as well as to highlight the limitations and the potential. The ultimate goal is to give quick tips for a rapid decision making when a method has to be selected and taking into consideration the advantage and drawback of the methods

Sample treatment for tissue proteomics in cancer, toxicology, and forensics

Since the birth of proteomics science in the 1990, the number of applications and of sample preparation methods has grown exponentially, making a huge contribution to the knowledge in life science disciplines. Continuous improvements in the sample treatment strategies unlock and reveal the fine details of disease mechanisms, drug potency, and toxicity as well as enable new disciplines to be investigated such as forensic science. This chapter will cover the most recent developments in sample preparation strategies for tissue proteomics in three areas, namely, cancer, toxicology, and forensics, thus also demonstrating breath of application within the domain of health and well-being, pharmaceuticals, and secure societies. In particular, in the area of cancer (human tumor biomarkers), the most efficient and multi-informative proteomic strategies will be covered in relation to the subsequent application of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and liquid extraction surface analysis (LESA), due to their ability to provide molecular localization of tumor biomarkers albeit with different spatial resolution. With respect to toxicology, methodologies applied in toxicoproteomics will be illustrated with examples from its use in two important areas: the study of drug-induced liver injury (DILI) and studies of effects of chemical and environmental insults on skin, i.e., the effects of irritants, sensitizers, and ionizing radiation. Within this chapter, mainly tissue proteomics sample preparation methods for LC-MS/MS analysis will be discussed as (i) the use of LC-MS/MS is majorly represented in the research efforts of the bioanalytical community in this area and (ii) LC-MS/MS still is the gold standard for quantification studies. Finally, the use of proteomics will also be discussed in forensic science with respect to the information that can be recovered from blood and fingerprint evidence which are commonly encountered at the scene of the crime. The application of proteomic strategies for the analysis of blood and fingerprints is novel and proteomic preparation methods will be reported in relation to the subsequent use of mass spectrometry without any hyphenation. While generally yielding more information, hyphenated methods are often more laborious and time-consuming; since forensic investigations need quick turnaround, without compromising validity of the information, the prospect to develop methods for the application of quick forensic mass spectrometry techniques such as MALDI-MS (in imaging or profiling mode) is of great interest

Evidence-Based PET for Abdominal and Pelvic Tumours

Evidence-based data about the usefulness of positron emission tomography (PET) and hybrid imaging methods (PET/CT and PET/MRI) in abdominal and pelvic tumours have been collected and discussed in this chapter. These data were divided in three sections: (1) gastrointestinal tumours, (2) uro-genital tumours, (3) gynaecological tumours. Several pooled data (diagnostic and prognostic data), clinical settings (e.g. staging, restaging, treatment evaluation) and radiotracers as fluorine-18 fluorodeoxyglucose (18F-FDG), radiolabelled choline and prostate-specific membrane antigen (PSMA) were considered

A Fast Automaton-Based Method for Detecting Anomalous Program Behaviors

Forrest et al introduced a new intrusion detection approach that identifies anomalous sequences of system calls executed by programs. Since their work, anomaly detection on system call sequences has become perhaps the most successful approach for detecting novel intrusions. A natural way for learning sequences is to use a finite-state automaton (FSA). However, previous research seemed to indicate that FSA-learning is computationally expensive, that it cannot be completely automated, or that the space usage of the FSA may be excessive. We present a new approach in this paper that overcomes these difficulties. Our approach builds a compact FSA in a fully automatic and efficient manner, without requiring access to source code for programs. The space requirements for the FSA is low --- of the order of a few kilobytes for typical programs. The FSA uses only a constant time per system call during the learning as well as detection period. This factor leads to low overheads for intrusion detection. Unlike many of the previous techniques, our FSA-technique can capture both short term and long term temporal relationships among system calls, and thus perform more accurate detection. For instance, the FSA can capture common program structures such as branches, joins, loops etc. This enables our approach to generalize and predict future behaviors from past behaviors. For instance, if a program executed a loop once in an execution, the FSA approach can generalize and predict that the same loop may be executed zero or more times in subsequent executions. As a result, the training periods needed for our FSA based approach are shorter. Moreover, false positives are reduced without increasing the likelihood of missing attacks. This paper describes our FSA based technique and presents a ..