OPTIma:a tracking solution for proton computed tomography in high proton flux environments

Currently there is a large discrepancy between the currents that are used for treatments in proton beam therapy facilities and the ultra low beam currents required for many proton CT imaging systems. Here we provide details of the OPTIma silicon strip based tracking system, which has been designed for performing proton CT imaging in conditions closer to the high proton flux environments of modern spot scanning treatment facilities. Details on the physical design, sensor testing, modelling, and track reconstruction are provided along with Monte-Carlo simulation studies of the expected performance for proton beam currents of up to 50 pA at the nozzle when using a σ = ∼10 mm spot scanning cyclotron system. Using a detailed simulation of the proposed OPTIma system, a discrepancy of less than 1% on the Relative Stopping Power is found for various tissues when embedded within a 150 mm diameter Perspex sphere. It is found that by accepting up to 7 protons per bunch it is possible to operate at cyclotron beam currents up to 5 times higher than would be possible with a single proton based readout, significantly reducing the total beam time required to produce an image, while also reducing the discrepancy between the beam currents required for treatment and those used for proton CT

Microsatellite instability analysis in hereditary non-polyposis colon cancer using the Bethesda consensus panel of microsatellite markers in the absence of proband normal tissue

BACKGROUND: Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant syndrome predisposing to the early development of various cancers including those of colon, rectum, endometrium, ovarium, small bowel, stomach and urinary tract. HNPCC is caused by germline mutations in the DNA mismatch repair genes, mostly hMSH2 or hMLH1. In this study, we report the analysis for genetic counseling of three first-degree relatives (the mother and two sisters) of a male who died of colorectal adenocarcinoma at the age of 23. The family fulfilled strict Amsterdam-I criteria (AC-I) with the presence of extracolonic tumors in the extended pedigree. We overcame the difficulty of having a proband post-mortem non-tumor tissue sample for MSI testing by studying the alleles carried by his progenitors. METHODS: Tumor MSI testing is described as initial screening in both primary and metastasis tumor tissue blocks, using the reference panel of 5 microsatellite markers standardized by the National Cancer Institute (NCI) for the screening of HNPCC (BAT-25, BAT-26, D2S123, D5S346 and D17S250). Subsequent mutation analysis of the hMLH1 and hMSH2 genes was performed. RESULTS: Three of five microsatellite markers (BAT-25, BAT-26 and D5S346) presented different alleles in the proband's tumor as compared to those inherited from his parents. The tumor was classified as high frequency microsatellite instability (MSI-H). We identified in the HNPCC family a novel germline missense (c.1864C>A) mutation in exon 12 of hMSH2 gene, leading to a proline 622 to threonine (p.Pro622Thr) amino acid substitution. CONCLUSION: This approach allowed us to establish the tumor MSI status using the NCI recommended panel in the absence of proband's non-tumor tissue and before sequencing the obligate carrier. According to the Human Gene Mutation Database (HGMD) and the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Database this is the first report of this mutation

The impact of parenthood on environmental attitudes and behaviour: a longitudinal investigation of the legacy hypothesis

Willingness to engage in sustainable actions may be limited by the psychological distance of climate change. In this study, we test the legacy hypothesis, which holds that having children leads parents to consider the legacy left to offspring in respect of environmental quality. Using the Understanding Society dataset, a longitudinal survey representative of the UK population (n = 18,176), we assess how having children may change people’s individual environmental attitudes and behaviour. Results indicate that having a new child is associated with a small decrease in the frequency of a few environmental behaviours. Only parents with already high environmental concern show a small increase in the desire to act more sustainably after the birth of their first child. Overall, the results do not provide evidence in support of the legacy hypothesis in terms of individual-level environmental attitudes and behaviours. We argue that the transition to parenthood is a time where concern is prioritised on the immediate wellbeing of the child and not on the future environmental threats

Effects of Stem Cell Factor on Hypoxia-Inducible Factor 1 Alpha Accumulation in Human Acute Myeloid Leukaemia and LAD2 Mast Cells

Stem cell factor (SCF) is a hematopoietic growth factor that exerts its activity by signalling through the tyrosine kinase receptor known as Kit or CD117. SCF-Kit signalling is crucial for the survival, proliferation and differentiation of hematopoietic cells of myeloid lineage. Furthermore, since myeloid leukaemia cells express the Kit receptor, SCF may play an important role in myeloid leukaemia progression too. However, the mechanisms of this pathophysiological effect remain unclear. Recent evidence shows that SCF triggers accumulation of the inducible alpha subunit of hypoxia-inducible factor 1 (HIF-1) in hematopoietic cells—a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability. However, it is unknown how SCF impacts on HIF-1α accumulation in human myeloid leukaemia and mast cells. Here we show that SCF induces HIF-1α accumulation in THP-1 human myeloid leukaemia cells but not in LAD2 mast cells. We demonstrated that LAD2 cells have a more robust glutathione (GSH)-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner. BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD) activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells, SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to a certain extent by redox-dependent mechanisms. These results demonstrate for the first time an important cross-talk of signalling pathways associated with HIF-1 activation—an important stage of the myeloid leukaemia cell life cycle

Embedded pitch adapters: a high-yield interconnection solution for strip sensors

A proposal to fabricate large area strip sensors with integrated, or embedded, pitch adapters is presented for the End-cap part of the Inner Tracker in the ATLAS experiment. To implement the embedded pitch adapters, a second metal layer is used in the sensor fabrication, for signal routing to the ASICs. Sensors with different embedded pitch adapters have been fabricated in order to optimize the design and technology. Inter-strip capacitance, noise, pick-up, cross-talk, signal efficiency, and fabrication yield have been taken into account in their design and fabrication. Inter-strip capacitance tests taking into account all channel neighbors reveal the important differences between the various designs considered. These tests have been correlated with noise figures obtained in full assembled modules, showing that the tests performed on the bare sensors are a valid tool to estimate the final noise in the full module. The full modules have been subjected to test beam experiments in order to evaluate the incidence of cross-talk, pick-up, and signal loss. The detailed analysis shows no indication of cross-talk or pick-up as no additional hits can be observed in any channel not being hit by the beam above 170 mV threshold, and the signal in those channels is always below 1% of the signal recorded in the channel being hit, above 100 mV threshold. First results on irradiated mini-sensors with embedded pitch adapters do not show any change in the interstrip capacitance measurements with only the first neighbors connected