A novel methodology for in vivo endoscopic phenotyping of colorectal cancer based on real-time analysis of the mucosal lipidome: a prospective observational study of the iKnife

Background: This pilot study assessed the diagnostic accuracy of rapid evaporative ionization mass spectrometry (REIMS) in colorectal cancer (CRC) and colonic adenomas. Methods: Patients undergoing elective surgical resection for CRC were recruited at St. Mary’s Hospital London and The Royal Marsden Hospital, UK. Ex vivo analysis was performed using a standard electrosurgery handpiece with aspiration of the electrosurgical aerosol to a Xevo G2-S iKnife QTof mass spectrometer (Waters Corporation). Histological examination was performed for validation purposes. Multivariate analysis was performed using principal component analysis and linear discriminant analysis in Matlab 2015a (Mathworks, Natick, MA). A modified REIMS endoscopic snare was developed (Medwork) and used prospectively in five patients to assess its feasibility during hot snare polypectomy. Results: Twenty-eight patients were recruited (12 males, median age 71, range 35–89). REIMS was able to reliably distinguish between cancer and normal adjacent mucosa (NAM) (AUC 0.96) and between NAM and adenoma (AUC 0.99). It had an overall accuracy of 94.4 % for the detection of cancer versus adenoma and an adenoma sensitivity of 78.6 % and specificity of 97.3 % (AUC 0.99) versus cancer. Long-chain phosphatidylserines (e.g., PS 22:0) and bacterial phosphatidylglycerols were over-expressed on cancer samples, while NAM was defined by raised plasmalogens and triacylglycerols expression and adenomas demonstrated an over-expression of ceramides. REIMS was able to classify samples according to tumor differentiation, tumor budding, lymphovascular invasion, extramural vascular invasion and lymph node micrometastases (AUC’s 0.88, 0.87, 0.83, 0.81 and 0.81, respectively). During endoscopic deployment, colonoscopic REIMS was able to detect target lipid species such as ceramides during hot snare polypectomy. Conclusion: REIMS demonstrates high diagnostic accuracy for tumor type and for established histological features of poor prognostic outcome in CRC based on a multivariate analysis of the mucosal lipidome. REIMS could augment endoscopic and imaging technologies for precision phenotyping of colorectal cancer

The GEO600 squeezed light source

The next upgrade of the GEO600 gravitational wave detector is scheduled for 2010 and will, in particular, involve the implementation of squeezed light. The required non-classical light source is assembled on a 1.5m^2 breadboard and includes a full coherent control system and a diagnostic balanced homodyne detector. Here, we present the first experimental characterization of this setup as well as a detailed description of its optical layout. A squeezed quantum noise of up to 9dB below the shot-noise level was observed in the detection band between 10Hz and 10kHz. We also present an analysis of the optical loss in our experiment and provide an estimation of the possible non-classical sensitivity improvement of the future squeezed light enhanced GEO600 detector.Comment: 8 pages, 4 figure

On equations over sets of integers

Systems of equations with sets of integers as unknowns are considered. It is shown that the class of sets representable by unique solutions of equations using the operations of union and addition S+T=\makeset{m+n}{m \in S, \: n \in T} and with ultimately periodic constants is exactly the class of hyper-arithmetical sets. Equations using addition only can represent every hyper-arithmetical set under a simple encoding. All hyper-arithmetical sets can also be represented by equations over sets of natural numbers equipped with union, addition and subtraction S \dotminus T=\makeset{m-n}{m \in S, \: n \in T, \: m \geqslant n}. Testing whether a given system has a solution is $\Sigma^1_1$-complete for each model. These results, in particular, settle the expressive power of the most general types of language equations, as well as equations over subsets of free groups.Comment: 12 apges, 0 figure

Prospects for radical emissions reduction through behaviour and lifestyle change

Over the past two decades, scholars and practitioners across the social sciences, in policy and beyond have proposed, trialled and developed a wide range of theoretical and practical approaches designed to bring about changes in behaviours and lifestyles that contribute to climate change. With the exception of the establishment of a small number of iconic behaviours such as recycling, it has however proved extremely difficult to bring about meaningful transformations in personal greenhouse gas emissions at either the individual or societal level, with multiple reviews now pointing to the limited efficacy of current approaches. We argue that the majority of approaches designed to achieve mitigation have been constrained by the need to operate within prevailing social scientific, economic and political orthodoxies which have precluded the possibility of non-marginal change. In this paper we ask what a truly radical approach to reducing personal emissions would look like from social science perspectives which challenge the unstated assumptions severely limiting action to date, and which explore new alternatives for change. We emphasise the difficulties likely to impede the instituting of genuinely radical societal change regarding climate change mitigation, whilst proposing ways that the ground could be prepared for such a transformation to take place

Long-term stable squeezed vacuum state of light for gravitational wave detectors

Currently, the German/British gravitational wave detector GEO600 is being upgraded in course of the GEO-HF program. One part of this upgrade consists of the integration of a squeezed light laser to nonclassically improve the detection sensitivity at frequencies where the instrument is limited by shot noise. This has been achieved recently [1]. The permanent employment of squeezed light in gravitational wave observatories requires a long-term stability of the generated squeezed state. In this paper, we discuss an unwanted mechanism that can lead to a varying squeezing factor along with a changing phase of the squeezed field. We present an extension of the implemented coherent control scheme [2] that allowed an increase in the long-term stability of the GEO600 squeezed light laser. With it, a quantum noise reduction by more than 9 dB in the frequency band of 10 Hz - 10 kHz was observed over up to 20 hours with a duty cycle of more than 99%

3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors

There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor–derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay. A study of 30 early-stage non–small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standard-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers. Mol Cancer Ther; 15(4); 753–63. ©2016 AACR

Fractal Reconnection in Solar and Stellar Environments

Recent space based observations of the Sun revealed that magnetic reconnection is ubiquitous in the solar atmosphere, ranging from small scale reconnection (observed as nanoflares) to large scale one (observed as long duration flares or giant arcades). Often the magnetic reconnection events are associated with mass ejections or jets, which seem to be closely related to multiple plasmoid ejections from fractal current sheet. The bursty radio and hard X-ray emissions from flares also suggest the fractal reconnection and associated particle acceleration. We shall discuss recent observations and theories related to the plasmoid-induced-reconnection and the fractal reconnection in solar flares, and their implication to reconnection physics and particle acceleration. Recent findings of many superflares on solar type stars that has extended the applicability of the fractal reconnection model of solar flares to much a wider parameter space suitable for stellar flares are also discussed.Comment: Invited chapter to appear in "Magnetic Reconnection: Concepts and Applications", Springer-Verlag, W. D. Gonzalez and E. N. Parker, eds. (2016), 33 pages, 18 figure

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

Assessing agreement between malaria slide density readings

BACKGROUND: Several criteria have been used to assess agreement between replicate slide readings of malaria parasite density. Such criteria may be based on percent difference, or absolute difference, or a combination. Neither the rationale for choosing between these types of criteria, nor that for choosing the magnitude of difference which defines acceptable agreement, are clear. The current paper seeks a procedure which avoids the disadvantages of these current options and whose parameter values are more clearly justified. METHODS AND RESULTS: Variation of parasite density within a slide is expected, even when it has been prepared from a homogeneous sample. This places lower limits on sensitivity and observer agreement, quantified by the Poisson distribution. This means that, if a criterion of fixed percent difference criterion is used for satisfactory agreement, the number of discrepant readings is over-estimated at low parasite densities. With a criterion of fixed absolute difference, the same happens at high parasite densities. For an ideal slide, following the Poisson distribution, a criterion based on a constant difference in square root counts would apply for all densities. This can be back-transformed to a difference in absolute counts, which, as expected, gives a wider range of acceptable agreement at higher average densities. In an example dataset from Tanzania, observed differences in square root counts correspond to a 95% limits of agreement of -2,800 and +2,500 parasites/microl at average density of 2,000 parasites/microl, and -6,200 and +5,700 parasites/microl at 10,000 parasites/microl. However, there were more outliers beyond those ranges at higher densities, meaning that actual coverage of these ranges was not a constant 95%, but decreased with density. In a second study, a trial of microscopist training, the corresponding ranges of agreement are wider and asymmetrical: -8,600 to +5,200/microl, and -19,200 to +11,700/microl, respectively. By comparison, the optimal limits of agreement, corresponding to Poisson variation, are +/- 780 and +/- 1,800 parasites/microl, respectively. The focus of this approach on the volume of blood read leads to other conclusions. For example, no matter how large a volume of blood is read, some densities are too low to be reliably detected, which in turn means that disagreements on slide positivity may simply result from within-slide variation, rather than reading errors. CONCLUSIONS: The proposed method defines limits of acceptable agreement in a way which allows for the natural increase in variability with parasite density. This includes defining the levels of between-reader variability, which are consistent with random variation: disagreements within these limits should not trigger additional readings. This approach merits investigation in other settings, in order to determine both the extent of its applicability, and appropriate numerical values for limits of agreement