In recent years, there has been a rapid increase in the number of CT scans performed, both in the US and the UK, which has fuelled concern about the long-term consequences of these exposures, ...particularly in terms of cancer induction. Statistics from the US and the UK indicate a 20-fold and 12-fold increase, respectively, in CT usage over the past two decades, with per caput CT usage in the US being about five times that in the UK. In both countries, most of the collective dose from diagnostic radiology comes from high-dose (in the radiological context) procedures such as CT, interventional radiology and barium enemas; for these procedures, the relevant organ doses are in the range for which there is now direct credible epidemiological evidence of an excess risk of cancer, without the need to extrapolate risks from higher doses. Even for high-dose radiological procedures, the risk to the individual patient is small, so that the benefit/risk balance is generally in the patients' favour. Concerns arise when CT examinations are used without a proven clinical rationale, when alternative modalities could be used with equal efficacy, or when CT scans are repeated unnecessarily. It has been estimated, at least in the US, that these scenarios account for up to one-third of all CT scans. A further issue is the increasing use of CT scans as a screening procedure in asymptomatic patients; at this time, the benefit/risk balance for any of the commonly suggested CT screening techniques has yet to be established.
The annual number of CT scans in the U.S. is now over 70 million. The concern is that organ doses from CT are typically far larger than those from conventional X-ray examinations, and there is ...epidemiological evidence of a small but significant increased cancer risk at typical CT doses. Because CT is a superb diagnostic tool and because individual CT risks are small, when a CT scan is clinically indicated, the CT benefit/risk balance is by far in the patient's favor. Nevertheless, CT should operate under the ALARA (As Low As Reasonably Achievable) principle, and opportunities exist to reduce the significant population dose associated with CT without compromising patient care. The first opportunity is to reduce the dose per scan, and improved technology has much potential here. The second opportunity is selective replacement of CT with other modalities, such as for many head and spinal examinations (with MRI), and for diagnosing appendicitis (selective use of ultrasound + CT). Finally, a fraction of CT scans could be avoided entirely, as indicated by CT decision rules: Clinical decision rules for CT use represent a powerful approach for slowing down the increase in CT use, because they have the potential to overcome some of the major factors that result in some CT scans being undertaken when they are potentially not clinically helpful. In the U.S. and potentially elsewhere, legislative approaches are a possible option, to improve quality control and reduce clinically unneeded CT use, and it is also possible that upcoming changes in heath care economics will tend to slow the increase in such CT use.
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Quantifying radiation-induced cancer risks associated with radiological examinations is not easy, which has resulted in much controversy. We can clarify the situation by distinguishing between higher ...dose examinations, such as CT, positron emission tomography-CT or fluoroscopically guided interventions, and lower dose "conventional" X-ray examinations. For higher dose examinations, the epidemiological data, from atomic bomb survivors exposed to low doses and from direct epidemiological studies of paediatric CT, are reasonably consistent, suggesting that we do have a reasonable quantitative understanding of the individual risks: in summary, very small but unlikely to be zero. For lower dose examinations, we have very little data, and the situation is much less certain, however, the collective dose from these lower dose examinations is comparatively unimportant from a public health perspective.
Programmed connection of amino acids or nucleotides into chains introduced a revolution in control of biological function. Reacting proteins together is more complex because of the number of reactive ...groups and delicate stability. Here we achieved sequence-programmed irreversible connection of protein units, forming polyprotein teams by sequential amidation and transamidation. SpyTag peptide is engineered to spontaneously form an isopeptide bond with SpyCatcher protein. By engineering the adhesin RrgA from Streptococcus pneumoniae, we developed the peptide SnoopTag, which formed a spontaneous isopeptide bond to its protein partner SnoopCatcher with >99% yield and no cross-reaction to SpyTag/SpyCatcher. Solid-phase attachment followed by sequential SpyTag or SnoopTag reaction between building-blocks enabled iterative extension. Linear, branched, and combinatorial polyproteins were synthesized, identifying optimal combinations of ligands against death receptors and growth factor receptors for cancer cell death signal activation. This simple and modular route to programmable “polyproteams” should enable exploration of a new area of biological space.
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Mechanical forces are central to developmental, physiological and pathological processes. However, limited understanding of force transmission within sub-cellular structures is a major obstacle to ...unravelling molecular mechanisms. Here we describe the development of a calibrated biosensor that measures forces across specific proteins in cells with piconewton (pN) sensitivity, as demonstrated by single molecule fluorescence force spectroscopy. The method is applied to vinculin, a protein that connects integrins to actin filaments and whose recruitment to focal adhesions (FAs) is force-dependent. We show that tension across vinculin in stable FAs is ∼2.5 pN and that vinculin recruitment to FAs and force transmission across vinculin are regulated separately. Highest tension across vinculin is associated with adhesion assembly and enlargement. Conversely, vinculin is under low force in disassembling or sliding FAs at the trailing edge of migrating cells. Furthermore, vinculin is required for stabilizing adhesions under force. Together, these data reveal that FA stabilization under force requires both vinculin recruitment and force transmission, and that, surprisingly, these processes can be controlled independently.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The effective dose is designed to provide a single number proportional to the radiobiological "detriment" from a particular, often inhomogeneous, radiation exposure, with detriment representing a ...balance between carcinogenesis, life shortening and hereditary effects. It is commonly used to allow a comparison of the risks associated with different spatial dose distributions produced by different imaging techniques. The effective dose represents questionable science: two of the most important reasons for this are that the tissue-specific weighting factors used to calculate effective dose are a subjective mix of different endpoints, and that the marked and differing age dependencies for different endpoints are not taken into account. Importantly, the effective dose is prone to misuse, with widespread confusion between effective dose, equivalent dose and absorbed dose. It is suggested here that effective dose could and should be replaced by a new quantity that does not have these problems. An appropriate new quantity could be "effective risk", which, like effective dose, is a weighted sum of equivalent doses to different tissues; unlike effective dose, where the tissue-dependent weighting factors are a set of subjective committee-defined numbers, the weighting factors for effective risk would simply be evaluated tissue-specific lifetime cancer risks per unit equivalent dose. The resulting quantity would perform the same comparative role as effective dose; it would have the potential to be age- and, if desired, gender-specific, just as easy to estimate, less prone to misuse, more directly interpretable, and based on more defensible science.
Summary
Background
Ectopic fat deposition in the pancreas and its association with hepatic steatosis have not previously been examined in patients with biopsy‐proven non‐alcoholic fatty liver disease ...(NAFLD).
Aim
To quantify pancreatic fat using a novel magnetic resonance imaging (MRI) technique and determine whether it is associated with hepatic steatosis and/or fibrosis in patients with NAFLD.
Methods
This is a cross‐sectional study including 43 adult patients with biopsy‐proven NAFLD who underwent clinical evaluation, biochemical testing and MRI. The liver biopsy assessment was performed using the NASH‐CRN histological scoring system, and liver and pancreas fat quantification was performed using a novel, validated MRI biomarker; the proton density fat fraction.
Results
The average MRI‐determined pancreatic fat in patients with NAFLD was 8.5% and did not vary significantly between head, body, and tail of the pancreas. MRI‐determined pancreatic fat content increased significantly with increasing histology‐determined hepatic steatosis grade; 4.6% in grade 1; 7.7% in grade 2; 13.0% in grade 3 (P = 0.004) respectively. Pancreatic fat content was lower in patients with histology‐determined liver fibrosis than in those without fibrosis (11.2% in stage 0 fibrosis vs. 5.8% in stage 1–2 fibrosis, and 6.9% in stage 3‐4 fibrosis, P = 0.013). Pancreatic fat did not correlate with age, body mass index or diabetes status.
Conclusions
In patients with NAFLD, increased pancreatic fat is associated with hepatic steatosis. However, liver fibrosis is inversely associated with pancreatic fat content. Further studies are needed to determine underlying mechanisms to understand if pancreatic steatosis affects progression of NAFLD.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
A set of effective chemical potentials (ECPs) are derived that connect energies of (Co, Fe, Ni, Zn)Fe2O4 spinels and oxides calculated at 0 K from density functional theory (DFT) to free energies in ...high temperature and pressure water. The ECPs are derived and validated by solving a system of linear equations that combine DFT and experimental free energies for NiO, ZnO, Fe2O3, Fe3O4, FeO(OH), CoFe2O4, ZnFe2O4, NiFe2O4 and H2O. To connect to solution phase chemistry, a set of ECPs are also derived for solvated Ni2+, Zn2+, Fe2+ and Fe3+ ions using an analogous set of linear equations and the solid ECPs. The ECPs are used to calculate free energies of low index stoichiometric surfaces of nickel oxide (NiO) and nickel ferrite (NiFe2O4) in water as a function of temperature from 300 to 600 K at a pressure of 155 bar. Surface denuding at high temperatures is predicted, the implications of which for the formation of oxide corrosion products on heat transfer surfaces in light-water nuclear reactors are discussed.
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