Uricase is an enzyme involved in purine catabolism and is found in all three domains of life. Curiously, uricase is not functional in some organisms despite its role in converting highly insoluble ...uric acid into 5-hydroxyisourate. Of particular interest is the observation that apes, including humans, cannot oxidize uric acid, and it appears that multiple, independent evolutionary events led to the silencing or pseudogenization of the uricase gene in ancestral apes. Various arguments have been made to suggest why natural selection would allow the accumulation of uric acid despite the physiological consequences of crystallized monosodium urate acutely causing liver/kidney damage or chronically causing gout. We have applied evolutionary models to understand the history of primate uricases by resurrecting ancestral mammalian intermediates before the pseudogenization events of this gene family. Resurrected proteins reveal that ancestral uricases have steadily decreased in activity since the last common ancestor of mammals gave rise to descendent primate lineages. We were also able to determine the 3D distribution of amino acid replacements as they accumulated during evolutionary history by crystallizing a mammalian uricase protein. Further, ancient and modern uricases were stably transfected into HepG2 liver cells to test one hypothesis that uricase pseudogenization allowed ancient frugivorous apes to rapidly convert fructose into fat. Finally, pharmacokinetics of an ancient uricase injected in rodents suggest that our integrated approach provides the foundation for an evolutionarily-engineered enzyme capable of treating gout and preventing tumor lysis syndrome in human patients.
Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange ...between injected 1-13Cpyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2−), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2− invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized 1-13Cpyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized 1-13Cpyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.
Hyperpolarized 13C Magnetic Resonance Imaging (13C-MRI) provides a highly sensitive tool to probe tissue metabolism in vivo and has recently been translated into clinical studies. We report the ...cerebral metabolism of intravenously injected hyperpolarized 1–13Cpyruvate in the brain of healthy human volunteers for the first time. Dynamic acquisition of 13C images demonstrated 13C-labeling of both lactate and bicarbonate, catalyzed by cytosolic lactate dehydrogenase and mitochondrial pyruvate dehydrogenase respectively. This demonstrates that both enzymes can be probed in vivo in the presence of an intact blood-brain barrier: the measured apparent exchange rate constant (kPL) for exchange of the hyperpolarized 13C label between 1–13Cpyruvate and the endogenous lactate pool was 0.012 ± 0.006 s−1 and the apparent rate constant (kPB) for the irreversible flux of 1–13Cpyruvate to 13Cbicarbonate was 0.002 ± 0.002 s−1. Imaging also revealed that 1–13Cpyruvate, 1–13Clactate and 13Cbicarbonate were significantly higher in gray matter compared to white matter. Imaging normal brain metabolism with hyperpolarized 1–13Cpyruvate and subsequent quantification, have important implications for interpreting pathological cerebral metabolism in future studies.
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Sodium magnetic resonance imaging (MRI) is a powerful, non-invasive technique to assess sodium distribution within the kidney. Here we undertook pre-clinical and clinical studies to quantify the ...corticomedullary sodium gradient in healthy individuals and in a porcine model of diuresis. The results demonstrated that sodium MRI could detect spatial differences in sodium biodistribution across the kidney. The sodium gradient of the kidney changed significantly after diuresis in the pig model and was independent of blood electrolyte measurements. Thus, rapid sodium MRI can be used to dynamically quantify sodium biodistribution in the porcine and human kidney.
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There is a widespread perception that computer crime sentencing is too harsh. But this criticism has occurred in the absence of comprehensive, multi‐year data on how computer crimes are actually ...sentenced and how those sentences compare to other, purportedly similar crimes, such as trespass, burglary, or fraud. This article uses an analysis of real‐world sentencing data to examine how the computer crimes are actually sentenced. We combined court filings and U.S. Sentencing Commission data files to build a custom data set of 1095 Computer Fraud and Abuse Act (CFAA) sentences from 2005 through 1998. Our results show that CFAA sentences are sentenced differently from trespass, burglary, or non‐CFAA fraud crimes; that sentences in which the defendant exceeded authorized access have declined over the years; and that the “sophisticated means” and “special skills” enhancements have been less routinely applied than has been assumed. These results have policy implications for how CFAA crimes are sentenced.
To investigate the behaviour of common healthcare related objects in a 3 tesla (T) MRI (magnetic resonance imaging) scanner, examining their ability to self-propel towards the scanner bore and their ...potential for tissue penetration.
Prospective in situ experimental study.
Clinical 3 T MRI scanner. Customised rig designed and built to guide objects towards the scanner bore.
12 categories of objects commonly found in hospitals, or on patients or healthcare professionals, or near an MRI scanning room. Human tissue penetration simulated with ballistic gel (Federal Bureau of Investigation and North Atlantic Treaty Organisation graded).
SANTA (site where applied newtonian mechanics triggers acceleration) measurements and depth of tissue penetration of the objects.
SANTA measurements ranged from 0 cm for the 20 pence, 50 pence, and £2 coins to 152-161 cm for a knife and the biscuit tins. One penny, two pence, five pence, and 10 pence coins showed self-propulsion and acceleration towards the scanner bore at a distance >100 cm from the gantry entry point. Linear regression analysis showed no apparent correlation between the weight of the objects and their SANTA measurements (R
<0.1). Only five objects penetrated the ballistic gel (simulated human tissue). The deepest penetration was by the knife (5.5 cm), closely followed by the teaspoon (5.0 cm), fork (4.0 cm), spoon (3.5 cm), and a 10 pence coin (0.5 cm). Although the biscuit tins did not penetrate the simulated human tissue, they exerted substantial impact force which could potentially cause bone fractures. A smartphone, digital thermometer, metallic credit card, and pen torch remained fully functional after several passes into the MRI scanner. No discernible loss of image quality for the MRI scanner after the experiments was found.
The study highlights the potential for harm (major tissue damage and bone fractures) when commonly found objects in a healthcare setting are unintentionally brought into the MRI scanner room. Patients and healthcare professionals need to be aware of the dangers associated with bringing ferromagnetic objects into the MRI environment.
PERCEPTION VERSUS PUNISHMENT IN CYBERCRIME GRAVES, JAMES T.; ACQUISTI, ALESSANDRO; ANDERSON, ROSS
The journal of criminal law & criminology,
03/2019, Volume:
109, Issue:
2
Journal Article
Peer reviewed
The U.S. Computer Fraud and Abuse Act (CFAA) is not a popular law. Enacted in 1986 to deal with the nascent computer crimes of that era, it has aged badly. It has been widely criticized as vague, ...poorly structured, and having an overly broad definition of loss that invites prosecutorial abuse. One of the problems with sentencing under the CFAA has received little attention: a misalignment between the facts that affect sentencing and the importance of those facts to the seriousness of CFAA crimes. It has been observed, for example, that CFAA sentences escalate rapidly as (easily inflated) losses increase. But this escalation may be rapid not only in an absolute sense, but in disproportion to other attributes of the crime. Other factors, such as the offender's motivation, the context of the crime, its scope, or the type of data affected, may play a larger role in the seriousness of a crime.
In this Essay, we examine some of the factors that make developing a "science of security" a significant research and policy challenge. We focus on how the empirical hurdles of missing data, ...inaccurate data, and invalid inferences can significantly impact—and sometimes impair—the security decisionmaking processes of individuals, firms, and policymakers. We offer practical examples of the sensitivity of policy modeling to those hurdles and highlight the relevance of these examples in the context of national security.
Purpose
This prospective study evaluated the use of vascular, extracellular and restricted diffusion for cytometry in tumours (VERDICT) MRI to investigate the tissue microstructure in glioma. ...VERDICT-derived parameters were correlated with both histological features and tumour subtype and were also used to explore the peritumoural region.
Methods
Fourteen consecutive treatment-naïve patients (43.5 years ± 15.1 years, six males, eight females) with suspected glioma underwent diffusion-weighted imaging including VERDICT modelling. Tumour cell radius and intracellular and combined extracellular/vascular volumes were estimated using a framework based on linearisation and convex optimisation. An experienced neuroradiologist outlined the peritumoural oedema, enhancing tumour and necrosis on T2-weighted imaging and contrast-enhanced T1-weighted imaging. The same regions of interest were applied to the co-registered VERDICT maps to calculate the microstructure parameters. Pathology sections were analysed with semi-automated software to measure cellularity and cell size.
Results
VERDICT parameters were successfully calculated in all patients. The imaging-derived results showed a larger intracellular volume fraction in high-grade glioma compared to low-grade glioma (0.13 ± 0.07 vs. 0.08 ± 0.02, respectively;
p
= 0.05) and a trend towards a smaller extracellular/vascular volume fraction (0.88 ± 0.07 vs. 0.92 ± 0.04, respectively;
p
= 0.10). The conventional apparent diffusion coefficient was higher in low-grade gliomas compared to high-grade gliomas, but this difference was not statistically significant (1.22 ± 0.13 × 10
−3
mm
2
/s vs. 0.98 ± 0.38 × 10
−3
mm
2
/s, respectively;
p
= 0.18).
Conclusion
This feasibility study demonstrated that VERDICT MRI can be used to explore the tissue microstructure of glioma using an abbreviated protocol. The VERDICT parameters of tissue structure correlated with those derived on histology. The method shows promise as a potential test for diagnostic stratification and treatment response monitoring in the future.
Key Points
• VERDICT MRI is an advanced diffusion technique which has been correlated with histopathological findings obtained at surgery from patients with glioma in this study.
• The intracellular volume fraction measured with VERDICT was larger in high-grade tumours compared to that in low-grade tumours.
• The results were complementary to measurements from conventional diffusion-weighted imaging, and the technique could be performed in a clinically feasible timescale.
Purpose To evaluate glioblastoma (GBM) metabolism by using hyperpolarized carbon 13 (
C) MRI to monitor the exchange of the hyperpolarized
C label between injected 1-
Cpyruvate and tumor lactate and ...bicarbonate. Materials and Methods In this prospective study, seven treatment-naive patients (age mean ± SD, 60 years ± 11; five men) with GBM were imaged at 3 T by using a dual-tuned
C-hydrogen 1 head coil. Hyperpolarized 1-
Cpyruvate was injected, and signal was acquired by using a dynamic MRI spiral sequence. Metabolism was assessed within the tumor, in the normal-appearing brain parenchyma (NABP), and in healthy volunteers by using paired or unpaired
tests and a Wilcoxon signed rank test. The Spearman ρ correlation coefficient was used to correlate metabolite labeling with lactate dehydrogenase A (LDH-A) expression and some immunohistochemical markers. The Benjamini-Hochberg procedure was used to correct for multiple comparisons. Results The bicarbonate-to-pyruvate (BP) ratio was lower in the tumor than in the contralateral NABP (
< .01). The tumor lactate-to-pyruvate (LP) ratio was not different from that in the NABP (
= .38). The LP and BP ratios in the NABP were higher than those observed previously in healthy volunteers (
< .05). Tumor lactate and bicarbonate signal intensities were strongly correlated with the pyruvate signal intensity (ρ = 0.92,
< .001, and ρ = 0.66,
< .001, respectively), and the LP ratio was weakly correlated with LDH-A expression in biopsy samples (ρ = 0.43,
= .04). Conclusion Hyperpolarized
C MRI demonstrated variation in lactate labeling in GBM, both within and between tumors. In contrast, bicarbonate labeling was consistently lower in tumors than in the surrounding NABP.
Hyperpolarized
C MRI, Glioblastoma, Metabolism, Cancer, MRI, Neuro-oncology
Published under a CC BY 4.0 license.
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