ProKinO: A Unified Resource for Mining the Cancer Kinome

Protein kinases represent a large and diverse family of evolutionarily related proteins that are abnormally regulated in human cancers. Although genome sequencing studies have revealed thousands of variants in protein kinases, translating “big” genomic data into biological knowledge remains a challenge. Here, we describe an ontological framework for integrating and conceptualizing diverse forms of information related to kinase activation and regulatory mechanisms in a machine readable, human understandable form. We demonstrate the utility of this framework in analyzing the cancer kinome, and in generating testable hypotheses for experimental studies. Through the iterative process of aggregate ontology querying, hypothesis generation and experimental validation, we identify a novel mutational hotspot in the αC‐β4 loop of the kinase domain and demonstrate the functional impact of the identified variants in epidermal growth factor receptor (EGFR) constitutive activity and inhibitor sensitivity. We provide a unified resource for the kinase and cancer community, ProKinO, housed at http://vulcan.cs.uga.edu/prokino .     

Total duodenopancreatectomy for non-secreting pancreatic nesidioblastoma

Non-secreting tumors of pancreatic islets of Langerhans are now rarely encountered as a result of the increasing performance of techniques for detecting the different hormones of insular origin or their precursors. Histologically, these tumors, that can be termed nesidioblastomas of the pancreas, have a poorly defined potential course, but there is a definite risk of malignancy. A case is reported of a pancreatic nesidioblastoma located in two regions, treatment being by total duodenopancreatectomy with a good result at 4-year follow up review. A bibliographic list of 13 published reports in the international literature is provided.     

Comparison of two methods for the analysis of [18F]6-fluoro-L-m-tyrosine PET data

PET and [18F]fluoro-L-m-tyrosine (FMT) have been used to quantify presynaptic striatal dopamine (DA) function in Parkinson disease (PD) and in primate models of PD. While dynamic imaging and a metabolite-corrected blood input function can be used to determine striatal FMT uptake rate constants (Ki), a simpler analytic approach using shorter imaging times is desirable for clinical studies. We compared the utility of using striatal Ki values versus striatal count ratios in two groups of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Striatal DA content was also measured in one of the groups to evaluate the relationship between the PET measures and an independent measure of striatal dopamine. Striatal Ki values were significantly correlated with striatal count ratios using the cerebellum as the denominator. Both Ki values and ratios were also correlated with striatal DA content. In addition, putamen-cerebellum ratios and putamen Ki values showed similar separation between baseline and post-MPTP values. These findings suggest that a simple ratio approach to analyzing FMT PET data may be a useful alternative to a kinetic approach especially for clinical applications.     

Effect of tapered grafts on hemodynamics and flow rate in dialysis access grafts

AIM: Aside from the high incidence of venous stenosis, high-output failure and peripheral steal syndromes remain serious problems of vascular access. Meanwhile commercial tapered grafts are available to address this topic, but little is known about its effect neither on graft flow nor on hemodynamics. METHODS: Anastomotic models were constructed using a clear silicon elastomer. The arterial anastomosis was shaped in two ways: 1) like a direct connection of artery and 7-mm graft and 2) with a 4-mm diameter segment between artery and graft. Hemodynamic measurements were performed in a pulsatile flow circuit to simulate blood flow at physiological conditions. Flow patterns were obtained by direct dye injection. Additionally, the correlation between the length of narrow segment and mean arterial pressure was investigated. RESULTS: In all models using a 4-mm segment, the oscillating anastomotic vortex was disappeared. This vortex was shifted to the area behind the well-rounded expansions of the graft demonstrating a new separation region, but the flow direction was constant during the whole simulated cycle. At identical pressure rates and waveforms the length of narrow segment determined the graft flow rate directly (e.g., at mean pressure 100 mmHg, flow reduction up to 28% in 4-mm segments, and up to 55% in 3-mm segments). CONCLUSION: These findings indicate that taper is an important consideration in the design of vascular access grafts.     

An evaluation of the baccalaureate-nursing program within the (MOPH), Thailand

This research study was designed to evaluate the baccalaureate-nursing curricula undertaken in the nursing colleges under the jurisdiction of the Ministry of Public Health (MOPH), Thailand. A stakeholder approach was used to incorporate mixed methods of data collection and models of evaluation within the research framework. Both qualitative and quantitative approaches were used. Newly registered nurses and their colleagues were generally positive about the course outcomes. However, qualitative data demonstrate a need to focus more on the development of abilities related to life-long learning and critical thinking. The findings suggest challenges in achieving program outcomes attributed to the feasibility of implementation strategies. Concepts in the curriculum plan are not fully translated into practice. A number of factors have a major impact on the actual program implementation or course organisation and teaching/learning processes. There is evidence of competing or conflicting ideologies about nursing practice and education. Findings suggest that the preferable educational models for contemporary and future nursing education are process rather than content-based. It is challenging to develop ways of accommodating the more desirable professional nursing and educational approaches within the context of Thailand and MOPH nursing education policies where resources are limited and the maintenance of Thai culture is of paramount importance.     

Electric fields induced in humans and rodents by 60 Hz magnetic fields

Numerical computations are used to evaluate electric field dosimetry for high-resolution anatomically based inhomogeneous models of a human male child, and male and female rats and mice, under exposure to 60 Hz uniform magnetic field sources of three perpendicular orientations. The goal is to compare the child data to previously computed adult dosimetry and to evaluate the accuracy of linear scaling of organ dosimetry between species. It is expected that this work will aid in the design and interpretation of experiments involving rodents. It is found that child-to-adult and mouse-to-rat organ dosimetry shows the expected linear dependence on the geometric scale factor between models. The comparison between mice and the human child shows that postural and individual organ differences do have significant effects, and that care is required in scaling-based extrapolation of rodent experiment results to humans. However, for unrestrained animals, linear scaling appears to be a reasonable and conservative approach. Most of the rodent organ fields, for at least one field orientation, are greater than those expected from linear scaling.     

Sympathetic innervation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinson's disease

Cardiac sympathetic denervation occurs commonly in Parkinson's disease. This study explored whether analogous denervation occurs in primates with Parkinsonism from systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 6-[18F]Fluorodopamine positron emission tomographic scanning and plasma levels of catecholamines and their deaminated metabolites were used to assess sympathetic and adrenomedullary function in rhesus monkeys, in the untreated state (n = 3), 2 weeks after a series of four MPTP injections, before establishment of Parkinsonism (acute phase, n = 1); a month later, after four more MPTP doses, associated with severe Parkinsonism (subacute phase, n = 1); or more than 2 years from the last dose (remote phase, n = 3), with persistent severe Parkinsonism. A positive control received i.v. 6-hydroxydopamine 1 week before 6-[18F]fluorodopamine scanning. Acute MPTP treatment increased cardiac 6-[18F]fluorodopamine-derived radioactivity, whereas 6-hydroxydopamine markedly decreased cardiac radioactivity, despite similarly low plasma levels of catecholamines and metabolites after either treatment. Subacutely, plasma catecholamines remained decreased, but now with myocardial 6-[18F]fluorodopamine-derived radioactivity also decreased. Remotely, MPTP-treated monkeys had lower plasma catecholamines and higher myocardial 6-[18F]fluorodopamine-derived radioactivity than did untreated animals. The results indicate that in nonhuman primates, systemic MPTP administration produces multiphasic effects on peripheral catecholamine systems, with nearly complete recovery by 2 years. MPTP- and 6-hydroxydopamine-induced changes differ markedly, probably from ganglionic or preganglionic neurotoxicity with the former and more severe cardiac sympathetic neurotoxicity with the latter. Because of multiphasic sympathetic and adrenomedullary effects, without cardioselective sympathetic denervation at any time, the primate MPTP model does not mimic the changes in peripheral catecholamine systems that characterize the human disease.     

In vitro reconstruction of the Aspergillus (= Emericella) nidulans genome

A physical map of the 31-megabase Aspergillus nidulans genome is reported, in which 94% of 5,134 cosmids are assigned to 49 contiguous segments. The physical map is the result of a two-way ordering process, in which clones and probes were ordered simultaneously on a binary DNA/DNA hybridization matrix. Compression by elimination of redundant clones resulted in a minimal map, which is a chromosome walk. Repetitive DNA is nonrandomly dispersed in the A. nidulans genome, reminiscent of heterochromatic banding patterns of higher eukaryotes. We hypothesize gene clusters may arise by horizontal transfer and spread by transposition to explain the nonrandom pattern of repeats alongchromosomes.