Preclinical animal research on therapy dosimetry with dual isotopes

Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray-emitting radionuclides for a chemically comparable beta-particle-emitting paired isotope for therapy evaluation would be feasible

Secular Evolution and the Formation of Pseudobulges in Disk Galaxies

We review internal processes of secular evolution in galaxy disks, concentrating on the buildup of dense central features that look like classical, merger-built bulges but that were made slowly out of disk gas. We call these pseudobulges. As an existence proof, we review how bars rearrange disk gas into outer rings, inner rings, and gas dumped into the center. In simulations, this gas reaches high densities that plausibly feed star formation. In the observations, many SB and oval galaxies show central concentrations of gas and star formation. Star formation rates imply plausible pseudobulge growth times of a few billion years. If secular processes built dense central components that masquerade as bulges, can we distinguish them from merger-built bulges? Observations show that pseudobulges retain a memory of their disky origin. They have one or more characteristics of disks: (1) flatter shapes than those of classical bulges, (2) large ratios of ordered to random velocities indicative of disk dynamics, (3) small velocity dispersions, (4) spiral structure or nuclear bars in the bulge part of the light profile, (5) nearly exponential brightness profiles, and (6) starbursts. These structures occur preferentially in barred and oval galaxies in which secular evolution should be rapid. So the cleanest examples of pseudobulges are recognizable. Thus a large variety of observational and theoretical results contribute to a new picture of galaxy evolution that complements hierarchical clustering and merging.Comment: 92 pages, 21 figures in 30 Postscript files; to appear in Annual Review of Astronomy and Astrophysics, Vol. 42, 2004, in press; for a version with full resolution figures, see http://chandra.as.utexas.edu/~kormendy/ar3ss.htm

Shot noise in mesoscopic systems

This is a review of shot noise, the time-dependent fluctuations in the electrical current due to the discreteness of the electron charge, in small conductors. The shot-noise power can be smaller than that of a Poisson process as a result of correlations in the electron transmission imposed by the Pauli principle. This suppression takes on simple universal values in a symmetric double-barrier junction (suppression factor 1/2), a disordered metal (factor 1/3), and a chaotic cavity (factor 1/4). Loss of phase coherence has no effect on this shot-noise suppression, while thermalization of the electrons due to electron-electron scattering increases the shot noise slightly. Sub-Poissonian shot noise has been observed experimentally. So far unobserved phenomena involve the interplay of shot noise with the Aharonov-Bohm effect, Andreev reflection, and the fractional quantum Hall effect.Comment: 37 pages, Latex, 10 figures (eps). To be published in "Mesoscopic Electron Transport," edited by L. P. Kouwenhoven, G. Schoen, and L. L. Sohn, NATO ASI Series E (Kluwer Academic Publishing, Dordrecht

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

Hadronic production of squark-squark pairs: The electroweak contributions

We compute the electroweak (EW) contributions to squark--squark pair production processes at the LHC within the framework of the Minimal Supersymmetric Standard Model (MSSM). Both tree-level EW contributions, of O(alpha_s alpha + alpha^2), and next-to-leading order (NLO) EW corrections, of O(alpha_s^2 alpha), are calculated. Depending on the flavor and chirality of the produced quarks, many interferences between EW-mediated and QCD-mediated diagrams give non-zero contributions at tree-level and NLO. We discuss the computational techniques and present an extensive numerical analysis for inclusive squark--squark production as well as for subsets and single processes. While the tree-level EW contributions to the integrated cross sections can reach the 20% level, the NLO EW corrections typically lower the LO prediction by a few percent.Comment: 36 pages, 18 figure

Methodological issues in cross-cultural research

Regardless of whether the research goal is to establish cultural universals or to identify and explain cross-cultural differences, researchers need measures that are comparable across different cultures when conducting cross-cultural studies. In this chapter, we describe two major strategies for enhancing cross-cultural comparability. First, we discuss a priori methods to ensure the comparability of data in cross-cultural surveys. In particular, we review findings on cross-cultural differences based on the psychology of survey response and provide suggestions on how to deal with these cultural differences in the survey design stage. Second, we discuss post hoc methods to ascertain data comparability and enable comparisons in the presence of threats to equivalence

Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial

OBJECTIVE: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. METHODS: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). RESULTS: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured. CONCLUSION: These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01847274

Familial Adenomatous Polyposis-Associated Desmoids Display Significantly More Genetic Changes than Sporadic Desmoids

Desmoid tumours (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumours arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most sporadic desmoids carry somatic mutations in CTNNB1. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumours. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumours, we analysed 17 FAP-associated and 38 sporadic desmoids by array comparative genomic hybridisation and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Recurrent gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumours. Recurrent losses were observed for a 700 kb region at 5q22.2, comprising the APC gene (11%), a 2 Mb region at 6p21.2-p21.1 (15%), and a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of copy number abnormalities (59%) than the sporadic tumours (37%). As predicted by the APC germline mutations among these patients, a high percentage (29%) of FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumours. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumour progression

Interactive seminars or small group tutorials in preclinical medical education: results of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Learning in small group tutorials is appreciated by students and effective in the acquisition of clinical problem-solving skills but poses financial and resource challenges. Interactive seminars, which accommodate large groups, might be an alternative. This study examines the educational effectiveness of small group tutorials and interactive seminars and students' preferences for and satisfaction with these formats.</p> <p>Methods</p> <p>Students in year three of the Leiden undergraduate medical curriculum, who agreed to participate in a randomized controlled trial (RCT, n = 107), were randomly allocated to small group tutorials (n = 53) or interactive seminars (n = 54). Students who did not agree were free to choose either format (n = 105). Educational effectiveness was measured by comparing the participants' results on the end-of-block test. Data on students' reasons and satisfaction were collected by means of questionnaires. Data was analyzed using student unpaired t test or chi-square test where appropriate.</p> <p>Results</p> <p>There were no significant differences between the two educational formats in students' test grades. Retention of knowledge through active participation was the most frequently cited reason for preferring small group tutorials, while a dislike of compulsory course components was mentioned more frequently by students preferring interactive seminars. Small group tutorials led to greater satisfaction.</p> <p>Conclusions</p> <p>We found that small group tutorials leads to greater satisfaction but not to better learning results. Interactive learning in large groups might be might be an effective alternative to small group tutorials in some cases and be offered as an option.</p

Structural and functional analysis of cellular networks with CellNetAnalyzer

BACKGROUND: Mathematical modelling of cellular networks is an integral part of Systems Biology and requires appropriate software tools. An important class of methods in Systems Biology deals with structural or topological (parameter-free) analysis of cellular networks. So far, software tools providing such methods for both mass-flow (metabolic) as well as signal-flow (signalling and regulatory) networks are lacking. RESULTS: Herein we introduce CellNetAnalyzer, a toolbox for MATLAB facilitating, in an interactive and visual manner, a comprehensive structural analysis of metabolic, signalling and regulatory networks. The particular strengths of CellNetAnalyzer are methods for functional network analysis, i.e. for characterising functional states, for detecting functional dependencies, for identifying intervention strategies, or for giving qualitative predictions on the effects of perturbations. CellNetAnalyzer extends its predecessor FluxAnalyzer (originally developed for metabolic network and pathway analysis) by a new modelling framework for examining signal-flow networks. Two of the novel methods implemented in CellNetAnalyzer are discussed in more detail regarding algorithmic issues and applications: the computation and analysis (i) of shortest positive and shortest negative paths and circuits in interaction graphs and (ii) of minimal intervention sets in logical networks. CONCLUSION: CellNetAnalyzer provides a single suite to perform structural and qualitative analysis of both mass-flow- and signal-flow-based cellular networks in a user-friendly environment. It provides a large toolbox with various, partially unique, functions and algorithms for functional network analysis.CellNetAnalyzer is freely available for academic use