A treatment planning method for sequentially combining radiopharmaceutical therapy and external radiation therapy.

PURPOSE: Effective cancer treatment generally requires combination therapy. The combination of external beam therapy (XRT) with radiopharmaceutical therapy (RPT) requires accurate three-dimensional dose calculations to avoid toxicity and evaluate efficacy. We have developed and tested a treatment planning method, using the patient-specific three-dimensional dosimetry package 3D-RD, for sequentially combined RPT/XRT therapy designed to limit toxicity to organs at risk. METHODS AND MATERIALS: The biologic effective dose (BED) was used to translate voxelized RPT absorbed dose (D(RPT)) values into a normalized total dose (or equivalent 2-Gy-fraction XRT absorbed dose), NTD(RPT) map. The BED was calculated numerically using an algorithmic approach, which enabled a more accurate calculation of BED and NTD(RPT). A treatment plan from the combined Samarium-153 and external beam was designed that would deliver a tumoricidal dose while delivering no more than 50 Gy of NTD(sum) to the spinal cord of a patient with a paraspinal tumor. RESULTS: The average voxel NTD(RPT) to tumor from RPT was 22.6 Gy (range, 1-85 Gy); the maximum spinal cord voxel NTD(RPT) from RPT was 6.8 Gy. The combined therapy NTD(sum) to tumor was 71.5 Gy (range, 40-135 Gy) for a maximum voxel spinal cord NTD(sum) equal to the maximum tolerated dose of 50 Gy. CONCLUSIONS: A method that enables real-time treatment planning of combined RPT-XRT has been developed. By implementing a more generalized conversion between the dose values from the two modalities and an activity-based treatment of partial volume effects, the reliability of combination therapy treatment planning has been expanded.

Viral self-assembly as a thermodynamic process

The protein shells, or capsids, of nearly all spherelike viruses adopt icosahedral symmetry. In the present Letter, we propose a statistical thermodynamic model for viral self-assembly. We find that icosahedral symmetry is not expected for viral capsids constructed from structurally identical protein subunits and that this symmetry requires (at least) two internal switching configurations of the protein. Our results indicate that icosahedral symmetry is not a generic consequence of free energy minimization but requires optimization of internal structural parameters of the capsid proteins

Mechanical properties of viral capsids

Viruses are known to tolerate wide ranges of pH and salt conditions and to withstand internal pressures as high as 100 atmospheres. In this paper we investigate the mechanical properties of viral capsids, calling explicit attention to the inhomogeneity of the shells that is inherent to their discrete and polyhedral nature. We calculate the distribution of stress in these capsids and analyze their response to isotropic internal pressure (arising, for instance, from genome confinement and/or osmotic activity). We compare our results with appropriate generalizations of classical (i.e., continuum) elasticity theory. We also examine competing mechanisms for viral shell failure, e.g., in-plane crack formation vs radial bursting. The biological consequences of the special stabilities and stress distributions of viral capsids are also discussed.

Biological Assessment of Iowa's Streams and Rivers, 2001

Summary of biological monitoring of Iowa's streams and rivers.

Entropic transport in confined media: a challenge for computational studies in biological and soft-matter systems

Transport in small-scale biological and soft-matter systems typically occurs under confinement conditions in which particles proceed through obstacles and irregularities of the boundaries that may significantly alter their trajectories. A transport model that assimilates the confinement to the presence of entropic barriers provides an efficient approach to quantify its effect on the particle current and the diffusion coefficient. We review the main peculiarities of entropic transport and treat two cases in which confinement effects play a crucial role, with the appearance of emergent properties. The presence of entropic barriers modifies the mean first-passage time distribution and therefore plays a very important role in ion transport through micro- and nano-channels. The functionality of molecular motors, modeled as Brownian ratchets, is strongly affected when the motor proceeds in a confined medium that may constitute another source of rectification. The interplay between ratchet and entropic rectification gives rise to a wide variety of dynamical behaviors, not observed when the Brownian motor proceeds in an unbounded medium. Entropic transport offers new venues of transport control and particle manipulation and new ways to engineer more efficient devices for transport at the nanoscale.

Lipoprotein distribution and biological variation of 24S- and 27-hydroxycholesterol in healthy volunteers.

24S- and 27-hydroxycholesterol are obligatory intermediates of cholesterol catabolism and play an important role in the maintenance of whole-body cholesterol homeostasis. Using an HPLC-MS method for oxysterol quantification, the distribution of esterified and unesterified oxysterols in lipoprotein subfractions as well as the influence of daytime, food intake and menstrual cycle on oxysterol concentrations were investigated in healthy volunteers. Moreover, reference intervals for 24S- and 27-hydroxycholesterol in plasma as well as the corresponding levels for 27-hydroxycholesterol in the HDL subfraction were established in 100 healthy volunteers. Both circulating oxysterols are mainly transported in association with HDL and LDL--primarily in the esterified form. No significant diurnal changes and no variations during menstrual cycle of either absolute or cholesterol-related plasma levels were detected. In contrast to 24S-hydroxycholesterol in plasma and 27-hydroxycholesterol in the HDL subfraction, the 95% reference intervals of 27-hydroxycholesterol both in plasma and the non-HDL subfraction were higher in males than in females. The concentrations of 27-hydroxycholesterol in plasma and the non-HDL subfraction showed strong positive correlations with the concentrations of cholesterol, non-HDL cholesterol and triglycerides. Our data on the lipoprotein distribution of oxysterols as well as on their intra- and inter-individual variation set the stage for future clinical studies.

Time-delayed fronts from biased random walks

We generalize a previous model of time-delayed reaction–diffusion fronts (Fort and Méndez 1999 Phys. Rev. Lett. 82 867) to allow for a bias in the microscopic random walk of particles or individuals. We also present a second model which takes the time order of events (diffusion and reproduction) into account. As an example, we apply them to the human invasion front across the USA in the 19th century. The corrections relative to the previous model are substantial. Our results are relevant to physical and biological systems with anisotropic fronts, including particle diffusion in disordered lattices, population invasions, the spread of epidemics, etc

ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients.

As culture-based methods for the diagnosis of invasive fungal diseases (IFD) in leukemia and hematopoietic SCT patients have limited performance, non-culture methods are increasingly being used. The third European Conference on Infections in Leukemia (ECIL-3) meeting aimed at establishing evidence-based recommendations for the use of biological tests in adult patients, based on the grading system of the Infectious Diseases Society of America. The following biomarkers were investigated as screening tests: galactomannan (GM) for invasive aspergillosis (IA); β-glucan (BG) for invasive candidiasis (IC) and IA; Cryptococcus Ag for cryptococcosis; mannan (Mn) Ag/anti-mannan (A-Mn) Ab for IC, and PCR for IA. Testing for GM, Cryptococcus Ag and BG are included in the revised EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) consensus definitions for IFD. Strong evidence supports the use of GM in serum (A II), and Cryptococcus Ag in serum and cerebrospinal fluid (CSF) (A II). Evidence is moderate for BG detection in serum (B II), and the combined Mn/A-Mn testing in serum for hepatosplenic candidiasis (B III) and candidemia (C II). No recommendations were formulated for the use of PCR owing to a lack of standardization and clinical validation. Clinical utility of these markers for the early management of IFD should be further assessed in prospective randomized interventional studies.

Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI).

Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (PfFAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations.

Soil biological attributes in pastures of different ages in a crop-livestock integrated system

The objective of this work was to evaluate the effect of the pasture (Urochloa brizantha) component age on soil biological properties, in a crop-livestock integrated system. The experiment was carried out in a Brazilian savannah (Cerrado) area with 92 ha, divided into six pens of approximately 15 ha. Each pen represented a different stage of the pasture component: formation, P0; one year, P1; two years, P2; three years, P3; and final with 3.5 years, Pf. Samples were taken in the 0-10 cm soil depth. The soil biological parameters - microbial biomass carbon (MBC), microbial biomass respiration (C-CO2), metabolic quotient (qCO2), microbial quotient (q mic), and total organic carbon (TOC) - were evaluated and compared among different stages of the pasture, and between an adjacent area under native Cerrado and another area under degraded pasture (PCD). The MBC, q mic and TOC increased and qCO2 reduced under the different pasture stages. Compared to PCD, the pasture stages had higher MBC, q mic and TOC, and lower qCO2. The crop-livestock integrated system improved soil microbiological parameters and immobilized carbon in the soil in comparison to the degraded pasture.

Investigation of resins suitable for the preparation of biological sample for 3-D electron microscopy.

In the last two decades, the third-dimension has become a focus of attention in electron microscopy to better understand the interactions within subcellular compartments. Initially, transmission electron tomography (TEM tomography) was introduced to image the cell volume in semi-thin sections (∼500nm). With the introduction of the focused ion beam scanning electron microscope, a new tool, FIB-SEM tomography, became available to image much larger volumes. During TEM tomography and FIB-SEM tomography, the resin section is exposed to a high electron/ion dose such that the stability of the resin embedded biological sample becomes an important issue. The shrinkage of a resin section in each dimension, especially in depth, is a well-known phenomenon. To ensure the dimensional integrity of the final volume of the cell, it is important to assess the properties of the different resins and determine the formulation which has the best stability in the electron/ion beam. Here, eight different resin formulations were examined. The effects of radiation damage were evaluated after different times of TEM irradiation. To get additional information on mass-loss and the physical properties of the resins (stiffness and adhesion), the topography of the irradiated areas was analysed with atomic force microscopy (AFM). Further, the behaviour of the resins was analysed after ion milling of the surface of the sample with different ion currents. In conclusion, two resin formulations, Hard Plus and the mixture of Durcupan/Epon, emerged that were considerably less affected and reasonably stable in the electron/ion beam and thus suitable for the 3-D investigation of biological samples.

Exposure of the Swiss population by radiodiagnostics: 2003 review.

A nationwide investigation was conducted in Switzerland to establish the exposure of the population by medical x rays and update the results of the 1998 survey. Both the frequency and the dose variations were studied in order to determine the change in the collective dose. The frequency study addressed 206 general practitioners (GPs), 30 hospitals, and 10 private radiology institutes. Except for the latter, the response rate was very satisfactory. The dose study relied on the assessment of the speed class of the screen-film combinations used by the GPs as well as the results of two separate studies dedicated to fluoroscopy and CT. The investigation showed that the total number of all medical x-ray examinations performed by GPs registered a 1% decrease between 1998 and 2003, and that the sensitivities of the film-screen combinations registered a shift towards higher values, leading to a reduction of the dose delivered by a GP of the order of 20%. The study indicated also that the total number of all x-ray examinations performed in hospitals increased by 4%, with a slight increase of radiographies by 1% but significant decrease of examinations involving fluoroscopy (39%), and a 70% increase for CT examinations. Concerning the doses, the investigation of a selection of examinations involving fluoroscopy showed a significant increase of the kerma-area product (KAP) per procedure. For CT the study showed an increase of the dose-length product (DLP) per procedure for skull and abdomen examinations, and a decrease for chest examination. Both changes in the frequency and the effective dose per examination led to a 20% increase in the total collective dose.

Biological aspects of Harmonia axyridis in comparison with Cycloneda sanguinea and Hippodamia convergens

The objective of this work was to evaluate the development, survival, reproductive capacity, and longevity of the Asian ladybug Harmonia axyridis in comparison with Cycloneda sanguinea and Hippodamia convergens. Coccinellid larvae and adults were fed daily with Schizaphis graminum. Ten couples of each species were isolated for evaluation of the adult phase. The duration of the larval stage of H. axyridis is the longest (10.2 days) and its adults are the heaviest (29.7 mg) compared with C. sanguinea and H. convergens. The three species showed similar percentages of survival during the developmental stages. An average of 82% of C. sanguinea, H. axyridis, and H. convergens larvae reached adulthood, which indicates that temperature (25°C) and the offered prey are favorable to coccinellid development. Harmonia axyridis produces a higher total number of eggs per female (1,029.2) than the other evaluated species. However, H. axyridis, which lives for an average of 147.2 days, does not show a significantly greater longevity than C. sanguinea (87.2 days) and H. convergens (134.3 days).