Renal Cryoablation: Investigation of Periprocedural Visualization Tools and Treatment Response Quantification

Cryoablation for small renal tumors has demonstrated sufficient clinical efficacy over the past decade as a non-surgical nephron-sparing approach for treating renal masses for patients who are not surgical candidates. Minimally invasive percutaneous cryoablations have been performed with image guidance from CT, ultrasound, and MRI. During the MRI-guided cryoablation procedure, the interventional radiologist visually compares the iceball size on monitoring images with respect to the original tumor on separate planning images. The comparisons made during the monitoring step are time consuming, inefficient and sometimes lack the precision needed for decision making, requiring the radiologist to make further changes later in the procedure. This study sought to mitigate uncertainty in these visual comparisons by quantifying tissue response to cryoablation and providing visualization of the response during the procedure. Based on retrospective analysis of MR-guided cryoablation patient data, registration and segmentation algorithms were investigated and implemented for periprocedural visualization to deliver iceball position/size with respect to planning images registered within 3.3mm with at least 70% overlap and a quantitative logit model was developed to relate perfusion deficit in renal parenchyma visualized in verification images as a result of iceball size visualized in monitoring images. Through retrospective study of 20 patient cases, the relationship between likelihood of perfusion loss in renal parenchyma and distance within iceball was quantified and iteratively fit to a logit curve. Using the parameters from the logit fit, the margin for 95% perfusion loss likelihood was found to be 4.28 mm within the iceball. The observed margin corresponds well with the clinically accepted margin of 3-5mm within the iceball. In order to display the iceball position and perfusion loss likelihood to the radiologist, algorithms were implemented to create a fast segmentation and registration module which executed in under 2 minutes, within the clinically-relevant 3 minute monitoring period. Using 16 patient cases, the average Hausdorff distance was reduced from 10.1mm to 3.21 mm with average DSC increased from 46.6% to 82.6% before and after registration.

*Ras proteins and human tumor cell radiosensitivity

Ras proteins (H-, N-, K4A-, and K4B) are associated with cellular resistance to ionizing radiation (IR) and, consequently, may provide a potential target for radiosensitization strategies in cancer treatment. Several approaches have been used to compromise Ras activity and enhance IR-induced cell killing; however, these techniques either target proteins in addition to Ras or only target one member of the Ras family. In this study, I have used an adenovirus (AV1Y28) that expresses a single-chain antibody fragment directed against Ras proteins to investigate the mechanism(s) responsible for Ras-mediated radiation resistance. AV1Y28 enhanced the radiosensitivity of a number of human tumor cell lines without affecting the radiosensitivity of normal human fibroblasts. Whereas AV1Y28-mediated sensitization was independent of ras gene mutational status, it was dependent on active Ras proteins suggesting that AV1Y28 may be useful against a broad range of tumors. AV1Y28-mediated cell killing was not the result of redistributing cells into a more radiosensitive phase of the cell cycle and did not enhance IR-induced apoptosis. Given that Ras proteins transduce environmental signals to the nucleus, the effect of AV1Y28 on the IR-inducible transcription factor NF-κB were determined. Although AV1Y28 inhibited IR-induced NF-κB through the suppression of IKK, additional work established that NF-κB did not play a role in AV1Y28-mediated radiosensitization. However, a novel component of the signaling pathway responsible for IR-induced NF-κB was identified. Previous studies had suggested a relationship between mutant ras genes and IR-induced G2 delay; therefore the effects of AV1Y28 on the progression of cells from G2 to M after IR were determined. Pretreatment of cells with AV1Y28 prevented the IR-induced G2 arrest. AV1Y28-mediated abrogation of IR-induced G2 arrest correlated with those cell line lines that were sensitized by AV1Y28. Moreover, a significant increase in cells undergoing mitotic catastrophe was found after IR in AV1Y28 treated cells. The abrogation of G2 arrest by AV1Y28 was the result of maintaining the active form of cdc2, an inducer of mitosis, after exposure to IR. This study identified the mechanism of AV1Y28-mediated radiosensitization and has provided insight into the signal transduction pathways responsible for Ras-mediated radiation resistance. ^

Sedimentation and mineral analysis on sediment cores from the Lena Delta

Core and outcrop analysis from Lena mouth deposits have been used to reconstruct the Late Quaternary sedimentation history of the Lena Delta. Sediment properties (heavy mineral composition, grain size characteristics, organic carbon content) and age determinations (14C AMS and IR-OSL) are applied to discriminate the main sedimentary units of the three major geomorphic terraces, which form the delta. The development of the terraces is controlled by complex interactions among the following four factors: (1) Channel migration. According to the distribution of 14C and IR-OSL age determinations of Lena mouth sediments, the major river runoff direction shifted from the west during marine isotope stages 5-3 (third terrace deposits) towards the northwest during marine isotope stage 2 and transition to stage 1 (second terrace), to the northeast and east during the Holocene (first terrace deposits). (2) Eustasy. Sea level rise from Last Glacial lowstand to the modern sea level position, reached at 6-5 ka BP, resulted in back-filling and flooding of the palaeovalleys. (3) Neotectonics. The extension of the Arctic Mid-Ocean Ridge into the Laptev Sea shelf acted as a halfgraben, showing dilatation movements with different subsidence rates. From the continent side, differential neotectonics with uplift and transpression in the Siberian coast ridges are active. Both likely have influenced river behavior by providing sites for preservation, with uplift, in particular, allowing accumulation of deposits in the second terrace in the western sector. The actual delta setting comprises only the eastern sector of the Lena Delta. (4) Peat formation. Polygenetic formation of ice-rich peaty sand (''Ice Complex'') was most extensive (7-11 m in thickness) in the southern part of the delta area between 43 and 14 ka BP (third terrace deposits). In recent times, alluvial peat (5-6 m in thickness) is accumulated on top of the deltaic sequences in the eastern sector (first terrace).

Geochemical investigation and determination of hiatuses on Voering Plateau sediment records

The sediments recovered on ODP Leg 104 have been reported to be characterized by hiatuses. The hiatuses were defined by biostratigraphy and were believed to be caused by erosion related to temporary changes of bottom current composition and velocity. They have been associated with major paleoenvironmental changes, reorganization of global deep water production, and increased bottom water flows. Because of the importance of hiatuses for ongoing research, we decided to closely investigate the sedimentation history for the most significant Pliocene and Miocene biostratigraphic hiatuses by sedimentologic and geochemical means. The sedimentologic studies include clay mineral distributions, grain size data, and organic carbon concentrations. The geochemical studies include determination of 87/86Sr ratios, 10Be and Ir concentrations. The results of the sedimentologic studies suggest either that paleoenvironmental changes associated with hiatuses are not represented in the preserved sediments, or that the hiatuses are an artifact of interpretation of the biostratigraphic data. Strontium isotopes indicate continuous sedimentation for the interval investigated at Site 642, an interpretation confirmed by the steady decline in 10Be. 87/86Sr ratios in the interval from above and below proposed hiatuses H 2.2/2.3 and H2.1/2.2 at Site 643 display stronger changes with depth than expected by steady sedimentation. Ir data for this same interval indicate reduced sedimentation rates. Combining both, sedimentologic and geochemical evidence, the proposed hiatuses could not be confirmed and may represent preservation artifacts.

Concentrations and accumulation rates of platinum-group elements and rhenium in Pacific and Atlantic sediments, DSDP and ODP data

The nature of Re-platinum-group element (PGE; Pt, Pd, Ir, Os, Ru) transport in the marine environment was investigated by means of marine sediments at and across the Cretaceous-Tertiary boundary (KTB) at two hemipelagic sites in Europe and two pelagic sites in the North and South Pacific. A traverse across the KTB in the South Pacific pelagic clay core found elevated levels of Re, Pt, Ir, Os, and Ru, each of which is approximately symmetrically distributed over a distance of ~1.8 m across the KTB. The Re-PGE abundance patterns are fractionated from chondritic relative abundances: Ru, Pt, Pd, and Re contents are slightly subchondritic relative to Ir, and Os is depleted by ~95% relative to chondritic Ir proportions. A similar depletion in Os (~90%) was found in a sample of the pelagic KTB in the North Pacific, but it is enriched in Ru, Pt, Pd, and Re relative to Ir. The two hemipelagic KTB clays have near-chondritic abundance patterns. The ~1.8-m-wide Re-PGE peak in the pelagic South Pacific section cannot be reconciled with the fallout of a single impactor, indicating that postdepositional redistribution has occurred. The elemental profiles appear to fit diffusion profiles, although bioturbation could have also played a role. If diffusion had occurred over ~65 Ma, the effective diffusivities are ~10**?13 cm**2/s, much smaller than that of soluble cations in pore waters (~10**?6 cm**2/s). The coupling of Re and the PGEs during redistribution indicates that postdepositional processes did not significantly fractionate their relative abundances. If redistribution was caused by diffusion, then the effective diffusivities are the same. Fractionation of Os from Ir during the KTB interval must therefore have occurred during aqueous transport in the marine environment. Distinctly subchondritic Os/Ir ratios throughout the Cenozoic in the South Pacific core further suggest that fractionation of Os from Ir in the marine environment is a general process throughout geologic time because most of the inputs of Os and Ir into the ocean have Os/Ir ratios >/=1. Mass balance calculations show that Os and Re burial fluxes in pelagic sediments account for only a small fraction of the riverine Os (<10%) and Re (<0.1%) inputs into the oceans. In contrast, burial of Ir in pelagic sediments is similar to the riverine Ir input, indicating that pelagic sediments are a much larger repository for Ir than for Os and Re. If all of the missing Os and Re is assumed to reside in anoxic sediments in oceanic margins, the calculated burial fluxes in anoxic sediments are similar to observed burial fluxes. However, putting all of the missing Os and Re into estuarine sediments would require high concentrations to balance the riverine input and would also fail to explain the depletion of Os at pelagic KTB sites, where at most ~25% of the K-T impactor's Os could have passed through estuaries. If Os is preferentially sequestered in anoxic marine environments, it follows that the Os/Ir ratio of pelagic sediments should be sensitive to changes in the rates of anoxic sediment deposition. There is thus a clear fractionation of Os and Re from Ir in precipitation out of sea water in pelagic sections. Accordingly, it is inferred here that Re and Os are removed from sea water in anoxic marine depositional regimes.

Dysfunctional 3D model based on structural and neuropsychological information

Acquired brain injury (ABI) 1-2 refers to any brain damage occurring after birth. It usually causes certain damage to portions of the brain. ABI may result in a significant impairment of an individuals physical, cognitive and/or psychosocial functioning. The main causes are traumatic brain injury (TBI), cerebrovascular accident (CVA) and brain tumors. The main consequence of ABI is a dramatic change in the individuals daily life. This change involves a disruption of the family, a loss of future income capacity and an increase of lifetime cost. One of the main challenges in neurorehabilitation is to obtain a dysfunctional profile of each patient in order to personalize the treatment. This paper proposes a system to generate a patient s dysfunctional profile by integrating theoretical, structural and neuropsychological information on a 3D brain imaging-based model. The main goal of this dysfunctional profile is to help therapists design the most suitable treatment for each patient. At the same time, the results obtained are a source of clinical evidence to improve the accuracy and quality of our rehabilitation system. Figure 1 shows the diagram of the system. This system is composed of four main modules: image-based extraction of parameters, theoretical modeling, classification and co-registration and visualization module.

Designing conditions for in vitro formation of amyloid protofilaments and fibrils

We have been able to convert a small α/β protein, acylphosphatase, from its soluble and native form into insoluble amyloid fibrils of the type observed in a range of pathological conditions. This was achieved by allowing slow growth in a solution containing moderate concentrations of trifluoroethanol. When analyzed with electron microscopy, the protein aggregate present in the sample after long incubation times consisted of extended, unbranched filaments of 30–50 Å in width that assemble subsequently into higher order structures. This fibrillar material possesses extensive β-sheet structure as revealed by far-UV CD and IR spectroscopy. Furthermore, the fibrils exhibit Congo red birefringence, increased fluorescence with thioflavine T and cause a red-shift of the Congo red absorption spectrum. All of these characteristics are typical of amyloid fibrils. The results indicate that formation of amyloid occurs when the native fold of a protein is destabilized under conditions in which noncovalent interactions, and in particular hydrogen bonding, within the polypeptide chain remain favorable. We suggest that amyloid formation is not restricted to a small number of protein sequences but is a property common to many, if not all, natural polypeptide chains under appropriate conditions.

Interaction of Class I Human Leukocyte Antigen (HLA-I) Molecules with Insulin Receptors and Its Effect on the Insulin-Signaling Cascade

Insulin receptor (IR) and class I major histocompatibility complex molecules associate with one another in cell membranes, but the functional consequences of this association are not defined. We found that IR and human class I molecules (HLA-I) associate in liposome membranes and that the affinity of IR for insulin and its tyrosine kinase activity increase as the HLA:IR ratio increases over the range 1:1 to 20:1. The same relationship between HLA:IR and IR function was found in a series of B-LCL cell lines. The association of HLA-I and IR depends upon the presence of free HLA heavy chains. All of the effects noted were reduced or abrogated if liposomes or cells were incubated with excess HLA-I light chain, β2-microglobulin. Increasing HLA:IR also enhanced phosphorylation of insulin receptor substrate-1 and the activation of phosphoinositide 3-kinase. HLA-I molecules themselves were phosphorylated on tyrosine and associated with phosphoinositide 3-kinase when B-LCL were stimulated with insulin.

Paper-like electronic displays: Large-area rubber-stamped plastic sheets of electronics and microencapsulated electrophoretic inks

Electronic systems that use rugged lightweight plastics potentially offer attractive characteristics (low-cost processing, mechanical flexibility, large area coverage, etc.) that are not easily achieved with established silicon technologies. This paper summarizes work that demonstrates many of these characteristics in a realistic system: organic active matrix backplane circuits (256 transistors) for large (≈5 × 5-inch) mechanically flexible sheets of electronic paper, an emerging type of display. The success of this effort relies on new or improved processing techniques and materials for plastic electronics, including methods for (i) rubber stamping (microcontact printing) high-resolution (≈1 μm) circuits with low levels of defects and good registration over large areas, (ii) achieving low leakage with thin dielectrics deposited onto surfaces with relief, (iii) constructing high-performance organic transistors with bottom contact geometries, (iv) encapsulating these transistors, (v) depositing, in a repeatable way, organic semiconductors with uniform electrical characteristics over large areas, and (vi) low-temperature (≈100°C) annealing to increase the on/off ratios of the transistors and to improve the uniformity of their characteristics. The sophistication and flexibility of the patterning procedures, high level of integration on plastic substrates, large area coverage, and good performance of the transistors are all important features of this work. We successfully integrate these circuits with microencapsulated electrophoretic “inks” to form sheets of electronic paper.

Fine-silt luminescence dating and mineral composition of sediments from the Arctic Ocean

New geochronometers are needed for sediments of the Arctic Ocean spanning at least the last half million years, largely because oxygen-isotope stratigraphy is relatively ineffective in this ocean, and because other dating techniques require significant assumptions about sedimentation rates. Multi-aliquot luminescence sediment-dating procedures were applied to polymineral, fine-silt samples from 9 core-top and 37 deeper samples from 20 cores representing 19 sites across the Arctic Ocean. Most samples have independent age assignments and other known properties (e.g., % coarse fraction, % carbonate, U-Th isotopes). Thick-source alpha-particle counting indicates that for most regions the contribution of measured unsupported 230Th and 231Pa to calculated dose rates is IR-PSL dating of polymineral fine-silt fractions from core-top and near-core-top samples indicates that three sites (mainly from the western Arctic Ocean) have long-bleach inherited ages of only 3-7 kyr, suggesting potential for accurate PSL and TL dating without an inherited correction when older interglacial samples are selected. Samples from a giant gravity core from the western region (Northwind Ridge) yield acceptable long-bleach TL and IR-PSL ages up to 100 kyr. A sample from the eastern region (near Gakkel Ridge) gives a long-bleach age of ca 60 kyr, agreeing with an independent age assignment. Several samples in the 10-40 kyr 14C range from other sites produce large long-bleach age overestimates, indicating the variable effects of ice-rafting and other depositional and bottom-currentreworking (re-suspension) processes during glacial stages. Short-bleach dating tests provide IR-PSL age estimates for core tops that appear to penetrate the 'reworking veil' of inherited ages, and not only suggest a procedure to greatly reduce long-bleach inherited ages but also have implications for the 14C reservoir correction. This study identifies the most promising regions for future luminescence dating, and suggests that for several regions of the Arctic Ocean, interglacial-stage (foram-'rich') sediments from ridge tops are preferred for the fine-grain luminescence dating methods.