Molecular Approaches to Sarcoma Therapy

Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Although conventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve a curative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminating the clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of gene alterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a single chromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML, these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric protein that displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additional growth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinase inhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cells may be effective. This review summarizes published approaches targeting a specific molecular mechanism associated with sarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. These include: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translational modifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptotic pathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and the conceptual obstacles to be overcome are discussed

Supporting, microporous, elastomeric degradable prostheses to improve the arterialization of autologous vein grafts

Arterial reconstructions with vein grafts fail more frequently than with arterial grafts. One of the causes of graft failure is damage due to overstretching of the graft wall. Overstretching is caused because the vein graft, which has a poorly developed medium, cannot withstand the arterial blood pressures. The aim of this study is to evaluate whether damage due to overstretching can be prevented and a gradual adaptation of the vein graft to the arterial blood pressures can be induced by applying a microporous, elastomeric, degradable prosthesis around the vein graft. Therefore, autologous vein grafts (length 1.0cm) with and without supporting prostheses (composite vein grafts and control vein grafts, respectively) were interposed into both carotid arteries of rabbits. Microporous, elastomeric, biofragmentable polyurethane-based prostheses and microporous, elastomeric, biodegradable prostheses made of poly--caprolactone or a copolymer of -caprolactone and 3.6-dimethyl-1,4-morpholine-2,5-dione with a monomer ratio of 95.5:4.5 were prepared. The grafts were evaluated up to 6 wk after implantation. The control vein grafts showed severe destructive changes such as de-endothelialization, disruption of the media with oedema, degradation of the elastic laminae and infiltration of polymorphonuclear leucocytes into the vein graft wall, leading eventually to a fibrotic wall. In contrast, the composite vein grafts showed a preservation of the smooth muscle cell layers and the elastic laminae with only few polymorphonuclear leucocytes infiltrated into the vein graft wall. Moreover, the wall of the vein graft gradually increased in thickness by the formation of regular circularly oriented cellular layers beneath the original longitudinally oriented smooth muscle cell layers, indicating a gradual adaptation of the vein graft to the arterial conditions. It appeared that the arterialization rate depended on the degradation rate of the supporting prostheses. Microporous prostheses made of a copolymer of -caprolactone and 3,6-dimethyl-1,4-morpholine-2,5-dione with a monomer ratio higher than 95.5:4.5 are recommended to support the vein grafts

The influence of rifle carriage on the kinetics of human gait

The influence that rifle carriage has on human gait has received little attention in the published literature. Rifle carriage has two main effects, to add load to the anterior of the body and to restrict natural arm swing patterns. Kinetic data were collected from 15 male participants, with 10 trials in each of four experimental conditions. The conditions were: walking without a load (used as a control condition); carrying a lightweight rifle simulator, which restricted arm movements but applied no additional load; wearing a 4.4 kg diving belt, which allowed arms to move freely; carrying a weighted (4.4 kg) replica SA80 rifle. Walking speed was fixed at 1.5 m/s (+5%) and data were sampled at 400 Hz. Results showed that rifle carriage significantly alters the ground reaction forces produced during walking, the most important effects being an increase in the impact peak and mediolateral forces. This study suggests that these effects are due to the increased range of motion of the body’s centre of mass caused by the impeding of natural arm swing patterns. The subsequent effect on the potential development of injuries in rifle carriers is unknown

Prevalence of Non-O157:H7 Shiga Toxin-Producing \u3ci\u3eEscherichia coli\u3c/i\u3e in Diarrheal Stool Samples from Nebraska

We determined the prevalence of Shiga toxin-producing Escherichia coli (STEC) in diarrheal stool samples from Nebraska by three methods: cefixime-tellurite sorbitol MacConkey (CT-SMAC) culture, enterohemorrhagic E. coli (EHEC) enzyme immunoassay, and stx1,2 polymerase chain reaction (PCR). Fourteen (4.2%) of 335 specimens were positive by at least one method (CT-SMAC culture [6 of 14], EHEC enzyme immunoassay [13 of 14], stx1,2 PCR [14 of 14]). Six contained serogroup 0157, while non-0157 were as prevalent as 0157 serogroups

Prevalence of non-O157:H7 shiga toxin-producing Escherichia coli in diarrheal stool samples from Nebraska.

We determined the prevalence of Shiga toxin-producing Escherichia coli (STEC) in diarrheal stool samples from Nebraska by three methods: cefixime-tellurite sorbitol MacConkey (CT- SMAC) culture, enterohemorrhagic E. coli (EHEC) enzyme immunoassay, and stx1,2 polymerase chain reaction (PCR). Fourteen (4.2%) of 335 specimens were positive by at least one method (CT-SMAC culture [6 of 14], EHEC enzyme immunoassay [13 of 14], stx1,2 PCR [14 of 14]). Six contained serogroup O157, while non-O157 were as prevalent as O157 serogroups

Target Mass Monitoring and Instrumentation in the Daya Bay Antineutrino Detectors

The Daya Bay experiment measures sin^2 2{\theta}_13 using functionally identical antineutrino detectors located at distances of 300 to 2000 meters from the Daya Bay nuclear power complex. Each detector consists of three nested fluid volumes surrounded by photomultiplier tubes. These volumes are coupled to overflow tanks on top of the detector to allow for thermal expansion of the liquid. Antineutrinos are detected through the inverse beta decay reaction on the proton-rich scintillator target. A precise and continuous measurement of the detector's central target mass is achieved by monitoring the the fluid level in the overflow tanks with cameras and ultrasonic and capacitive sensors. In addition, the monitoring system records detector temperature and levelness at multiple positions. This monitoring information allows the precise determination of the detectors' effective number of target protons during data taking. We present the design, calibration, installation and in-situ tests of the Daya Bay real-time antineutrino detector monitoring sensors and readout electronics.Comment: 22 pages, 20 figures; accepted by JINST. Changes in v2: minor revisions to incorporate editorial feedback from JINS

Identifying disease sensitive and quantitative trait-relevant biomarkers from multidimensional heterogeneous imaging genetics data via sparse multimodal multitask learning

Motivation: Recent advances in brain imaging and high-throughput genotyping techniques enable new approaches to study the influence of genetic and anatomical variations on brain functions and disorders. Traditional association studies typically perform independent and pairwise analysis among neuroimaging measures, cognitive scores and disease status, and ignore the important underlying interacting relationships between these units

The Enduring Questions: What's for Dinner? Where's My Knife? …and Can I Use My Fingers? (Unanswered) Questions Related to Organic Matter and Microbes in Marine Sediments

Heterotrophic microbial communities play key roles in processing and remineralizing organic matter in marine sediments: they are the “final gatekeepers” that determine the types and quantity of organicmatter that is ultimately buried in sediments—processes important to our understanding of past global environments, as well as to the production of petroleum products that still fuel much of modern society. These communities’ capabilities also help us understand the energetic and metabolic boundaries of life. Work over the past decades has revealed much information about sedimentary microbial communities: their overall composition (Bacteria and Archaea), the sequence of terminal respiration processes occurring with progressive burial depth in sediments, and the depth to which they can be detected; research on the members and metabolism in the “deep biosphere” has assumed a central position in organic geochemistry, environmental microbiology, and molecular ecology (Orcutt et al., 2013; D’Hondt et al., 2019)

Multipoint identity-by-descent computations for single-point polymorphism and microsatellite maps

We used the LOKI software to generate multipoint identity-by-descent matrices for a microsatellite map (with 31 markers) and two single-nucleotide polymorphism (SNP) maps to examine information content across chromosome 7 in the Collaborative Study on the Genetics of Alcoholism dataset. Despite the lower information provided by a single SNP, SNP maps overall had higher and more uniform information content across the chromosome. The Affymetrix map (578 SNPs) and the Illumina map (271 SNPs) provided almost identical information. However, increased information has a computational cost: SNP maps require 100 times as many iterations as microsatellites to produce stable estimates