Mathematical modelling of tumour response in primary breast cancer.

Although breast cancer is perceived to be relatively chemosensitive, cytotoxic drug therapy only leads to cure in the adjuvant setting. In advanced disease, primary resistance and inadequate cell kill may be important in determining the lack of a durable response to cytotoxics, but for an individual patient's tumour there is no consistent way of determining the importance of these two factors. An adaptation of Skipper's log cell kill model of tumour response to chemotherapy was applied to serial tumour measurements of 46 locally advanced primary breast carcinomas undergoing neoadjuvant chemotherapy. Assuming a log-normal distribution of errors in the clinically measured volumes, the model produced, for each tumour separately, in vivo estimates of proportional cell kill, initial resistance and tumour doubling times during therapy. After 4 weeks' treatment, these data could then be used to predict subsequent tumour volumes with good accuracy. In addition, for the 13 tumours that became operable after the neoadjuvant chemotherapy, there was a significant association between the final volume as predicted by the model and the final pathological volume (P < 0.05). This approach could be usefully employed to determine those tumours that are primarily resistant to the treatment regimen, permitting changes of therapy to more effective drugs at a time when the tumour is clinically responding but destined to progress

Paper Session II-B - Strategies for Conducting Life Science Experiments Beyond Low Earth Orbit

Human exploration beyond low Earth orbit will require terrestrial life to survive and ultimately flourish in environments fundamentally different to those in which it has evolved. The effects of deep space and conditions on the surface of other planets must be studied to understand and reduce the risks to explorers, provide bioregenerative life support, and make full use of the broad research opportunities and scientific benefits offered by such unique environments. Though much is already known about biological adaptations to the space environment, key changes in terrestrial life may only be revealed over complete life cycles and across multiple generations living beyond Earth. The demands and potential risks of exploring and inhabiting other worlds necessitate a detailed understanding of these changes at all levels of biological organization, from genetic alterations to impacts on critical elements of reproduction, development, and aging. Results from experiments conducted beyond low Earth orbit will contribute to the safety of space exploration and address fundamental questions of life\u27s potential beyond its planet of origin. Research campaigns will include a combination of core studies and innovative, Pl-driven investigations. Multiple flight platforms-including free flyers and planetary bases-may support a range of manned and unmanned mission opportunities

Smarter Vaccine Design Will Circumvent Regulatory T Cell-Mediated Evasion in Chronic HIV and HCV Infection

Despite years of research, vaccines against HIV and HCV are not yet available, due largely to effective viral immunoevasive mechanisms. A novel escape mechanism observed in viruses that cause chronic infection is suppression of viral-specific effector CD4(+) and CD8(+) T cells by stimulating regulatory T cells (Tregs) educated on host sequences during tolerance induction. Viral class II MHC epitopes that share a T cell receptor (TCR)-face with host epitopes may activate Tregs capable of suppressing protective responses. We designed an immunoinformatic algorithm, JanusMatrix, to identify such epitopes and discovered that among human-host viruses, chronic viruses appear more human-like than viruses that cause acute infection. Furthermore, an HCV epitope that activates Tregs in chronically infected patients, but not clearers, shares a TCR-face with numerous human sequences. To boost weak CD4(+) T cell responses associated with persistent infection, vaccines for HIV and HCV must circumvent potential Treg activation that can handicap efficacy. Epitope-driven approaches to vaccine design that involve careful consideration of the T cell subsets primed during immunization will advance HIV and HCV vaccine development

Intravesical rAd-IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study.

Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd-IFNα/Syn3 (randomly assigned 1:1 to 1 × 10(11) viral particles (vp)/mL or 3 × 10(11) vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd-IFNα/Syn3 (1 × 10(11) vp/mL, n = 21; 3 × 10(11) vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd-IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd-IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy

Elongase Reactions as Control Points in Long-Chain Polyunsaturated Fatty Acid Synthesis

Extent: 9p.Background: Δ6-Desaturase (Fads2) is widely regarded as rate-limiting in the conversion of dietary α-linolenic acid (18:3n-3; ALA) to the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (22:6n-3; DHA). However, increasing dietary ALA or the direct Fads2 product, stearidonic acid (18:4n-3; SDA), increases tissue levels of eicosapentaenoic acid (20:5n-3; EPA) and docosapentaenoic acid (22:5n-3; DPA), but not DHA. These observations suggest that one or more control points must exist beyond ALA metabolism by Fads2. One possible control point is a second reaction involving Fads2 itself, since this enzyme catalyses desaturation of 24:5n-3 to 24:6n-3, as well as ALA to SDA. However, metabolism of EPA and DPA both require elongation reactions. This study examined the activities of two elongase enzymes as well as the second reaction of Fads2 in order to concentrate on the metabolism of EPA to DHA. Methodology/Principal Findings: The substrate selectivities, competitive substrate interactions and dose response curves of the rat elongases, Elovl2 and Elovl5 were determined after expression of the enzymes in yeast. The competitive substrate interactions for rat Fads2 were also examined. Rat Elovl2 was active with C20 and C22 polyunsaturated fatty acids and this single enzyme catalysed the sequential elongation reactions of EPA→DPA→24:5n-3. The second reaction DPA→24:5n-3 appeared to be saturated at substrate concentrations not saturating for the first reaction EPA→DPA. ALA dose-dependently inhibited Fads2 conversion of 24:5n-3 to 24:6n-3. Conclusions: The competition between ALA and 24:5n-3 for Fads2 may explain the decrease in DHA levels observed after certain intakes of dietary ALA have been exceeded. In addition, the apparent saturation of the second Elovl2 reaction, DPA→24:5n-3, provides further explanations for the accumulation of DPA when ALA, SDA or EPA is provided in the diet. This study suggests that Elovl2 will be critical in understanding if DHA synthesis can be increased by dietary means.Melissa K. Gregory, Robert A. Gibson, Rebecca J. Cook-Johnson, Leslie G. Cleland and Michael J. Jame

Multilayers of InGaAs Nanostructures Grown on GaAs(210) Substrates

Multilayers of InGaAs nanostructures are grown on GaAs(210) by molecular beam epitaxy. With reducing the thickness of GaAs interlayer spacer, a transition from InGaAs quantum dashes to arrow-like nanostructures is observed by atomic force microscopy. Photoluminescence measurements reveal all the samples of different spacers with good optical properties. By adjusting the InGaAs coverage, both one-dimensional and two-dimensional lateral ordering of InGaAs/GaAs(210) nanostructures are achieved

Data Recovery Investigations: Murvaul Creek Site (41PN175), Panola County, Texas

This report summarizes the archeological findings of the 2011 data recovery investigations at the Murvaul Creek site, 41PN175, in far northeastern Texas in Panola County. The site is located along Farm-to-Market Road (FM) 10 approximately 1 mile north of Gary, Texas (Figure 1). Geo-Marine, Inc. (GMI), performed this work under contract to the Texas Department of Transportation, Environmental Affairs Division (TxDOT ENV) under the Texas Antiquities Permit Number 5879 (Work Authorization [WA] 579 06 SA005; WA 590 08 SA005; CSJ:1222-01-014; Geo-Marine project numbers 22005.00.06 and 22005.00.09). The fieldwork for this project was conducted in advance of the planned widening of FM 10 that was to replace three bridges and a culvert over Murvaul Creek with a larger structure and shift the road approximately 26 meters (m; 85 feet [ft]) to the east. Since the planned improvements of FM 10 would result in the loss of information at the Murvaul Creek site—a site that was recommended eligible for inclusion in the National Register of Historic Places (NRHP) and for designation as a State Antiquities Landmark (SAL; formerly State Archeological Landmark)—the current data recovery investigations were initiated. The data recovery investigations were conducted between February 7, 2011, and April 3, 2011. During this period, the fieldwork was conducted in several stages: site clearing, geophysical survey, 50-x-50-centimeter (cm) excavations, block excavations, and mechanical site scraping. With the exception of the site clearing stage, the results of each of the fieldwork stages are reviewed individually in this report. The investigations resulted in the documentation of numerous features that appeared to have been the remains of a small Middle-to-Late Caddo settlement or farmstead situated on the edge of an interfluve south of the Murvaul Creek floodplain. Additionally, materials pertaining to the Archaic period were documented across the site. Although the site has been intensively studied within the TxDOT right-of-way (ROW), both the current investigations and previous work were limited to the ROW (cf. Cliff and Perttula 2002). Hence, the site is very likely larger than has been adequately documented

Optical Spectroscopy of Supernova 1993J During Its First 2500 Days

We present 42 low-resolution spectra of Supernova (SN) 1993J, our complete collection from the Lick and Keck Observatories, from day 3 after explosion to day 2454, as well as one Keck high-dispersion spectrum from day 383. SN 1993J began as an apparent SN II, albeit an unusual one. After a few weeks, a dramatic transition took place, as prominent helium lines emerged in the spectrum. SN 1993J had metamorphosed from a SN II to a SN IIb. Nebular spectra of SN 1993J closely resemble those of SNe Ib and Ic, but with a persistent H_alpha line. At very late times, the H_alpha emission line dominated the spectrum, but with an unusual, box-like profile. This is interpreted as an indication of circumstellar interaction.Comment: 19 pages plus 13 figures, AASTeX V5.0. One external table in AASTeX V4.0, in landscape format. Accepted for publication in A

Bridging photochemistry and photomechanics with NMR crystallography: the molecular basis for the macroscopic expansion of an anthracene ester nanorod

Crystals composed of photoreactive molecules represent a new class of photomechanical materials with the potential to generate large forces on fast timescales. An example is the photodimerization of 9-tert-butyl-anthracene ester (9TBAE) in molecular crystal nanorods that leads to an average elongation of 8%. Previous work showed that this expansion results from the formation of a metastable crystalline product. In this article, it is shown how a novel combination of ensemble oriented-crystal solid-state NMR, X-ray diffraction, and first principles computational modeling can be used to establish the absolute unit cell orientations relative to the shape change, revealing the atomic-resolution mechanism for the photomechanical response and enabling the construction of a model that predicts an elongation of 7.4%, in good agreement with the experimental value. According to this model, the nanorod expansion does not result from an overall change in the volume of the unit cell, but rather from an anisotropic rearrangement of the molecular contents. The ability to understand quantitatively how molecular-level photochemistry generates mechanical displacements allows us to predict that the expansion could be tuned from +9% to −9.5% by controlling the initial orientation of the unit cell with respect to the nanorod axis. This application of NMR-assisted crystallography provides a new tool capable of tying the atomic-level structural rearrangement of the reacting molecular species to the mechanical response of a nanostructured sample