A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial.

Lessons learnedThe addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation.BackgroundThis randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer.MethodsPatients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS).ResultsOne hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen.ConclusionAddition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup

The Little Paint Site: A Classic Toyah Camp on the South Llano River, Kimble County, Texas

On behalf of the Texas Department of Transportation (TxDOT), SWCA Environmental Consultants (SWCA) conducted testing and data recovery investigations at the Little Paint site (41KM226), a prehistoric multi-component site in the US 377 right-of-way along the South Llano River in Kimble County, Texas. While the site revealed Archaic and Late Prehistoric components, the earlier components were stratigraphically intermixed. Consequently, data recovery focused almost entirely on a discrete Toyah component, which, based on earlier test excavations conducted in August and September 2006, had previously been determined to be eligible for listing on the National Register of Historic Places and as a State Archeological Landmark. SWCA performed the investigations under Texas Antiquities Permits 4184 and 4318. Kevin A. Miller served as Principal Investigator. The excavations recovered approximately 102 m2 of a stratigraphically-discrete Toyah component consisting of rock-lined hearths, Perdiz points, Cliffton points, a bird-bone bead, bone-tempered ceramics, bifaces, scrapers (notably end scrapers on blade-flakes), various informal lithic tools, drills, awls, debitage, and faunal remains. Based on the assemblage, the site is interpreted as a Toyah basecamp as indicated by a diversity of tool forms and site furniture. The component has good integrity, is vertically and horizontally discrete, and contains a substantial amount of archaeological materials. The suite of 16 radiometric dates indicates intermittent Toyah occupations between 240 and 570 years ago, a time range that is generally consistent with recognized span of the Toyah assemblage. The archaeological assemblage and site structure, however, suggests a possible single Toyah occupation. While not a focal point of the data recovery investigations, the excavations also recovered mixed Archaic components below the Toyah component. Artifacts include diagnostic point styles that indicate Late Archaic to early Late Prehistoric occupations, representing 1,000 to 2,000 years of the regional cultural chronology compressed within a thin stratum. Based on the findings, the depositional conditions below the Toyah component, as was previously determined by the testing data, were found to be generally not conducive to the formation of stratigraphic separation of the successive occupations. This compression resulted in intermixing of components and poor integrity. Below the mixed Archaic zone, deeply buried Middle to Early Archaic deposits were identified. These retained a better potential for significant isolable strata, but these deeper deposits were beyond the project impacts and therefore were not the subject of mitigative efforts. The deeper deposits are preserved by avoidance. As previously determined and further substantiated by the data recovery investigations, the Little Paint site, because of the Toyah component and perhaps earlier deposits, is eligible for National Register of Historic Places listing under Criterion D, 36 CFR 60.4, and eligible for State Archeological Landmark designation under Criteria 1 and 2 of the Rules of Practice and Procedure for the Antiquities Code of Texas, 13 TAC 26.8. The excavations have mitigated the adverse effects of the US 377 bridge replacement by recovering the vast majority of the Toyah component within the area of potential effect of the roadway undertaking. No further archaeological work is recommended. Portions of the site outside of the right-of-way have not been fully evaluated. The artifacts and records from the project are curated at the Center for Archaeological Studies, Texas State University

Center for Environmental Kinetics Analysis

Over the past two decades, numerous studies have produced high quality information on the rates at which bacteria can reduce metal oxides. The prototypical study--such as the one depicted to the right--focuses on only a few of the myriad variables affecting the rate. This approach allows for effective dissection of the mechanisms underlying DMRB activity, but, it also produces disjoint information that must be synthesized if we hope to predict the behavior of bacteria at the systems level

White Matter Injury and General Movements in High-Risk Preterm Infants

BACKGROUND AND PURPOSE: Very preterm infants (birth weight, MATERIALS AND METHODS: In this prospective study of 47 preterm infants of 24-30 weeks' gestation, brain MR imaging was performed at term-equivalent age. Infants underwent T1- and T2-weighted imaging for volumetric analysis and DTI. General movements were assessed at 10-15 weeks' postterm age, and neurodevelopmental outcomes were evaluated at 2 years by using the Bayley Scales of Infant and Toddler Development Ill. RESULTS: Nine infants had aberrant general movements and were more likely to have adverse neurodevelopmental outcomes, compared with infants with normal movements. In infants with aberrant movements, Tract-Based Spatial Statistics analysis identified significantly lower fractional anisotropy in widespread white matter tracts, including the corpus callosum, inferior longitudinal and fronto-occipital fasciculi, internal capsule, and optic radiation. The subset of infants having both aberrant movements and abnormal neurodevelopmental outcomes in cognitive, language, and motor skills had significantly lower fractional anisotropy in specific brain regions. CONCLUSIONS: Aberrant general movements at 10-15 weeks' postterm are associated with adverse neurodevelopmental outcomes and specific white matter microstructure abnormalities for cognitive, language, and motor delays

Ionic Tuning of Cobaltites at the Nanoscale

Control of materials through custom design of ionic distributions represents a powerful new approach to develop future technologies ranging from spintronic logic and memory devices to energy storage. Perovskites have shown particular promise for ionic devices due to their high ion mobility and sensitivity to chemical stoichiometry. In this work, we demonstrate a solid-state approach to control of ionic distributions in (La,Sr)CoO$_{3}$ thin films. Depositing a Gd capping layer on the perovskite film, oxygen is controllably extracted from the structure, up-to 0.5 O/u.c. throughout the entire 36 nm thickness. Commensurate with the oxygen extraction, the Co valence state and saturation magnetization show a smooth continuous variation. In contrast, magnetoresistance measurements show no-change in the magnetic anisotropy and a rapid increase in the resistivity over the same range of oxygen stoichiometry. These results suggest significant phase separation, with metallic ferromagnetic regions and oxygen-deficient, insulating, non-ferromagnetic regions, forming percolated networks. Indeed, X-ray diffraction identifies oxygen-vacancy ordering, including transformation to a brownmillerite crystal structure. The unexpected transformation to the brownmillerite phase at ambient temperature is further confirmed by high-resolution scanning transmission electron microscopy which shows significant structural - and correspondingly chemical - phase separation. This work demonstrates room-temperature ionic control of magnetism, electrical resistivity, and crystalline structure in a 36 nm thick film, presenting new opportunities for ionic devices that leverage multiple material functionalities

Efficient Photon Upconversion Enabled by Strong Coupling Between Organic Molecules and Quantum Dots

Hybrid structures formed between organic molecules and inorganic quantum dots can accomplish unique photophysical transformations by taking advantage of their disparate properties. The electronic coupling between these materials is typically weak, leading photoexcited charge carriers to spatially localize to a dot or a molecule at its surface. However, we show that by converting a chemical linker that covalently binds anthracene molecules to silicon quantum dots from a carbon-carbon single bond to a double bond, we access a strong-coupling regime where excited carriers spatially delocalize across both anthracene and silicon. By pushing the system to delocalize, we design a photon upconversion system with a higher efficiency (17.2%) and lower threshold intensity (0.5 W/cm^2) than that of a corresponding weakly-coupled system. Our results show that strong coupling between molecules and nanostructures achieved through targeted linking chemistry provides a new route for tailoring properties in materials for light-driven applications.Comment: 33 pages (20 in main text, 13 in supporting information), 12 figures (5 in main text, 7 in supporting information

Tumor cell-organized fibronectin is required to maintain a dormant breast cancer population [preprint]

Tumors can undergo long periods of dormancy, with cancer cells entering a largely quiescent, non-proliferative state before reactivation and outgrowth. For a patient, these post-remission tumors are often drug resistant and highly aggressive, resulting in poor prognosis. To understand the role of the extracellular matrix (ECM) in regulating tumor dormancy, we created an in vitro cell culture system that combines carefully controlled ECM substrates with nutrient deprivation to observe entrance into and exit from dormancy with live imaging. We saw that cell populations capable of surviving entrance into long-term dormancy were heterogeneous, containing quiescent, cell cycle arrested, and actively proliferating cells. Cell populations that endured extended periods of serum-deprivation-induced dormancy formed an organized, fibrillar fibronectin matrix via αvβ3 and α5β1 integrin adhesion, ROCK-generated tension, and TGFβ2 stimulation. We surmised that the fibronectin matrix was primarily a mediator of cell survival, not proliferation, during the serum-deprivation stress, bacause cancer cell outgrowth after dormancy required MMP-2-mediated fibronectin degradation. Given the difficulty of animal models in observing entrance and exit from dormancy in real-time, we propose this approach as a new, in vitro method to study factors important in regulating dormancy, and we used it here to elucidate a role for fibronectin deposition and MMP activation

From Boolean Equalities to Constraints

Although functional as well as logic languages use equality to discriminate between logically different cases, the operational meaning of equality is different in such languages. Functional languages reduce equational expressions to their Boolean values, True or False, logic languages use unification to check the validity only and fail otherwise. Consequently, the language Curry, which amalgamates functional and logic programming features, offers two kinds of equational expressions so that the programmer has to distinguish between these uses. We show that this distinction can be avoided by providing an analysis and transformation method that automatically selects the appropriate operation. Without this distinction in source programs, the language design can be simplified and the execution of programs can be optimized. As a consequence, we show that one kind of equational expressions is sufficient and unification is nothing else than an optimization of Boolean equality