Parallel Profiles Research Articles

Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects

While recent publications have suggested the pharmacokinetics (PK) of vismodegib appear to be non-linear, there has not been a report describing the mechanisms of non-linearity. This study provides evidence that two separate processes, namely, solubility-limited absorption and concentration-dependent plasma protein binding, can explain the non-linear PK of vismodegib. This study provides quantitative results which can account for the lower than expected accumulation of vismodegib with continuous daily dosing. Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of (14) C-vismodegib with single and multiple oral doses. Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a (14) C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for (14) C-vismodegib by accelerator mass spectrometry. Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h(-1) , 16.4 l and 31.8%, respectively. Parallel concentration-time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h(-1) and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing. Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.

Compton broadening effect on spectral line formation

We have investigated the effects of Compton broadening due to electron scattering in an expanding stellar atmospheres. The line transfer equation is solved by including the second approximation of Edmonds (Astrophys. J. 119:58, 1954) which is due to Compton broadening and obtained the line profiles in (1) plane parallel (PP) (2) spherical (SS) atmospheres. The effect on spectral line formation is studied for different parameters like (a) optical depths (b) densities (c) frequencies (d) temperatures (e) thickness of the atmosphere and (f) expanding velocities. Various combination of the above parameters are used in computing the line profiles observed at infinity.

Geophysical Models for the Cu-Dominated VHMS Mineralization in Katta District, Western Ethiopia

Volcanic hosted massive sulfides (VHMS) have been recognized for many years within the Arabian–Nubian Shield of western Ethiopia. The Shield is a collision belt formed when East and West Gondwana collided during the Neoproterozoic time. It covers NE Africa and the Middle East and is known to have hosted several economic mineral deposits. Situated within the Shield, the Katta VHMS mineralization is primarily made up of chalcopyrite, sphalerite, pyrite, pyrrhotite, and magnetite. These minerals are known to have contrasting values in resistivity, chargeability, and magnetic susceptibility with the enclosing host rocks. These physical attributes make resistivity, IP, and magnetic methods ideal to study and detect the mineralization and possibly delineate the ore body. Dipole–dipole DC resistivity and induced polarization data collected along parallel profiles are inverted to generate both 2D and 3D models of resistivity and chargeability. The chargeability model successfully delineates the zone of sulfide mineralization and the resistivity model gives information on the stratigraphic horizons and the structures. Magnetic data collected along more closely spaced profiles were also inverted to recover the 3D magnetic susceptibility model. The recovered model shows a linear magnetic anomaly that could be associated with the sulfides. This anomaly shows good spatial continuity and is in good agreement with the result obtained in the chargeability model. The geophysical inversion results indicate a NNW oriented mineralized zone of considerable strike length and extending to a depth of about 380 m. This study suggests the presence of exploitable VHMS presence in Katta district and that the inversion methodology is an important interpretation tool in guiding the exploration and exploitation of sulfide mineralization.

Induced polarization 3D tomography of an archaeological direct reduction slag heap

ABSTRACTBoth environmentalists and archaeologists are interested in the detection and quantification of the remains of mine slag heaps from ancient smelters: possible pollution of the slag heaps and information concerning the history of the smelter's mine. Although magnetic surveys can be used to detect subsurface slag accumulations, it is not possible to derive the total amount of material from such surveys or to accurately delineate the heaps through the use of this method. Conversely, ‘Induced Polarization’ (IP) surveying allows a relevant and robust assessment of the volume of slag concentrations to be determined. In the present study, we follow up on results obtained in a previous study, carried out at the 14th Castel‐Minier mine (Ariège, France) site, where we have shown that the chargeability is proportional to the slag concentration in the ground and have used this property to perform 3D tomography of the heap. Based on a previous investigation using spectral induced polarization along a simple profile showing that the phase peak related to the slags is situated at approximately 1 Hz, in the present paper we extend our prospection to 3D by using a Terrameter SAS1000 and measuring temporal chargeability. The set of three‐dimensional data is recorded by means of classical transect measurements along parallel close profiles and is then interpreted using the RES3DINV code. Finally, archaeological and auger soundings confirmed the assessments derived from this geophysical investigation. We also briefly discuss the source of the IP signal, which we suspect to be induced by magnetite particles embedded in the slags.

Q01 SIRT 1 mediated modulation of circulating cytokines in huntington's disease- pharmacodynamics results from phase 1B study of selisistat—A SIRT 1 inhibitor

BackgroundEvidence suggests simultaneous dysfunction of CNS and peripheral inflammatory pathways in Huntington's disease (HD). A pattern of pro-inflammatory cytokine elevation has been observed in plasma in HD, with IL-6 significantly...

Numerical investigation of edge plasma phenomena in an enhanced D-alpha discharge at Alcator C-Mod: Parallel heat flux and quasi-coherent edge oscillations

Reduced-model scrape-off layer turbulence (SOLT) simulations of an enhanced D-alpha (EDA) H-mode shot observed in the Alcator C-Mod tokamak were conducted to compare with observed variations in the scrape-off-layer (SOL) width of the parallel heat flux profile. In particular, the role of the competition between sheath- and conduction-limited parallel heat fluxes in determining that width was studied for the turbulent SOL plasma that emerged from the simulations. The SOL width decreases with increasing input power and with increasing separatrix temperature in both the experiment and the simulation, consistent with the strong temperature dependence of the parallel heat flux in balance with the perpendicular transport by turbulence and blobs. The particularly strong temperature dependence observed in the case analyzed is attributed to the fact that these simulations produce SOL plasmas which are in the conduction-limited regime for the parallel heat flux. A persistent quasi-coherent (QC) mode dominates the SOLT simulations and bears considerable resemblance to the QC mode observed in C-Mod EDA operation. The SOLT QC mode consists of nonlinearly saturated wave-fronts located just inside the separatrix that are convected poloidally by the mean flow, continuously transporting particles and energy and intermittently emitting blobs into the SOL.

2-D and 3-D Resistivity Imaging of Karst Sites in Missouri, USA

Two-dimensional (2-D) electrical resistivity tomography data were acquired across and in proximity to active sinkholes at two highway construction sites in Missouri. Site 1 is located in Greene County in southwestern Missouri; site 2 is located in Jefferson County in east-central Missouri. Eleven 2-D electrical resistivity tomography profiles were acquired along a suite of parallel traverses (spaced at 7.5 m intervals) at site 1 as part of the geotechnical investigation of a proposed interchange. The primary objectives were to identify and map air-filled karstic cavities (if present) and the top of bedrock. The resistivity data from site 1 were processed as both conventional 2-D data and as three-dimensional (3-D) data using two different inversion schemes. The top of bedrock was imaged, and five prominent north-trending, clay-filled, solution-widened fractures were identified. Interpreted air-filled voids were not imaged. At site 2, a pattern of 17 parallel electrical resistivity tomography profiles was acquired across and in proximity to a preexisting sinkhole (approximately 15 m × 10 m × 5 m L/W/D). During construction of the highway, the soil was emptied from the sinkhole overnight following a heavy rainstorm. Electrical resistivity tomography data were acquired to determine if the sinkhole was underlain by a large air-filled cavity. Interpretation of the 2-D and 3-D resistivity images from site 2 showed that the sinkhole was not underlain by a substantive cavity. Rather, the soil in the sinkhole appears to have “flowed” into the subsurface through solution-widened fractures that do not pose a significant risk to the overlying roadway.

Proteomic and Transcriptomic Profiling of Staphylococcus aureus Surface LPXTG-proteins: Correlation with agr Genotypes and Adherence Phenotypes

Staphylococcus aureus infections involve numerous adhesins and toxins, which expression depends on complex regulatory networks. Adhesins include a family of surface proteins covalently attached to the peptidoglycan via a conserved LPXTG motif. Here we determined the protein and mRNA expression of LPXTG-proteins of S. aureus Newman in time-course experiments, and their relation to fibrinogen adherence in vitro. Experiments were performed with mutants in the global accessory-gene regulator (agr), surface protein A (Spa), and fibrinogen-binding protein A (ClfA), as well as during growth in iron-rich or iron-poor media. Surface proteins were recovered by trypsin-shaving of live bacteria. Released peptides were analyzed by liquid chromatography coupled to tandem mass-spectrometry. To unambiguously identify peptides unique to LPXTG-proteins, the analytical conditions were refined using a reference library of S. aureus LPXTG-proteins heterogeneously expressed in surrogate Lactococcus lactis. Transcriptomes were determined by microarrays. Sixteen of the 18 LPXTG-proteins present in S. aureus Newman were detected by proteomics. Nine LPXTG-proteins showed a bell-shape agr-like expression that was abrogated in agr-negative mutants including Spa, fibronectin-binding protein A (FnBPA), ClfA, iron-binding IsdA, and IsdB, immunomodulator SasH, functionally uncharacterized SasD, biofilm-related SasG and methicillin resistance-related FmtB. However, only Spa and SasH modified their proteomic and mRNA profiles in parallel in the parent and its agr- mutant, whereas all other LPXTG-proteins modified their proteomic profiles independently of their mRNA. Moreover, ClfA became highly transcribed and active in fibrinogen-adherence tests during late growth (24 h), whereas it remained poorly detected by proteomics. On the other hand, iron-regulated IsdA-B-C increased their protein expression by >10-times in iron-poor conditions. Thus, proteomic, transcriptomic, and adherence-phenotype demonstrated differential profiles in S. aureus. Moreover, trypsin peptide signatures suggested differential protein domain exposures in various environments, which might be relevant for anti-adhesin vaccines. A comprehensive understanding of the S. aureus physiology should integrate all three approaches.

PARALIND-based identifiability results for parameter estimation via uniform linear array

This article applies PARAllel profiles with LINear Dependencies (PARALIND) model to analyze identifiability of parameter estimation in the presence of incoherent multipath via uniform linear array (ULA). New identifiability results are derived based on the uniqueness property of PARALIND model and structure property of ULA. With the strong properties of trilinear model, the proposed identifiability conditions for propagation parameter identification are superior to early studies. We give a new tradeoff between the number of receiving antennae and sampling diversity to ensure parameter identification. Furthermore, a new lower bound of the number of receiving antennae for identifiability is derived. It also shows that the identifiability results is not only determined by traditional factors, such as the number of receiving antennae, oversampling factor or the total number of transmitting paths, but also related to the structure of multipath of sources.

PARALIND-based blind joint angle and delay estimation for multipath signals with uniform linear array

A novel joint angle and delay estimation (JADE) algorithm for multipath signals, based on the PARAllel profiles with LINear Dependencies (PARALIND) model, is proposed. Capitalizing on the structure property of Vandermonde matrices, PARALIND model is proved to be unique. Angle and delay of multiple rays of sources can be estimated by PARALIND decomposition and an ESPRIT-like shift-invariance technique. Simulation results show that the proposed algorithm outperforms the traditional JADE algorithm. It can automatically distinguish the estimated parameters between sources, and still be available when the number of rays is larger than the number of receiving antennae.

AN OPTIMIZED TECHNIQUE FOR RED BLOOD CELLS VELOCITY MEASUREMENT IN MICROVESSELS

Oxygen and nutrient delivery to living tissues, as well as metabolic waste removal, are essentially determined by the dynamics of blood flow in microvascular networks. In these vessels, measuring the velocity distribution of red blood cells (RBCs) is still challenging. One of the most popular techniques used for that purpose is the Dual-Slit (DS), a temporal correlation technique, first introduced by Wayland and Johnson (1967):the vessel under study is trans-illuminated and two photo-sensors (slits) are positioned, separated by a known distance, Ls, along the vessel axis. The time modulation of light is recorded at both positions. A cross-correlation velocity, Vds=Ls/Td, is obtained, where Td is the time delay for which the cross-correlation between the two signals is maximum. However, RBCs are positioned at different depths within the channel and thus move at different velocities. Baker and Wayland (1974) suggested that Vds is related to a dynamic averaged velocity,but this has never been proved. The aim of this work is to determine the relationship between the measured velocity Vds and the actual velocity scales of the flow. For that purpose, the DS technique is first optimized using sequences of synthetic images representing RBCs flow. By this way, all the parameters characterizing the RBCs flow, including the shape of their velocity profile in the direction parallel to the incident light beam, which is inaccessible to the observer in real experiments, are controlled. The DS is then applied to in vitro RBCs flows in microchannels.

The Paleoproterozoic Kaminak dykes, Hearne craton, western Churchill Province, Nunavut, Canada: Preliminary constraints on their age and petrogenesis

The NNW- to NNE-trending Kaminak diabase dykes, exposed in the Hearne craton of the western Churchill Province, Canada, are components of a Neoarchean–Paleoproterozoic LIP that forms an important pin in plate tectonic reconstructions impacting models for the assembly of the Nuna supercontinent. This study provides the first detailed information on the age, geochemistry and isotopic composition of these dykes.A precise U–Pb baddeleyite date of 2497.6±1.1Ma, obtained for one dyke sample, provides the best estimate for the timing of Kaminak mafic magmatism. The dykes are tholeiitic basalts to basaltic andesites with consistent compositions over an areal extent of ∼10,000km2. Major and compatible trace element variations indicate that the dykes were not in equilibrium with anhydrous peridotitic mantle and evolved through fractionation of Pl+Cpx±Ol from parental melts in the deep crust. All dykes record remarkably similar, incompatible element enriched, closely parallel multi-element profiles with variable HFSE troughs, comparable to Phanerozoic low-TiO2 continental tholeiites. Time-corrected Nd isotopic compositions overlap, or are slightly below bulk Earth (εNd2500 Ma=+0.4 to −0.8), and yield TDM values (2.75–2.87Ga) comparable to those of igneous crust in the Hearne craton. Implied short residence times, along with the geological, geochemical and isotopic data, are interpreted to imply that parental magmas of the dykes were low-TiO2 tholeiites generated via contamination of primary, depleted N-MORB-like magmas by low-degree, calc-alkaline lamprophyre melts in the continental lithospheric mantle. The melts homogenized in chambers near the Moho and underwent extensive fractional crystallization (Pl+Cpx±Ol), and possibly minor assimilation of lower crust, prior to injection into the upper crust. Paucity of evidence for contemporaneous lithospheric rifting, homogeneous lithogeochemical and Nd isotopic compositions, and petrochemical variations distinct from the Matachewan and Mistassini swarms of the Superior Province suggest the Kaminak dykes are the magmatic products of a Late Archean–Early Paleoproterozoic mantle thermal anomaly that extended, but did not break apart the Hearne craton. The results of this study do not support direct correlation of the Kaminak and Matachewan or Mistassini dyke swarms. Further evaluation of the proposed linkage of the Hearne and Superior cratons prior to Nuna supercontinent assembly requires additional geochronological, lithogeochemical and radiogenic isotopic constraints.

WE‐A‐BRB‐02: Characterization of a New Cervical Applicator for Use with the Axxent 50kVp EBx Source

Purpose: To characterize the dosimetric properties of a new cervical applicator designed for the Xoft 50 kVp X‐ray Electronic Brachytherapy (eBx) system. Methods: The Axxent Cervical Applicator was developed to treat invasive cancer of the cervix using the existing Xoft Axxent Controller and X‐ray source. This applicator is a Henschke‐type design, consisting of a central tandem with ovoids mounted on the distal end of colpostats on either side. Filtration through the thin‐walled titanium tandems and colpostats allows for improved dose penetration, lowering the surface dose and reducing the dose to non‐target tissues. Dose profiles in a plane parallel to the straight, 15 degree, 30 degree, and 45 degree curved tandems were measured using GAFChromic EBT2 film. The tandem depth dose was calculated and the dose profile was compared to the distribution calculated using Varian BrachyVision treatment planning software. Results: The dose measured within 1.5 mm of the surface of the tandem was 6.4 +/‐ 0.4 times the dose at 2.0 cm for all curvature tandems measured. The maximum dose near the surface was 6.8 times the 2.0 cm dose. The dose rate in water for a nominal strength source at 2.0 cm from the centerline of the tandem was 24 +/‐ 3 Gy/hr. The ovoids produced 35 +/‐ 1 Gy/hr at a distance of 2.0 from the colpostat centerline. Dose profiles agree with expectations to within 10% over the majority of the treatment volume out to 2 cm. Conclusions: The Axxent Cervical Applicator can be used to treat cervical cancer using eBx with the Xoft X‐ray Source. Dose profiles measured for each tandem compare well with the profiles expected from the treatment planning software. Titanium filtering produces improved dose penetration resulting in a lower surface ‐ Point A dose ratio comparable to that of Ir‐192 and Cs‐ 137. Research supported by Xoft ‐ a subsidiary of iCAD

A dominant role for meiosis-specific 3′ RNA processing in controlling expression of a fission yeast cyclin gene

Meiotic gene regulation provides a rich source of insight into mechanisms of temporal control during development. We previously reported that accumulation of many meiotic mRNAs in fission yeast is governed by changes in 3' RNA processing and elucidated the molecular basis of this regulatory mechanism for an early meiotic gene. Here, we report that cleavage/polyadenylation is also the nexus of negative control for middle meiotic genes. Parallel profiles of splicing and polyadenylation are observed over a meiotic time course for both rem1 and spo4 but not for a constitutive control gene. Nevertheless, polyadenylation of rem1 transcripts is restricted to meiosis by a splicing-independent mechanism. Through systematic sequence substitutions, we identified a negative control region (NCR) located upstream of the rem1 transcription start site and found that it is required to block 3' RNA processing in proliferating cells. Ablation of the NCR relieves inhibition regardless of whether the intron is present, absent, or carries splice site mutations. Consistent with the previous report of a polypeptide encoded by the first exon of rem1, we discovered a second 3' processing site just downstream from the 5' splice site. Polyadenylation within the intron is activated concurrent with the downstream site during meiosis, is controlled by the NCR, and is enhanced when splicing is blocked via 5' junction or branch point mutations. Taken together, these data suggest a novel regulatory mechanism in which a 5' element modulates the dynamic interplay between splicing and polyadenylation.

Lidar sampling — Using an airborne profiler to estimate forest biomass in Hedmark County, Norway

An airborne profiling lidar was used to estimate total aboveground dry biomass, a surrogate for aboveground carbon stocks, for all land cover types in Hedmark County, Norway. One-hundred-five parallel profiling flight lines systematically spaced three km apart, totaling 8309km, were acquired to measure forest canopy height and density across the 27,390km2 County. Two sampling/estimation strategies were investigated; both use profiling lidar data to augment field data collected as part of a systematic network of Norwegian National Forest Inventory (NFI) ground plots. The two strategies include (1) a model-dependent (MD), two-phase approach which permits calculation of sampling and model error, and (2) a model-assisted (MA), probability-based, two-stage approach which utilizes asymptotically design-unbiased estimators. The lidar-augmented survey results from these two sampling strategies were compared to NFI ground estimates for the County. The MD estimate (38.88±1.07Mgha−1, one σ) differs from the NFI ground estimate (37.64±0.94Mgha−1) by +1.24Mgha−1 (+3.3%) and the MA (36.09±1.56Mgha−1) versus NFI difference is −1.55Mgha−1 (−4.1%). As expected, as smaller geographical areas are considered, lidar–NFI differences increase, and at the individual cover class level, MD lidar–ground absolute differences average 3.1Mgha−1 for the eight individual classes (8.2% of the County mean). The comparable MA lidar–ground average absolute difference for the individual cover classes is 4.3Mgha−1 (11.4% of the County mean). For all of Hedmark, in general, the MD approach agreed most closely with NFI estimates. The standard errors (SE) generated using the MA approach were, in general, 2–3 times larger than the MD SEs for productive forest classes at the County level, though neither lidar sample was consistently more precise than the NFI ground estimates alone. For Hedmark County, the results indicate that profiling lidar surveys can provide estimates comparable to ground surveys but, at this particular juncture, the MD and MA estimators did not improve the precision of adequately designed (in terms of sample size), probability-based ground samples. However when smaller political units are considered, i.e., as estimates are made on smaller and smaller subunits within Hedmark County, in general, MD-SE < NFI-SE ≪ MA-SE. Of the two designs considered in this study, the MD approach is most amenable to satellite lidar surveys since it does not require that profiling lidar satellite pulses intercept ground plots already established for a regional or national forest inventory. Direct comparisons of lidar and ground SEs are complicated by two factors: (1) the influence of treating both lidar and ground surveys as random samples when, in fact, they’re systematic, and (2) by the two stage/phase structure of the lidar surveys versus the single stage structure of the NFI. These results should be viewed as preliminary, subject to validation using a Monte Carlo simulator.

Barocco Padano 6: Atti del XIV Convegno internazionale sulla musica italiana nei secoli XVII–XVIII, Brescia, 16–18 Iuglio 2007 (review)

Barocco Padano 6: Atti del XIV Convegno internazionale sulla musica italiana nei secoli XVII-XVIII, Brescia, 16-18 Iuglio 2007. Edited by Alberto Colzani, Andrea Luppi, and Maurizio Padoan. (Contributi musicologici del Centro Ricerche dell'A.M.I.S.- Como.) Como: Antiquae Musicae Italicae Studiosi, 2010. [697 p. euro30.] Music examples, illustrations, indexes. This rich offering of studies emanating from the 2007 Brescia symposium spans studies exploring aspects of performance practice, examinations of genre, and focused historical, biographical, and bibliographical accounts of diverse northern Italian baroque repertories. Among other rewarding studies on aspects of modality, Gregory Barnett (Lo stile tonale seicentesco nella teoria settecentesca di Giuseppe Paolucci) presents particularly cogent reassessment of the relationship between modality and tonality in musical composition from the cinquecento through the eighteenth century. Barnett interrogates the notion and deployment of the term tuono as exposited by eighteenth-century musical theorist Giuseppe Paolucci as means to reevaluate and refine current scholarly interpretation of the emergence of functional tonality. In another treatment of modal concerns, Piotr Pozniak (Palestrina-Frescobaldi. Una melodia- due modi) discusses the divergent modal implications of parallel melodic profiles in Palestrina's O lux et decus Hispaniae and Frescobaldi's Canzon seconda (1615). Another major strand addressed in the collection involves the investigation of stylistic features in the motet form and the relation of this form to others like the cantata. A case in point, Reinmars Emans's Geistliche und weltliche Stilelemente in Giovanni Legrenzis Acclamationi divote voce sola op. collates secular and sacred stylistic aspects of Giovanni Legrenzi's op. 10 motets with his cantata output in order to extrapolate the degree of stylistic fluidity existing between the two genres. Stewart Carter (Musical Form and Liturgical Function in the Late-Seventeenth-Century Motet: the Case of Isabella Leonarda) utilizes the solo motets of Isabella Leonarda as case study to investigate late seicento stylistic trends and similarities across the secular-sacred continuum and to situate them within the frame of both liturgical and nonliturgical contexts. Examining features such as textual conceits, formal construction, and typology, Carter extrapolates the positioning of these works as a bridge between the sacred and secular realms (p. 295). Rodobaldo Tibaldi (Strumenti e forme strumentali nel mottetto italiano del primo Seicento: alcune riflessioni. Con una nota su Incipite Domino di Pietro Lappi) gives an account of the role of instrumental writing in the corpus of motet publications in the early seicento. If not thoroughly exhaustive, the treatment classifies various typologies of instrumental interpolation in the motet genre, namely mere instrumental substitution, added instrumental parts to motet structures, and full-fledged vocalinstrumental interaction. Tibaldi's appendix contains an incomplete list of prints containing motets with instrumental writing. Some very intriguing case studies on local repertories present new perspectives on the diverse and multivalent spectrum of style and performance practice in the northern Italian baroque. In his study L'oratorio di Papa Odescalchi. La congregazione filippina di Como e la musica, Francesco Bustaffa recreates the Como oratory, which came under the protectorship of Cardinal Benedetto Odescalchi, the soon-to-be Pope Innocent XI. The study considers the institution's musical life and the role of music in light of the pope's manifest inferiority in the patronage of the arts as contrasted to his immediate predecessors. The musical activity at the Ora - tory of Santa Maria della Steccata in Parma serves as the focal point for Maurizio Padoan's comprehensive study (Organici in Santa Maria della Steccata (1582-1630) e contesto. …

Abstract SY16-01: Clinical trial design to match patients to treatment based on molecular profiling of tumors

Abstract Recent advances in the systematic sequencing of cancer genomes have revealed that individual tumors frequently harbor “driver” somatic mutations that confer growth advantage and positive selection. Therefore, it seems likely that evaluating drug efficacy against tumors defined by a combination of histopathology and molecular genetic profiles will result in a greater therapeutic gain. The identification of specific somatic mutations and other genetic aberrations that drive cancers leave us on the threshold of a new era of “personalized cancer medicine,” in which specific biomarkers will be used to direct targeted agents only to those patients deemed most likely to respond, or avoided in those least likely to benefit. With the promise of personalized cancer medicine, there is an urgency to translate scientific discoveries in biomarker research rapidly and reliably to benefit patients, both in the setting of clinical trials and as standard of care. Recent examples of molecularly targeted agents which have obtained US FDA regulatory approval, such as vemurafenib for malignant melanoma with B-Raf V600E mutation and crizotinib for non-small cell lung carcinoma harboring EML4-ALK fusion, highlight that “driver” genomic alterations represent key predictors of clinical efficacy. The fundamental categories of cancer genomic aberrations including base mutation, copy number alteration and translocation/rearrangement, as well as epigenetic modifications of DNA or histones, are considered as being potential “druggable” characteristics of human malignancies. In the meantime, emerging technology renders parallel sequencing and profiling of such molecular characteristics increasingly feasible at point-of-care, using clinical tumor specimens. The optimal way to validate the personalized medicine approach remains a challenge for the clinical trialist. A tumor-based approach (e.g. BATTLE and I-SPY2 trials) requires access to different molecularly targeted agents, which can be difficult unless there is cooperation and collaboration of multiple industrial sponsors. A histology-independent, genomics-based approach is of interest but requires screening of large numbers of patients especially if mutations are uncommon in the selected tumor types for inclusion. Furthermore, it is possible that the functionality varies for the same mutation in different tumor types. Innovation in clinical trial designs is necessary to help address this impending paradigm shift in cancer treatment allocations. Additional considerations such as clonal evolution and tumor heterogeneity in malignancies, presence of crosstalks and emergence of resistance pathways, can further complicate the evaluation of personalized cancer medicine in the clinical trial setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY16-01. doi:1538-7445.AM2012-SY16-01

Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis

Cooperativity between oncogenic mutations is recognized as a fundamental feature of malignant transformation, and it may be mediated by synergistic regulation of the expression of pro- and antitumorigenic target genes. However, the mechanisms by which oncogenes and tumor suppressors coregulate downstream targets and pathways remain largely unknown. Here, we used ChIP coupled to massively parallel sequencing (ChIP-seq) and gene expression profiling in mouse prostates to identify direct targets of the tumor suppressor Nkx3.1. Further analysis indicated that a substantial fraction of Nkx3.1 target genes are also direct targets of the oncoprotein Myc. We also showed that Nkx3.1 and Myc bound to and crossregulated shared target genes in mouse and human prostate epithelial cells and that Nkx3.1 could oppose the transcriptional activity of Myc. Furthermore, loss of Nkx3.1 cooperated with concurrent overexpression of Myc to promote prostate cancer in transgenic mice. In human prostate cancer patients, dysregulation of shared NKX3.1/MYC target genes was associated with disease relapse. Our results indicate that NKX3.1 and MYC coregulate prostate tumorigenesis by converging on, and crossregulating, a common set of target genes. We propose that coregulation of target gene expression by oncogenic/tumor suppressor transcription factors may represent a general mechanism underlying the cooperativity of oncogenic mutations during tumorigenesis.

Jewish American Identity: Patterns of Centrality and Regard

Previous identity research has explored the presence and patterning of racial centrality and regard among African American, Latino, Asian, and multiracial Americans and their connection with important life outcomes. Extending that work, this study used cluster analysis to explore the unique combinations of centrality and regard among 174 Jewish American emerging adults (48 men, 125 women, 1 undifferentiated). Results parallel identity profiles observed among African American adolescents and adults, yet suggest potential age-related differences in profile content.

Topological complexity of frictional interfaces: friction networks

Abstract. Through research conducted in this study, a network approach to the correlation patterns of void spaces in rough fractures (crack type II) was developed. We characterized friction networks with several networks characteristics. The correlation among network properties with the fracture permeability is the result of friction networks. The revealed hubs in the complex aperture networks confirmed the importance of highly correlated groups to conduct the highlighted features of the dynamical aperture field. We found that there is a universal power law between the nodes' degree and motifs frequency (for triangles it reads T(k) &amp;amp;propto; kβ (β &amp;amp;approx; 2 ± 0.3)). The investigation of localization effects on eigenvectors shows a remarkable difference in parallel and perpendicular aperture patches. Furthermore, we estimate the rate of stored energy in asperities so that we found that the rate of radiated energy is higher in parallel friction networks than it is in transverse directions. The final part of our research highlights 4 point sub-graph distribution and its correlation with fluid flow. For shear rupture, we observed a similar trend in sub-graph distribution, resulting from parallel and transversal aperture profiles (a superfamily phenomenon).