Rationale for targeted therapies and potential role of pazopanib in advanced renal cell carcinoma

Advanced renal cell carcinoma (RCC) remains a challenging, major health problem. Recent advances in understanding the fundamental biology underlying one form of RCC, ie, clear cell (or conventional) RCC, have opened the door to a series of targeted agents, such as the tyrosine kinase inhibitors (TKIs), which have become the standard of care in managing advanced clear cell RCC. Among the newest of these agents to receive Food and Drug Administration approval in this disease is pazopanib. This review will summarize what is known about the fundamental biology that underlies clear cell RCC, the data surrounding the previously approved targeted agents for this disease, including not only the TKIs but also the mTOR inhibitors and the vascular endothelial growth factor-specific agent, bevacizumab, and the newest TKI, pazopanib. It will also explore the potential role for pazopanib relative to the other available agents and where it may fit into the armamentarium for treatment of advanced/metastatic RCC

Tensin1 expression and function in chronic obstructive pulmonary disease

open access articleChronic obstructive pulmonary disease (COPD) constitutes a major cause of morbidity and mortality. Genome wide association studies have shown significant associations between airflow obstruction or COPD with a non-synonymous SNP in the TNS1 gene, which encodes tensin1. However, the expression, cellular distribution and function of tensin1 in human airway tissue and cells are unknown. We therefore examined these characteristics in tissue and cells from controls and people with COPD or asthma. Airway tissue was immunostained for tensin1. Tensin1 expression in cultured human airway smooth muscle cells (HASMCs) was evaluated using qRT-PCR, western blotting and immunofluorescent staining. siRNAs were used to downregulate tensin1 expression. Tensin1 expression was increased in the airway smooth muscle and lamina propria in COPD tissue, but not asthma, when compared to controls. Tensin1 was expressed in HASMCs and upregulated by TGFβ1. TGFβ1 and fibronectin increased the localisation of tensin1 to fibrillar adhesions. Tensin1 and α-smooth muscle actin (αSMA) were strongly co-localised, and tensin1 depletion in HASMCs attenuated both αSMA expression and contraction of collagen gels. In summary, tensin1 expression is increased in COPD airways, and may promote airway obstruction by enhancing the expression of contractile proteins and their localisation to stress fibres in HASMCs

Optimal monetary policy rules in a rational expectations model of the Phillips curve

In this paper we construct a rational expectations model based on a Phillips curve that embodies persistence in inflation. As we assume that the central bank targets the natural rate of output, there is no inflation bias. We derive optimal monetary policy rules that are state-contingent and shock-dependent both in the case where the central bank follows a commitment strategy and where it pursues a discretionary procedure. Numerical solutions show that in the state-contingent part there always exists a tradeoff between these two optimal rules in that the commitment rule involves smaller expected deviations of inflation from its target but larger expected deviations of output from its target; in the shock-dependent part there can be situations in which the discretionary rule is more effective in reducing the impact of the random shock on inflation and less effective in reducing the random shock on output. Only in the latter case it is possible that one rule is superior; otherwise it is generally the case that a tradeoff exists between these two rules

Sedimentological Observations from the Tiskilwa Till, Illinois, and Sky Pilot Till, Manitoba

We present sedimentological observations from the Tiskilwa Till in northern Illinois, and the Sky Pilot Till in northern Manitoba, that indicate deposition of these tills by subglacial deformation. These generally homogenous tills grade downward into more heterogeneous tills that incorporate underlying sediment into their matrix, indicating entrainment of older sediments by sediment deformation. Deformed sand inclusions within these tills imply deformation of the tills and inclusions prior to deposition. The Tiskilwa Till has relatively high fabric strength throughout its thickness, whereas fabric strength in the Sky Pilot Till generally increases up-section in 2 to 3 m thick increments. Fabric orientations in both tills rotate up-section, possibly due to changes in ice-flow direction associated with the thickening and thinning of ice, and changes in ice-flow divide location. In both the Tiskilwa and Sky Pilot Tills, the change in fabric orientation occurs over intervals of ~1 m, suggesting that the maximum depth of deformation was ≤1 m insofar as any greater depth of deformation would have reoriented till fabric during maximum ice extent and retreat. In the case of the Sky Pilot Till, the up-section increase in macrofabric strength indicates that strain increased up-section. These data suggest that these tills were deposited in a time transgressive manner as strain migrated upwards with the delivery of new till either released from the ice base or advected from up-ice.Les observations sédimentologiques des tills de Tiskilwa, Illinois, et de Sky Pilot, Manitoba, indiquent que ces tills sont issus d’une déformation sous-glaciaire. Ces tills, généralement homogènes, deviennent hétérogènes vers leur base et ils incorporent du matériel sous-jacent dans leur matrice, ce qui indique un déplacement des sédiments plus âgés par déformation. La présence d’inclusions de sable dans ces tills impliquent leur déformation avant leur dépôt. Le till de Tiskilwa présente une matrice très cohérente sur toute son épaisseur tandis que celle du till de Sky Pilot augmente vers le haut tous les 2 ou 3 mètres. La rotation de l’orientation des matrices de ces deux tills est probablement associée aux changements de l’écoulement glaciaire liés à l’épaisseur de la glace et à la migration de la ligne de partage des marges glaciaires. Pour ces tills, le changement d’orientation du matériel se produit sur des intervalles d’environ 1 m, où la profondeur maximale de déformation devrait réorienter le matériel du till durant le maximum glaciaire et le retrait des glaces. Dans le cas du till de Sky Pilot, la section supérieure montre une augmentation dans la force de cohésion du matériel. Ces données indiquent que ces tills se sont déposés de manière diachronique, où la force de tension a migré vers le haut, entraînant le dépôt de matériel basal frais à partir de la base de la glace ou par advection depuis la glace

Noise Impacts from Professional Dog Grooming Forced-Air Dryers

This study was designed to measure the sound output of four commonly used brands of forced-air dryers used by dog groomers in the United States. Many dog groomers have questions about the effect of this exposure on their hearing, as well as on the hearing of the dogs that are being groomed. Readings taken from each dryer at 1 meter (the likely distance of the dryer from the groomer and the dog) showed average levels ranging from 105.5 to 108.3 dB SPL or 94.8 to 108.0 dBA. Using the 90 dBA criterion required by the US Occupational Safety and Health Administration, dog groomers/bathers are at risk if exposure to the lowest intensity dryer (94.8 dBA) exceeds 4 hours per day. If the more stringent 85 dBA criterion and 3 dB tradeoff is applied, less than one hour of exposure is permissible in an 8 hour day. Cautions are recommended for any persons exposed to noise from forced-air dryers

Short Subjects: Southeastern State Archives and Local Records: A Sampler

Georgia has 159 counties, 187 school systems, over 500 chartered municipalities and numerous local boards, commissions, and authorities. Many are experiencing dramatic growth, and that is straining their resources and necessitating change in their traditional operations. Preservation of the historical record is a responsibility recognized by Georgia\u27s local government officials. This fact is supported by requests to the Department of Archives and History, by laws passed by the legislature, and by recent studies

Polarized Raman Scattering Studies of Orientational Order in Uniaxial Liquid Crystalline Phases

The measurement of vibrational Raman depolarization ratios has been used to study molecular orientational order in uniaxial single domain nematic and smectic liquid crystal samples. This technique is demonstrated to obtain the same microscopic order parameter $\langle P_2 \rangle =1/2 \langle 3 cos^2\theta −1 \rangle$, where $\theta$ is the angle between a molecular long axis and the uniaxial direction, as other existing methods. In addition, the next higher moment of the orientational distribution function $\langle P_4 \rangle=1/8 \langle 35 cos^4 \theta−30 cos^2 \theta+3 \rangle$ has been measured for the first time. The physical basis, theoretical apparatus, and experimental methods necessary for the application of this technique are thoroughly detailed in this paper. Measurements are presented of the temperature dependence of $\langle P_2 \rangle$ and $\langle P_4 \rangle$ of N‐(p'‐butoxybenzylidene)‐p‐cyanoaniline (BBCA) dissolved in N‐(p'‐methoxybenzylidene)‐p‐cyanoaniline (MBBA) and of pure MBBA in the isotropic and nematic phases, and in the isotropic, nematic, smectic A, and smectic B phases of N‐(p'‐butoxybenzylidene)‐p‐n‐octylaniline (40.8). In the nematic phases the new quantitative information marks significant discrepancies with existing theories of nematic ordering. In the smectic phases the results show unambiguously the anticipated high degree of molecular orientational order.Engineering and Applied Science

Tumor Growth Increases Neuroinflammation, Fatigue and Depressive-like Behavior Prior to Alterations in Muscle Function

Cancer patients frequently suffer from fatigue, a complex syndrome associated with loss of muscle mass, weakness, and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, during treatment, and persists for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. Currently there are no effective treatments to reduce CRF. The aim of this study was to use a mouse model of tumor growth and discriminate between two main components of fatigue: loss of muscle mass/function and altered mood/motivation. Here we show that tumor growth increased fatigue- and depressive-like behaviors, and reduced body and muscle mass. Decreased voluntary wheel running activity (VWRA) and increased depressive-like behavior in the forced swim and sucrose preference tests were evident in tumor-bearing mice within the first two weeks of tumor growth and preceded the loss of body and muscle mass. At three weeks, tumor-bearing mice had reduced grip strength but this was not associated with altered expression of myosin isoforms or impaired contractile properties of muscles. These increases in fatigue and depressive-like behaviors were paralleled by increased expression of IL-1β mRNA in the cortex and hippocampus. Minocycline administration reduced tumor-induced expression of IL-1β in the brain, reduced depressive-like behavior, and improved grip strength without altering muscle mass. Taken together, these results indicate that neuroinflammation and depressed mood, rather than muscle wasting, contribute to decreased voluntary activity and precede major changes in muscle contractile properties with tumor growth

Far‐field lithospheric deformation in Tibet during continental collision

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95177/1/tect2049.pd

Aboveground Total and Green Biomass of Dryland Shrub Derived from Terrestrial Laser Scanning

Sagebrush (Artemisia tridentata), a dominant shrub species in the sagebrush-steppe ecosystem of the western US, is declining from its historical distribution due to feedbacks between climate and land use change, fire, and invasive species. Quantifying aboveground biomass of sagebrush is important for assessing carbon storage and monitoring the presence and distribution of this rapidly changing dryland ecosystem. Models of shrub canopy volume, derived from terrestrial laser scanning (TLS) point clouds, were used to accurately estimate aboveground sagebrush biomass. Ninety-one sagebrush plants were scanned and sampled across three study sites in the Great Basin, USA. Half of the plants were scanned and destructively sampled in the spring (n = 46), while the other half were scanned again in the fall before destructive sampling (n = 45). The latter set of sagebrush plants was scanned during both spring and fall to further test the ability of the TLS to quantify seasonal changes in green biomass. Sagebrush biomass was estimated using both a voxel and a 3-D convex hull approach applied to TLS point cloud data. The 3-D convex hull model estimated total and green biomass more accurately (R2 = 0.92 and R2 = 0.83, respectively) than the voxel-based method (R2 = 0.86 and R2 = 0.73, respectively). Seasonal differences in TLS-predicted green biomass were detected at two of the sites (p \u3c 0.001 and p = 0.029), elucidating the amount of ephemeral leaf loss in the face of summer drought. The methods presented herein are directly transferable to other dryland shrubs, and implementation of the convex hull model with similar sagebrush species is straightforward