Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize ...through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the ocular vasculature. Metastatic Rb patients have very high mortality rates. While current therapy for Rb is directed toward blocking tumor cell division and tumor growth, there are no specific treatments targeted to block Rb metastasis. Two such targets are matrix metalloproteinases-2 and -9 (MMP-2, -9), which degrade extracellular matrix as a prerequisite for cellular invasion and have been shown to be involved in other types of cancer metastasis. Cancer Clinical Trials with an anti-MMP-9 therapeutic antibody were recently initiated, prompting us to investigate the role of MMP-2, -9 in Rb metastasis.
We compare MMP-2, -9 activity in two well-studied Rb cell lines: Y79, which exhibits high metastatic potential and Weri-1, which has low metastatic potential. The effects of inhibitors of MMP-2 (ARP100) and MMP-9 (AG-L-66085) on migration, angiogenesis, and production of immunomodulatory cytokines were determined in both cell lines using qPCR, and ELISA. Cellular migration and potential for invasion were evaluated by the classic wound-healing assay and a Boyden Chamber assay.
Our results showed that both inhibitors had differential effects on the two cell lines, significantly reducing migration in the metastatic Y79 cell line and greatly affecting the viability of Weri-1 cells. The MMP-9 inhibitor (MMP9I) AG-L-66085, diminished the Y79 angiogenic response. In Weri-1 cells, VEGF was significantly reduced and cell viability was decreased by both MMP-2 and MMP-9 inhibitors. Furthermore, inhibition of MMP-2 significantly reduced secretion of TGF-β1 in both Rb models.
Collectively, our data indicates MMP-2 and MMP-9 drive metastatic pathways, including migration, viability and secretion of angiogenic factors in Rb cells. These two subtypes of matrix metalloproteinases represent new potential candidates for targeted anti-metastatic therapy for Rb.
The definitive cardiac outflow channels have three components: the intrapericardial arterial trunks; the arterial roots with valves; and the ventricular outflow tracts (OFTs). We studied the normal ...and abnormal development of the most distal of these, the arterial trunks, comparing findings in mice and humans.
Using lineage tracing and three-dimensional visualization by episcopic reconstruction and scanning electron microscopy, we studied embryonic day 9.5-12.5 mouse hearts, clarifying the development of the OFTs distal to the primordia of the arterial valves. We characterize a transient aortopulmonary (AP) foramen, located between the leading edge of a protrusion from the dorsal wall of the aortic sac and the distal margins of the two outflow cushions. The foramen is closed by fusion of the protrusion, with its cap of neural crest cells (NCCs), with the NCC-filled cushions; the resulting structure then functioning transiently as an AP septum. Only subsequent to this closure is it possible to recognize, more proximally, the previously described AP septal complex. The adjacent walls of the intrapericardial trunks are derived from the protrusion and distal parts of the outflow cushions, whereas the lateral walls are formed from intrapericardial extensions of the pharyngeal mesenchyme derived from the second heart field.
We provide, for the first time, objective evidence of the mechanisms of closure of an AP foramen that exists distally between the lumens of the developing intrapericardial arterial trunks. Our findings provide insights into the formation of AP windows and the variants of common arterial trunk.
We used a genetic lineage-labeling system to establish the material contributions of the progeny of 3 specific cell types to the cardiac valves. Thus, we labeled irreversibly the myocardial ...(alphaMHC-Cre+), endocardial (Tie2-Cre+), and neural crest (Wnt1-Cre+) cells during development and assessed their eventual contribution to the definitive valvar complexes. The leaflets and tendinous cords of the mitral and tricuspid valves, the atrioventricular fibrous continuity, and the leaflets of the outflow tract valves were all found to be generated from mesenchyme derived from the endocardium, with no substantial contribution from cells of the myocardial and neural crest lineages. Analysis of chicken-quail chimeras revealed absence of any substantial contribution from proepicardially derived cells. Molecular and morphogenetic analysis revealed several new aspects of atrioventricular valvar formation. Marked similarities are seen during the formation of the mural leaflets of the mitral and tricuspid valves. These leaflets form by protrusion and growth of a sheet of atrioventricular myocardium into the ventricular lumen, with subsequent formation of valvar mesenchyme on its surface rather than by delamination of lateral cushions from the ventricular myocardial wall. The myocardial layer is subsequently removed by the process of apoptosis. In contrast, the aortic leaflet of the mitral valve, the septal leaflet of the tricuspid valve, and the atrioventricular fibrous continuity between these valves develop from the mesenchyme of the inferior and superior atrioventricular cushions. The tricuspid septal leaflet then delaminates from the muscular ventricular septum late in development.
Core Ideas
Vegetative buffer strip (VBS) soils sorb imidacloprid (ICD) more than cropland soils due to greater SOC.
Riparian VBS soils retard ICD leaching more than cropland and grass VBS soils.
...Results indicate ICD sorption to two or three sites, likely through different mechanisms.
A VBS may reduce the mobility of ICD in agroecosystems.
An understanding of neonicotinoid sorption and transport in soil is critical for determining and mitigating environmental risk associated with the most widely used class of insecticides. The objective of this study was to evaluate mobility and transport of the neonicotinoid imidacloprid (ICD) in soils collected from cropland, grass vegetative buffer strip (VBS), and riparian VBS soils. Soils were collected at six randomly chosen sites within grids that encompassed all three land uses. Single‐point equilibrium batch sorption experiments were conducted using radio‐labeled (14C) ICD to determine solid–solution partition coefficients (Kd). Column experiments were conducted using soils collected from the three vegetation treatments at one site by packing soil into glass columns. Water flow was characterized by applying Br− as a nonreactive tracer. A single pulse of 14C‐ICD was then applied, and ICD leaching was monitored for up to 45 d. Bromide and ICD breakthrough curves for each column were simulated using CXTFIT and HYDRUS‐1D models. Sorption results indicated that ICD sorbs more strongly to riparian VBS (Kd = 22.6 L kg−1) than crop (Kd = 11.3 L kg−1) soils. Soil organic C was the strongest predictor of ICD sorption (p < 0.0001). The column transport study found mean peak concentrations of ICD at 5.83, 10.84, and 23.8 pore volumes for crop, grass VBS, and riparian VBS soils, respectively. HYDRUS‐1D results indicated that the two‐site, one‐rate linear reversible model best described results of the breakthrough curves, indicating the complexity of ICD sorption and demonstrating its mobility in soil. Greater sorption and longer retention by the grass and riparian VBS soils than the cropland soil suggests that VBS may be a viable means to mitigate ICD loss from agroecosystems, thereby preventing ICD transport into surface water, groundwater, or drinking water resources.
...in the definitive heart, the proximal parts of the aorta and pulmonary trunk, along with the sinuses of the arterial roots and the subpulmonary infundibulum, possess their own discrete walls, ...separated by extra-cardiac space. Appreciation of the precise structure of these separating walls underpins the understanding of the developmental steps involved in their formation. ...careful examination of the heart subsequent to separation of the chambers shows that several of the structures usually described as "septums" in classical accounts).
Knowledge of the vegetation and environment of eastern North America during the Last Glacial Maximum (LGM) is important to understanding postglacial vegetational and biogeographic dynamics, assessing ...climate sensitivity, and constraining and evaluating earth-system models. Our understanding of LGM conditions in the region has been hampered by low site density, problems of data quality (particularly dating), and the possibility that LGM vegetation and climate lacked modern analogs. In order to generate improved reconstructions of LGM vegetation and environment, we assembled pollen and plant macrofossil data from 21 and 17 well-dated LGM sites, respectively. All sites have assemblages within the LGM timespan of 21,000±1500 calendar yr BP. Based on these data, we prepared maps of isopolls, macrofossil presence/absence, pollen-analogs, biomes, inferred mean January and July temperatures and mean annual precipitation for the LGM. Tundra and open
Picea-dominated forest grew along the Laurentide ice sheet, with tundra predominantly in the west. In the east,
Pinus-dominated vegetation (mainly
P. banksiana with local
P. resinosa and
P. strobus) occurred extensively to 34°N and possibly as far south as 30°N.
Picea glauca and a now-extinct species,
P. critchfieldii, occurred locally.
Picea-dominated forest grew in the continental interior, with temperate hardwoods (
Quercus,
Carya,
Juglans,
Liriodendron,
Fagus,
Ulmus) growing locally near the Lower Mississippi Valley at least as far north as 35°N.
Picea critchfieldii was the dominant species in this region. The Florida peninsula was occupied by open vegetation with warm-temperate species of
Pinus. Eastern Texas was occupied by open vegetation with at least local
Quercus and
Picea. Extensive areas of peninsular Florida and the continental interior had vegetation unmatched by any modern pollen samples. The paleovegetational data indicate more extensive cooling in eastern North America at the LGM than simulated by either the NCAR CCM0 or CCM1 climate models. The occurrence of cool-temperate conifers and hardwoods as far north as 34-35°N, however, indicates less severe cooling than some previous reconstructions. Paleoclimate inferences for the LGM are complicated by lowered atmospheric CO
2 concentrations, which may be responsible for the open nature and dominance of conifers in LGM vegetation.
The developmental anatomy of the ventricular outlets and intrapericardial arterial trunks is a source of considerable confusion. First, major problems exist because of the multiple names and ...definitions used to describe this region of the heart as it develops. Second, there is no agreement on the boundaries of the described components, nor on the number of ridges or cushions to be found dividing the outflow tract, and the pattern of their fusion. Evidence is also lacking concerning the role of the fused cushions relative to that of the so‐called aortopulmonary septum in separating the intrapericardial components of the great arterial trunks. In this review, we discuss the existing problems, as we see them, in the context of developmental and postnatal morphology. We concentrate, in particular, on the changes in the nature of the wall of the outflow tract, which is initially myocardial throughout its length. Key features that, thus far, do not seem to have received appropriate attention are the origin, and mode of separation, of the intrapericardial portions of the arterial trunks, and the formation of the walls of the aortic and pulmonary valvar sinuses. Also as yet undetermined is the formation of the free‐standing muscular subpulmonary infundibulum, the mechanism of its separation from the aortic valvar sinuses, and its differentiation, if any, from the muscular ventricular outlet septum.
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