Bowman Birk Inhibitor Concentrate and Oral Leukoplakia: A Randomized Phase IIb Trial

Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non-BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering Green chemoprevention. © 2013 AACR

Role of Muscarinic Acetylcholine Receptors in Serial Feature-Positive Discrimination Task during Eyeblink Conditioning in Mice.

We investigated the role of muscarinic acetylcholine receptors (mAChRs) in eyeblink serial feature-positive discrimination learning in mice using the mAChR antagonist. A 2-s light cue was delivered 5 or 6 s before the presentation of a 350-ms tone paired with a 100-ms periorbital electrical shock (cued trial) but not before the tone-alone presentation (non-cued trial). Mice received 30 cued and 30 non-cued trials each day in a random order. We found that saline-injected control mice were successfully discriminating between cued and non-cued trials within a few days of conditioning. The mice responded more frequently to the tone in cued trials than in non-cued trials. Analysis of conditioned response (CR) dynamics revealed that the CR onset latency was shorter in cued trials than in non-cued trials, despite the CR peak amplitude not differing significantly between the two conditions. In contrast, scopolamine-injected mice developed an equal number of CRs with similar temporal patterns irrespective of the presence of the cue during the 7 days of conditioning, indicating in a failure to acquire conditional discrimination. In addition, the scopolamine administration to the control mice after they had successfully acquired discrimination did not impair the conditional discrimination and expression of pre-acquired CR. These results suggest that mAChRs may play a pivotal role in memory formation in the conditional brain state associated with the feature cue; however they are unlikely to be involved in the development of discrimination after conditional memory had formed in the serial feature-positive discrimination task during eyeblink conditioning

Left−Right Asymmetry Defect in the Hippocampal Circuitry Impairs Spatial Learning and Working Memory in iv Mice

Although left-right (L−R) asymmetry is a fundamental feature of higher-order brain function, little is known about how asymmetry defects of the brain affect animal behavior. Previously, we identified structural and functional asymmetries in the circuitry of the mouse hippocampus resulting from the asymmetrical distribution of NMDA receptor GluR ε2 (NR2B) subunits. We further examined the ε2 asymmetry in the inversus viscerum (iv) mouse, which has randomized laterality of internal organs, and found that the iv mouse hippocampus exhibits right isomerism (bilateral right-sidedness) in the synaptic distribution of theε2 subunit, irrespective of the laterality of visceral organs. To investigate the effects of hippocampal laterality defects on higher-order brain functions, we examined the capacity of reference and working memories of iv mice using a dry maze and a delayed nonmatching-to-position (DNMTP) task, respectively. The iv mice improved dry maze performance more slowly than control mice during acquisition, whereas the asymptotic level of performance was similar between the two groups. In the DNMTP task, the iv mice showed poorer accuracy than control mice as the retention interval became longer. These results suggest that the L−R asymmetry of hippocampal circuitry is critical for the acquisition of reference memory and the retention of working memory

Hydrogeological system of erosional convergent margins and its influence on tectonics and interplate seismogenesis

[1] Fluid distribution in convergent margins is by most accounts closely related to tectonics. This association has been widely studied at accretionary prisms, but at half of the Earth's convergent margins, tectonic erosion grinds down overriding plates, and here fluid distribution and its relation to tectonics remain speculative. Here we present a new conceptual model for the hydrological system of erosional convergent margins. The model is based largely on new data and recently published observations from along the Middle America Trench offshore Nicaragua and Costa Rica, and it is consistent with observations from other erosional margins. The observations indicate that erosional margins possess previously unrecognized distinct hydrogeological systems: Most fluid contained in the sediment pores and liberated by early dehydration reactions drains from the plate boundary through a fractured upper plate to seep at the seafloor across the slope, rather than migrating along the décollement toward the deformation front as described for accretionary prisms. The observations indicate that the relative fluid abundance across the plate-boundary fault zone and fluid migration influence long-term tectonics and the transition from aseismic to seismogenic behavior. The segment of the plate boundary where fluid appears to be more abundant corresponds to the locus of long-term tectonic erosion, where tectonic thinning of the overriding plate causes subsidence and the formation of the continental slope. This correspondence between observations indicates that tectonic erosion is possibly linked to the migration of overpressured fluids into the overriding plate. The presence of overpressured fluids at the plate boundary is compatible with the highest flow rates estimated at slope seeps. The change from aseismic to seismogenic behavior along the plate boundary of the erosional margin begins where the amount of fluid at the fault declines with depth, indicating a control on interplate earthquakes. A previously described similar observation along accreting plate boundaries strongly indicates that fluid abundance exerts a first-order control on interplate seismogenesis at all types of subduction zones. We hypothesize that fluid depletion with depth increases grain-to-grain contact, increasing effective stress on the fault, and modifies fault zone architecture from a thick fault zone to a narrower zone of localized slip

The dynamical control of subduction parameters on surface topography

he long-wavelength surface deflection of Earth's outermost rocky shell is mainly controlled by large-scale dynamic processes like isostasy or mantle flow. The largest topographic amplitudes are therefore observed at plate boundaries due to the presence of large thermal heterogeneities and strong tectonic forces. Distinct vertical surface deflections are particularly apparent at convergent plate boundaries mostly due to the convergence and asymmetric sinking of the plates. Having a mantle convection model with a free surface that is able to reproduce both realistic single-sided subduction and long-wavelength surface topography self-consistently, we are now able to better investigate this interaction. We separate the topographic signal into distinct features and quantify the individual topographic contribution of several controlling subduction parameters. Results are diagnosed by splitting the topographic signal into isostatic and residual components, and by considering various physical aspects like viscous dissipation during plate bending. Performing several systematic suites of experiments, we are then able to quantify the topographic impact of the buoyancy, rheology, and geometry of the subduction-zone system to each and every topographic feature at a subduction zone and to provide corresponding scaling laws. We identify slab dip and, slightly less importantly, slab buoyancy as the major agents controlling surface topography at subduction zones on Earth. Only the island-arc high and the back-arc depression extent are mainly controlled by plate strength. Overall, his modeling study sets the basis to better constrain deep-seated mantle structures and their physical properties via the observed surface topography on present-day Earth and back through time

Locked and loading megathrust linked to active subduction beneath the Indo-Burman Ranges

The Indo-Burman mountain rangesmarkthe boundary between the Indian and Eurasian plates, north of the Sumatra–Andaman subduction zone. Whether subduction still occurs along this subaerial section of the plate boundary, with 46mm/yr of highly oblique motion, is contentious. About 21mm/yr of shear motion is taken up along the Sagaing Fault, on the eastern margin of the deformation zone. It has been suggested that the remainder of the relative motion is taken up largely or entirely by horizontal strike-slip faulting and that subduction has stopped. Here we present GPS measurements of plate motions in Bangladesh, combined with measurements from Myanmar and northeast India, taking advantage of a more than 300 km subaerial accretionary prism spanning the Indo-Burman Ranges to the Ganges–Brahmaputra Delta. They reveal 13–17mm/yr of plate convergence on an active, shallowly dipping and locked megathrust fault. Most of the strike-slip motion occurs on a few steep faults, consistent with patterns of strain partitioning in subduction zones. Our results strongly suggest that subduction in this region is active, despite the highly oblique plate motion and thick sediments. We suggest that the presence of a locked megathrust plate boundary represents an underappreciated hazard in one of the most densely populated regions of the world

Geological interpretation of volcanism and segmentation of the Mariana back-arc spreading center between 12.7°N and 18.3°N

The relationships between tectonic processes, magmatism, and hydrothermal venting along ∼600 km of the slow-spreading Mariana back-arc between 12.7°N and 18.3°N reveal a number of similarities and differences compared to slow-spreading mid-ocean ridges. Analysis of the volcanic geomorphology and structure highlights the complexity of the back-arc spreading center. Here, ridge segmentation is controlled by large-scale basement structures that appear to predate back-arc rifting. These structures also control the orientation of the chains of cross-arc volcanoes that characterize this region. Segment-scale faulting is oriented perpendicular to the spreading direction, allowing precise spreading directions to be determined. Four morphologically distinct segment types are identified: dominantly magmatic segments (Type I); magmatic segments currently undergoing tectonic extension (Type II); dominantly tectonic segments (Type III); and tectonic segments currently undergoing magmatic extension (Type IV). Variations in axial morphology (including eruption styles, neovolcanic eruption volumes, and faulting) reflect magma supply, which is locally enhanced by cross-arc volcanism associated with N-S compression along the 16.5°N and 17.0°N segments. In contrast, cross-arc seismicity is associated with N-S extension and increased faulting along the 14.5°N segment, with structures that are interpreted to be oceanic core complexes—the first with high-resolution bathymetry described in an active back-arc basin. Hydrothermal venting associated with recent magmatism has been discovered along all segment types

Androgen receptor expression predicts breast cancer survival: the role of genetic and epigenetic events

Background: Breast cancer outcome, including response to therapy, risk of metastasis and survival, is difficult to predict using currently available methods, highlighting the urgent need for more informative biomarkers. Androgen receptor (AR) has been implicated in breast carcinogenesis however its potential to be an informative biomarker has yet to be fully explored. In this study, AR protein levels were determined in a cohort of 73 Grade III invasive breast ductal adenocarcinomas

Subducting slabs: jellyfishes in the Earth mantle

International audienceThe constantly improving resolution of geophysical data, seismic tomography and seismicity in particular, shows that the lithosphere does not subduct as a slab of uniform thickness but is rather thinned in the upper mantle and thickened around the transition zone between the upper and lower mantle. This observation has traditionally been interpreted as evidence for the buckling and piling of slabs at the boundary between the upper and lower mantle, where a strong contrast in viscosity may exist and cause resistance to the penetration of slabs into the lower mantle. The distribution and character of seismicity reveal, however, that slabs undergo vertical extension in the upper mantle and compression near the transition zone. In this paper, we demonstrate that during the subduction process, the shape of low viscosity slabs (1 to 100 times more viscous than the surrounding mantle) evolves toward an inverted plume shape that we coin jellyfish. Results of a 3D numerical model show that the leading tip of slabs deform toward a rounded head skirted by lateral tentacles that emerge from the sides of the jellyfish head. The head is linked to the body of the subducting slab by a thin tail. A complete parametric study reveals that subducting slabs may achieve a variety of shapes, in good agreement with the diversity of natural slab shapes evidenced by seismic tomography. Our work also suggests that the slab to mantle viscosity ratio in the Earth is most likely to be lower than 100. However, the sensitivity of slab shapes to upper and lower mantle viscosities and densities, which remain poorly constrained by independent evidence, precludes any systematic deciphering of the observations