The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6 months. Label-retaining cancer cells (LRCC) represent a novel subpopulation of cancer stem cells (CSC). The objective was to test whether LRCC are resistant to sorafenib.
Methods
We tested human HCC derived LRCC and non-LRCC before and after treatment with sorafenib.
Results
LRCC derived from human HCC are relatively resistant to sorafenib. The proportion of LRCC in HCC cell lines is increased after sorafenib while the general population of cancer cells undergoes growth suppression. We show that LRCC demonstrate improved viability and toxicity profiles, and reduced apoptosis, over non-LRCC. We show that after treatment with sorafenib, LRCC upregulate the CSC marker aldehyde dehydrogenase 1 family, wingless-type MMTV-integration-site family, cell survival and proliferation genes, and downregulate apoptosis, cell cycle arrest, cell adhesion and stem cells differentiation genes. This phenomenon was accompanied by non-uniform activation of specific isoforms of the sorafenib target proteins extracellular-signal-regulated kinases and v-akt-murine-thymoma-viral-oncogene homologue (AKT) in LRCC but not in non-LRCC. A molecular pathway map for sorafenib treated LRCC is proposed.
Conclusions
Our results suggest that HCC derived LRCC are relatively resistant to sorafenib. Since LRCC can generate tumours with as few as 10 cells, our data suggest a potential role for these cells in disease recurrence. Further investigation of this phenomenon might provide novel insights into cancer biology, cancer recurrence and drug resistance with important implications for the development of novel cancer therapies based on targeting LRCC.
To interpret individual results from automated perimeters, a normative database must be developed. Typically, a set of criteria determines those subjects that may be included in the database. This study examined whether a criterion of normal performance on an established perimeter generates a subgroup with supernormal perimetric performance.The right-eye perimetric results of 100 subjects were analyzed. Subjects had visual acuities of 6/12 or better, no history of eye disease, and normal slit lamp biomicroscopic and ophthalmoscopic examinations. Subjects performed test-retest visual field examinations on a Humphrey Field Analyzer (HFA) 24-2 test (Zeiss Humphrey Systems, Dublin, CA), and on a custom frequency-doubling (FD) perimeter with targets spaced in the same 24-2 pattern.Test-retest correlation (Spearman rank correlation coefficients, rs) for mean defect (MD) and pattern SD (PSD) were 0.65 and 0.40 (HFA), and 0.82 and 0.39 (FD perimeter). Three subjects with HFA MDs in the lower 5% had similarly low MDs on retest, whereas no subject was common between the test and retest for the lower 5% of HFA PSD. Correlation between the HFA and FD test results were 0.41 (MD) and 0.05 (PSD). Based on these correlations, the bias introduced into perimetric probability limits were determined, by using Monte Carlo simulations.Although a criterion of a normal MD may produce a subpopulation with supernormal perimetric performance, a criterion of a normal PSD is less likely to do so. Also, a criterion on one test type is less likely to create a supernormal group on a different test type. The bias introduced into perimetric probability limits is small.
Previous work has suggested that sensitivities measured on the iCare MAIA and Nidek MP-1 microperimeters differ systematically, although it is unclear whether one or both devices are inaccurate. Here, we assess the discrepancy between these two instruments as well as with a rigorous reference standard.Fifteen healthy participants underwent visual field testing on the MAIA and MP-1 microperimeters. Results were compared to a reference measure of increment thresholds on a laboratory-based, calibrated computer monitor system using the same background luminance and target size. Discrepancies were assessed as a function of eccentricity along the vertical meridian. Differences in decibels (dB) due to differences in the maximum stimulus luminance between devices were accounted for mathematically.The mean sensitivity measured with the MAIA was <1 dB lower than laboratory-based measures, which was statistically significant but of limited clinical importance. In contrast, the mean sensitivity measured with the MP-1 was >8 dB lower than the laboratory measures. The difference was greater for an eccentric superior retinal location, in contrast to what would be predicted if the discrepancy was due to a ceiling effect caused by the MP-1's limited dynamic range.While MAIA measurements showed low bias compared with our rigorously determined reference standard, the MP-1 showed large discrepancies that could not be explained purely by the limited dynamic range of the instrument. MAIA and MP-1 sensitivity values cannot be compared directly, and caution is advised when assessing absolute sensitivities or eccentricity effects in the extensive MP-1 literature.
A multiple transputer system is demonstrated to work in handling adaptive deconvolution smoothing. The cooperation between its four units allow the separate tasks of data I/O, parameter estimation and smoothing filter to proceed in parallel, with the different data items and parameters being passed across the transputer channels connecting the four units. Although the performance of the transputer system was found to be slow compared to the TMS32010 system, the hardware and software flexibility provided by the transputer did allow the easy integration of a supervisor into the system. The use of a supervisor is shown to enhance the robustness of an adaptive signal processor. From the evaluation, the transputer would be well suited to applications within adaptive control. Future research will consider the application of supervisor transputers to adaptive control problems. >
The perception of motion is considered critical for performing everyday tasks, such as locomotion and driving, and relies on different levels of visual processing. However, it is unclear whether healthy aging differentially affects motion processing at specific levels of processing, or whether performance at central and peripheral spatial eccentricities is altered to the same extent. The aim of this study was to explore the effects of aging on hierarchically different components of motion processing: the minimum displacement of dots to perceive motion (Dmin), the minimum contrast and speed to determine the direction of motion, spatial surround suppression of motion, global motion coherence (translational and radial), and biological motion. We measured motion perception in both central vision and at 15° eccentricity, comparing performance in 20 older (60–79 years) and 20 younger (19–34 years) adults. Older adults had significantly elevated thresholds, relative to younger adults, for motion contrast, speed, Dmin, and biological motion. The differences between younger and older participants were of similar magnitude in central and peripheral vision, except for surround suppression of motion, which was weaker in central vision for the older group, but stronger in the periphery. Our findings demonstrate that the effects of aging are not uniform across all motion tasks. Whereas the performance of some tasks in the periphery can be predicted from the results in central vision, the effects of age on surround suppression of motion shows markedly different characteristics between central and peripheral vision.
Abstract Purpose Expertise in viewing medical images is thought to be due to the ability to process holistic image information. Eye care clinicians can inspect photographs of the retina to search for signs of disease. However, they commonly also view the eye in vivo using the restricted view of a slit lamp, which removes the potential benefits of holistic processing. We investigated how expert and novice clinicians inspect the fundus using these two methods. Methods Twenty clinicians (10 experienced, 10 novices) examined 64 photographs of human retinae. Each participant viewed half of the images as fundus photographs while having their eye position recorded. The other half were viewed via a simple slit lamp simulation, whereby a computer mouse was used to control the position of a viewing window that revealed the underlying fundus photograph. Results Experienced clinicians made decisions significantly faster than novices, with faster decision‐making when viewing the fundus photograph compared to via the slit lamp simulation. The distribution of inspection was similar, although novices spent longer examining the optic nerve head than other regions. Experienced clinicians showed significantly earlier inspection of the optic nerve head when it was judged to be unhealthy. Conclusions Our results support the idea that experienced eyecare clinicians use holistic image information, if available, when inspecting the fundus. This was particularly prominent for the optic nerve head region, which was the region that novices spent most of their time examining. Holistic processing benefits were only present in experts’ free‐viewing fundus photographs; the limited field of view from the slit lamp disrupts such global image benefits.
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