Author Correction: CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.

Model-Based Recommendations for Optimal Surgical Placement of Epiretinal Implants.

A major limitation of current electronic retinal implants is that in addition to stimulating the intended retinal ganglion cells, they also stimulate passing axon fibers, producing perceptual 'streaks' that limit the quality of the generated visual experience. Recent evidence suggests a dependence between the shape of the elicited visual percept and the retinal location of the stimulating electrode. However, this knowledge has yet to be incorporated into the surgical placement of retinal implants. Here we systematically explored the space of possible implant configurations to make recommendations for optimal intraocular positioning of the electrode array. Using a psychophysically validated computational model, we demonstrate that better implant placement has the potential to reduce the spatial extent of axonal activation in existing implant users by up to ~55%. Importantly, the best implant location, as inferred from a population of simulated virtual patients, is both surgically feasible and is relatively stable across individuals. This study is a first step towards the use of computer simulations in patient-specific planning of retinal implant surgery.

Structure based design of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen.

Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo.

A lack of experience-dependent plasticity after more than a decade of recovered sight.

In 2000, monocular vision was restored to M. M., who had been blind between the ages of 3 and 46 years. Tests carried out over 2 years following the surgery revealed impairments of 3-D form, object, and face processing and an absence of object- and face-selective blood-oxygen-level-dependent responses in ventral visual cortex. In the present research, we reexamined M. M. to test for experience-dependent recovery of visual function. Behaviorally, M. M. remains impaired in 3-D form, object, and face processing. Accordingly, we found little to no evidence of the category-selective organization within ventral visual cortex typically associated with face, body, scene, or object processing. We did observe remarkably normal object selectivity within lateral occipital cortex, consistent with M. M.'s previously reported shape-discrimination performance. Together, these findings provide little evidence for recovery of high-level visual function after more than a decade of visual experience in adulthood.

Temporal interactions during paired-electrode stimulation in two retinal prosthesis subjects.

PURPOSE: Since 2002, six blind patients have undergone implantation of an epiretinal 4 × 4 electrode array designed to directly stimulate the remaining cells of the retina after severe photoreceptor degeneration due to retinitis pigmentosa. This study was conducted to investigate how the brightness of percepts is affected by pulse timing across electrodes in two of these patients. METHODS: Subjects compared the perceived brightness of a standard stimulus (synchronous pulse trains presented across pairs of electrodes) to the perceived brightness of a test stimulus (pulse trains across the electrode pair phase shifted by 0.075, 0.375, 1.8, or 9 ms). The current amplitude necessary for each phase-shifted test stimulus to match the brightness of the standard was determined. RESULTS: Depending on the electrode pair, interactions between electrodes were either facilitatory (the perceived brightness produced by stimulating the pair of electrodes was greater than that produced by stimulating either electrode alone) or suppressive (the perceived brightness produced by stimulating the pair of electrodes was less than that produced by stimulating either electrode alone). The amount of interaction between electrodes decreased as a function of increased separation both in time (the phase-shift between pulse trains) and space (center-to-center distance between the electrode pair). CONCLUSIONS: For visual prostheses to represent visual scenes that are changing in both space and time requires the development of spatiotemporal models describing the effects of stimulation across multiple electrodes. During multielectrode stimulation, interactions between electrodes have a significant influence on subjective brightness that includes both facilitatory and suppressive effects, and these interactions can be described with a simple computational model. (ClinicalTrials.gov number, NCT00279500.).