Note and Comment

Termination of the Liability as Common Carrier; Is a Vendee Seeking Specific Performance Entitled to Compensation for the Inchoate Dower Right of the Vendor\u27s Wife?; An Executor\u27s Right to an Allowance out of the Estate for Counsel Fees for Services Rendered Before Letters Testamentary Issue; The Kansas Manhattan Cocktail Case and Some Others Concerning Judicial Notice

Drug repurposing for Alzheimer's disease based on transcriptional profiling of human iPSC-derived cortical neurons

Alzheimer's disease is a complex disorder encompassing multiple pathological features with associated genetic and molecular culprits. However, target-based therapeutic strategies have so far proved ineffective. The aim of this study is to develop a methodology harnessing the transcriptional changes associated with Alzheimer's disease to develop a high content quantitative disease phenotype that can be used to repurpose existing drugs. Firstly, the Alzheimer's disease gene expression landscape covering severe disease stage, early pathology progression, cognitive decline and animal models of the disease has been defined and used to select a set of 153 drugs tending to oppose disease-associated changes in the context of immortalised human cancer cell lines. The selected compounds have then been assayed in the more biologically relevant setting of iPSC-derived cortical neuron cultures. It is shown that 51 of the drugs drive expression changes consistently opposite to those seen in Alzheimer's disease. It is hoped that the iPSC profiles will serve as a useful resource for drug repositioning within the context of neurodegenerative disease and potentially aid in generating novel multi-targeted therapeutic strategies.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was funded by the Wellcome foundation: A systematic programme to develop and evaluate the best candidate treatments for repositioning as therapies for Alzheimer’s disease (SMART-AD) reference 102001/Z/13/Z. C.B. reports grants and personal fees from Lundbeck and Acadia and personal fees from Roche, Orion, GSK, Otusaka, Heptares and Lilly outside the submitted work.published version, accepted version, submitted versio

Avoiding lead-time bias by estimating stage-specific proportions of cancer and non-cancer deaths

PURPOSE: Understanding how stage at cancer diagnosis influences cause of death, an endpoint that is not susceptible to lead-time bias, can inform population-level outcomes of cancer screening. METHODS: Using data from 17 US Surveillance, Epidemiology, and End Results registries for 1,154,515 persons aged 50-84 years at cancer diagnosis in 2006-2010, we evaluated proportional causes of death by cancer type and uniformly classified stage, following or extrapolating all patients until death through 2020. RESULTS: Most cancer patients diagnosed at stages I-II did not go on to die from their index cancer, whereas most patients diagnosed at stage IV did. For patients diagnosed with any cancer at stages I-II, an estimated 26% of deaths were due to the index cancer, 63% due to non-cancer causes, and 12% due to a subsequent primary (non-index) cancer. In contrast, for patients diagnosed with any stage IV cancer, 85% of deaths were attributed to the index cancer, with 13% non-cancer and 2% non-index-cancer deaths. Index cancer mortality from stages I-II cancer was proportionally lowest for thyroid, melanoma, uterus, prostate, and breast, and highest for pancreas, liver, esophagus, lung, and stomach. CONCLUSION: Across all cancer types, the percentage of patients who went on to die from their cancer was over three times greater when the cancer was diagnosed at stage IV than stages I-II. As mortality patterns are not influenced by lead-time bias, these data suggest that earlier detection is likely to improve outcomes across cancer types, including those currently unscreened

Neuronal RARβ signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration

Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor β (RARβ) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)–CNS transition of regrown axons. RARβ agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, in RARβ-agonist-treated neurons, PTEN activity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect of RARβ signaling, both neuronal and neuronal–glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs. SIGNIFICANCE STATEMENT Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Here, we identify a single target, neuronal retinoic acid receptor β (RARβ), which modulates these two aspects of the postinjury physiological response. Activation of RARβ in the neuron inactivates phosphatase and tensin homolog and induces its transfer into the astrocytes in small vesicles, where it prevents scar formation. This may open new therapeutic avenues for SCIs

The Dutchman Vol. 6, No. 1

● Editorial ● Somerset County Decorated Barns ● Butter Molds ● Restaurants, too, Go Dutch ● The Hostetter Fractur Collection ● Bindnagle\u27s Church ● The Harry S. High Folk Art Collection ● Lebanon Valley Date Stones ● Of Bells and Bell Towers ● John Durang, the First Native American Dancer ● Stoffel Rilbps\u27 Epistle ● The First Singing of Our National Anthem ● Pennsylvania Dutch Pioneershttps://digitalcommons.ursinus.edu/dutchmanmag/1000/thumbnail.jp

Active Galactic Nuclei Jets and Multiple Oblique Shock Acceleration: Starved Spectra

Shocks in jets and hot spots of Active Galactic Nuclei (AGN) are one prominent class of possible sources of very high energy cosmic ray particles (above 10^18eV). Extrapolating their spectrum to their plausible injection energy from some shock, implies an enormous hidden energy for a spectrum of index ~-2. Some analyzes suggest the particles' injection spectrum at source to be as steep as -2.4 to -2.7, making the problem much worse, by a factor of order 10^6. Nevertheless, it seems implausible that more than at the very best 1/3 of the jet energy, goes into the required flux of energetic particles thus, one would need to allow for the possibility that there is an energy problem, which we would like to address in this work. Sequences of consecutive oblique shock features, or conical shocks, have been theorized and eventually observed in many AGN jets. Based on that, we use by analogy the 'Comptonisation' effect and we propose a scenario of a single injection of particles which are accelerated consecutively by several oblique shocks along the axis of an AGN jet. We use detailed test-particle approximation Monte Carlo simulations in order to calculate particle spectra by acceleration at such a shock pattern while monitoring the efficiency of acceleration, calculating differential spectra. We find that the first shock of a sequence of oblique shocks, establishes a low energy power-law spectrum with ~E^-2.7. The consecutive shocks push the spectrum up in energy, rendering flatter distributions with steep cut-offs and characteristic depletion at low energies, an effect which could explain the puzzling apparent extra source power as well as the flat or inverted spectra from distant flaring sources.Comment: 14 pages, submitted to A&

Cancer risk in childhood-onset systemic lupus

INTRODUCTION: The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE). METHODS: We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population. RESULTS: There were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian; mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this interval, only three invasive cancers were expected. However, 14 invasive cancers occurred with an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers were found (two non-Hodgkin’s lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1 to 15.2). The SIRs stratified by age group and sex, were similar across these strata. There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis. CONCLUSIONS: These results suggest an increased cancer risk in pediatric onset SLE versus the general population. In absolute terms, this represents relatively few events. Of note, risk may be highest only after patients have transferred to adult care

Pennsylvania Folklife Vol. 9, No. 1

• Half-Timbering in American Architecture • The Strouse Dance • Schuylkill Boatmen and Their Ways • Some Early Phases of the Philadelphia Mummers\u27 Parade • Fantasticals • Joseph Henry Dubbs as a Folklorist • About the Authors • Horse Companies in Montgomery County • Books Not for Burninghttps://digitalcommons.ursinus.edu/pafolklifemag/1000/thumbnail.jp

RARb agonist drug (C286) demonstrates efficacy in a pre-clinical neuropathic pain model restoring multiple pathways via DNA repair mechanisms

Neuropathic pain (NP) is associated with profound gene expression alterations within the nociceptive system. DNA mechanisms, such as epigenetic remodelling and repair pathways have been implicated in NP. Here we have used a rat model of peripheral nerve injury to study the effect of a recently developed RARb agonist, C286, currently under clinical research, in NP. A four week treatment initiated two days after the injury normalised pain sensation. Genome-wide and pathway enrichment analysis showed that multiple mechanisms persistently altered in the spinal cord were restored to preinjury levels by the agonist. Concomitant upregulation of DNA repair proteins, ATM and BRCA1, the latter being required for C286 mediated pain modulation, suggest that early DNA repair may be important to prevent phenotypic epigenetic imprints in NP. Thus, C286 is a promising drug candidate for neuropathic pain and DNA repair mechanisms may be useful therapeutic targets to explore

Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of KCL‐286, a novel retinoic acid receptor‐β agonist for treatment of spinal cord injury, in male healthy participants

Aims: KCL‐286 is an orally available agonist taht activates the retinoic acid receptor (RAR) β2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL‐286 in male healthy volunteers to establish dosing to be used in the SCI patient population. Methods: The design was a double blind, randomized, placebo‐controlled dose escalation study in 2 parts: a single ascending dose adaptive design with a food interaction arm, and a multiple ascending dose design. RARβ2 mRNA expression was evaluated in white blood cells. Results: At the highest single and multiple ascending doses (100 mg), no trends or clinically important differences were noted in the incidence or intensity of adverse events (AEs), serious AEs or other safety assessments with none leading to withdrawal from the study. The AEs were dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There was an increase in mean maximum observed concentration and area under the plasma concentration–time curve up to 24 h showing a trend to subproportionality with dose. RARβ2 was upregulated by the investigational medicinal product in white blood cells. Conclusion: KCL‐286 was well tolerated by healthy human participants following doses that exceeded potentially clinically relevant plasma exposures based on preclinical in vivo models. Target engagement shows the drug candidate activates its receptor. These findings support further development of KCL‐286 as a novel oral treatment for SCI