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Recent Publications

Hydrogel-mediated co-transplantation of retinal pigmented epithelium and photoreceptors restores vision in an animal model of advanced retinal degeneration.

Hydrogel-mediated co-transplantation of retinal pigmented epithelium and photoreceptors restores vision in an animal model of advanced retinal degeneration.

Biomaterials. 2020 Jul 30;257:120233

Authors: Mitrousis N, Hacibekiroglu S, Ho MT, Sauvé Y, Nagy A, van der Kooy D, Shoichet MS

Abstract
We demonstrate a novel approach to reverse advanced stages of blindness using hydrogel-mediated delivery of retinal pigmented epithelium (RPE) and photoreceptors directly to the degenerated retina of blind mice. With sodium iodate (NaIO3) injections in mice, both RPE and photoreceptors degenerate, resulting in complete blindness and recapitulating the advanced retinal degeneration that is often observed in humans. We observed vision restoration only with co-transplantation of RPE and photoreceptors in a hyaluronic acid-based hydrogel, and not with transplantation of each cell type alone as determined with optokinetic head tracking and light avoidance assays. Both RPE and photoreceptors survived significantly better when co-transplanted than in their respective single cell type controls. While others have pursued transplantation of one of either RPE or photoreceptors, we demonstrate the importance of transplanting both cell types with a minimally-invasive hydrogel for vision repair in a degenerative disease model of the retina.

PMID: 32791386 [PubMed - as supplied by publisher]



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Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma.

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Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma.

J Med Chem. 2020 09 10;63(17):10061-10085

Authors: Smil D, Wong JF, Williams EP, Adamson RJ, Howarth A, McLeod DA, Mamai A, Kim S, Wilson BJ, Kiyota T, Aman A, Owen J, Poda G, Horiuchi KY, Kuznetsova E, Ma H, Hamblin JN, Cramp S, Roberts OG, Edwards AM, Uehling D, Al-Awar R, Bullock AN, O'Meara JA, Isaac MB

Abstract
There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.

PMID: 32787083 [PubMed - indexed for MEDLINE]



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Single-Cell Profiling Shows Murine Forebrain Neural Stem Cells Reacquire a Developmental State when Activated for Adult Neurogenesis.

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Single-Cell Profiling Shows Murine Forebrain Neural Stem Cells Reacquire a Developmental State when Activated for Adult Neurogenesis.

Cell Rep. 2020 Aug 11;32(6):108022

Authors: Borrett MJ, Innes BT, Jeong D, Tahmasian N, Storer MA, Bader GD, Kaplan DR, Miller FD

Abstract
The transitions from developing to adult quiescent and activated neural stem cells (NSCs) are not well understood. Here, we use single-cell transcriptional profiling and lineage tracing to characterize these transitions in the murine forebrain. We show that the two forebrain NSC parental populations, embryonic cortex and ganglionic eminence radial precursors (RPs), are highly similar even though they make glutamatergic versus gabaergic neurons. Both RP populations progress linearly to transition from a highly active embryonic to a dormant adult stem cell state that still shares many similarities with embryonic RPs. When adult NSCs of either embryonic origin become reactivated to make gabaergic neurons, they acquire a developing ganglionic eminence RP-like identity. Thus, transitions from embryonic RPs to adult NSCs and back to neuronal progenitors do not involve fundamental changes in cell identity, but rather reflect conversions between activated and dormant NSC states that may be determined by the niche environment.

PMID: 32783944 [PubMed - in process]



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Functional characterization of a PROTAC directed against BRAF mutant V600E.

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Functional characterization of a PROTAC directed against BRAF mutant V600E.

Nat Chem Biol. 2020 11;16(11):1170-1178

Authors: Posternak G, Tang X, Maisonneuve P, Jin T, Lavoie H, Daou S, Orlicky S, Goullet de Rugy T, Caldwell L, Chan K, Aman A, Prakesch M, Poda G, Mader P, Wong C, Maier S, Kitaygorodsky J, Larsen B, Colwill K, Yin Z, Ceccarelli DF, Batey RA, Taipale M, Kurinov I, Uehling D, Wrana J, Durocher D, Gingras AC, Al-Awar R, Therrien M, Sicheri F

Abstract
The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation and survival, enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAF(V600E) have shown great efficacy in the clinic, but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis-targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC, termed P4B, displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAF(V600E) cell lines. In addition, P4B displayed utility in cell lines harboring alternative BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a proof of concept for a substitute to conventional chemical inhibition to therapeutically constrain oncogenic BRAF.

PMID: 32778845 [PubMed - indexed for MEDLINE]



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The dose threshold for nanoparticle tumour delivery.

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The dose threshold for nanoparticle tumour delivery.

Nat Mater. 2020 Aug 10;:

Authors: Ouyang B, Poon W, Zhang YN, Lin ZP, Kingston BR, Tavares AJ, Zhang Y, Chen J, Valic MS, Syed AM, MacMillan P, Couture-Senécal J, Zheng G, Chan WCW

Abstract
Nanoparticle delivery to solid tumours over the past ten years has stagnated at a median of 0.7% of the injected dose. Varying nanoparticle designs and strategies have yielded only minor improvements. Here we discovered a dose threshold for improving nanoparticle tumour delivery: 1 trillion nanoparticles in mice. Doses above this threshold overwhelmed Kupffer cell uptake rates, nonlinearly decreased liver clearance, prolonged circulation and increased nanoparticle tumour delivery. This enabled up to 12% tumour delivery efficiency and delivery to 93% of cells in tumours, and also improved the therapeutic efficacy of Caelyx/Doxil. This threshold was robust across different nanoparticle types, tumour models and studies across ten years of the literature. Our results have implications for human translation and highlight a simple, but powerful, principle for designing nanoparticle cancer treatments.

PMID: 32778816 [PubMed - as supplied by publisher]



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A Comprehensive, Flexible Collection of SARS-CoV-2 Coding Regions.

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A Comprehensive, Flexible Collection of SARS-CoV-2 Coding Regions.

G3 (Bethesda). 2020 09 02;10(9):3399-3402

Authors: Kim DK, Knapp JJ, Kuang D, Chawla A, Cassonnet P, Lee H, Sheykhkarimli D, Samavarchi-Tehrani P, Abdouni H, Rayhan A, Li R, Pogoutse O, Coyaud É, van der Werf S, Demeret C, Gingras AC, Taipale M, Raught B, Jacob Y, Roth FP

Abstract
The world is facing a global pandemic of COVID-19 caused by the SARS-CoV-2 coronavirus. Here we describe a collection of codon-optimized coding sequences for SARS-CoV-2 cloned into Gateway-compatible entry vectors, which enable rapid transfer into a variety of expression and tagging vectors. The collection is freely available. We hope that widespread availability of this SARS-CoV-2 resource will enable many subsequent molecular studies to better understand the viral life cycle and how to block it.

PMID: 32763951 [PubMed - indexed for MEDLINE]



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The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation.

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The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation.

Genome Biol. 2020 Aug 06;21(1):195

Authors: Kosti A, de Araujo PR, Li WQ, Guardia GDA, Chiou J, Yi C, Ray D, Meliso F, Li YM, Delambre T, Qiao M, Burns SS, Lorbeer FK, Georgi F, Flosbach M, Klinnert S, Jenseit A, Lei X, Sandoval CR, Ha K, Zheng H, Pandey R, Gruslova A, Gupta YK, Brenner A, Kokovay E, Hughes TR, Morris QD, Galante PAF, Tiziani S, Penalva LOF

Abstract
BACKGROUND: RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiation and growth. Identification and characterization of oncogenic RBPs and their regulatory networks provide new opportunities for targeted therapy.
RESULTS: We identify the RNA-binding protein SERBP1 as a novel regulator of glioblastoma (GBM) development. High SERBP1 expression is prevalent in GBMs and correlates with poor patient survival and poor response to chemo- and radiotherapy. SERBP1 knockdown causes delay in tumor growth and impacts cancer-relevant phenotypes in GBM and glioma stem cell lines. RNAcompete identifies a GC-rich region as SERBP1-binding motif; subsequent genomic and functional analyses establish SERBP1 regulation role in metabolic routes preferentially used by cancer cells. An important consequence of these functions is SERBP1 impact on methionine production. SERBP1 knockdown decreases methionine levels causing a subsequent reduction in histone methylation as shown for H3K27me3 and upregulation of genes associated with neurogenesis, neuronal differentiation, and function. Further analysis demonstrates that several of these genes are downregulated in GBM, potentially through epigenetic silencing as indicated by the presence of H3K27me3 sites.
CONCLUSIONS: SERBP1 is the first example of an RNA-binding protein functioning as a central regulator of cancer metabolism and indirect modulator of epigenetic regulation in GBM. By bridging these two processes, SERBP1 enhances glioma stem cell phenotypes and contributes to GBM poorly differentiated state.

PMID: 32762776 [PubMed - as supplied by publisher]



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Underlying dyslipidemia postpartum in women with a recent GDM pregnancy who develop Type 2 diabetes.

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Underlying dyslipidemia postpartum in women with a recent GDM pregnancy who develop Type 2 diabetes.

Elife. 2020 Aug 04;9:

Authors: Lai M, Al Rijjal D, Röst HL, Dai FF, Gunderson EP, Wheeler MB

Abstract
Approximately 35% of women with Gestational Diabetes (GDM) progress to Type2 Diabetes (T2D) within 10 years. However, links between GDM and T2D are not well understood. We used a well-characterised GDM prospective cohort of 1,035 women following up to 8 years postpartum. Lipidomics profiling covering >1000 lipids, was performed on fasting plasma samples from participants 6-9week postpartum (171 incident T2D vs. 179 controls). We discovered 311 lipids positively and 70 lipids negatively associated with T2D risk. The upregulation of glycerolipid metabolism involving triacylglycerol and diacylglycerol biosynthesis suggested activated lipid storage before diabetes onset. In contrast, decreased sphingomyelines, hexosylceramide and lactosylceramide indicated impaired sphingolipid metabolism. Additionally, a lipid signature was identified to effectively predict future diabetes risk. These findings demonstrate an underlying dyslipidemia during the early postpartum in those GDM women who progress to T2D and suggest endogenous lipogenesis may be a driving force for future diabetes onset.

PMID: 32748787 [PubMed - as supplied by publisher]



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Alternative splicing of coq-2 controls the level of rhodoquinone in animals.

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Alternative splicing of coq-2 controls the level of rhodoquinone in animals.

Elife. 2020 Aug 03;9:

Authors: Tan JH, Lautens M, Romanelli-Cedrez L, Wang J, Schertzberg MR, Reinl SR, Davis RE, Shepherd JN, Fraser AG, Salinas G

Abstract
Parasitic helminths use two benzoquinones as electron carriers in the electron transport chain. In normoxia they use ubiquinone (UQ), but in the anaerobic conditions inside the host, they require rhodoquinone (RQ) and greatly increase RQ levels. We previously showed the switch from UQ to RQ synthesis is driven by a change in substrates by the polyprenyltransferase COQ-2 (Del Borrello et al., 2019; Roberts Buceta et al., 2019) - how this substrate choice is made is unknown. Here, we show helminths make two coq-2 splice forms, coq-2a and coq-2e, and the coq-2e-specific exon is only found in species that make RQ. We show that in C. elegans COQ-2e is required for efficient RQ synthesis and for survival in cyanide. Crucially, parasites switch from COQ-2a to COQ-2e as they transition into anaerobic environments. We conclude helminths switch from UQ to RQ synthesis principally via changes in the alternative splicing of coq-2.

PMID: 32744503 [PubMed - as supplied by publisher]



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Education and the moderating roles of age, sex, ethnicity and apolipoprotein epsilon 4 on the risk of cognitive impairment.

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Education and the moderating roles of age, sex, ethnicity and apolipoprotein epsilon 4 on the risk of cognitive impairment.

Arch Gerontol Geriatr. 2020 Nov/Dec;91:104112

Authors: Makkar SR, Lipnicki DM, Crawford JD, Kochan NA, Castro-Costa E, Lima-Costa MF, Diniz BS, Brayne C, Stephan B, Matthews F, Llibre-Rodriguez JJ, Llibre-Guerra JJ, Valhuerdi-Cepero AJ, Lipton RB, Katz MJ, Zammit A, Ritchie K, Carles S, Carriere I, Scarmeas N, Yannakoulia M, Kosmidis M, Lam L, Fung A, Chan WC, Guaita A, Vaccaro R, Davin A, Kim KW, Han JW, Suh SW, Riedel-Heller SG, Roehr S, Pabst A, Ganguli M, Hughes TF, Jacobsen EP, Anstey KJ, Cherbuin N, Haan MN, Aiello AE, Dang K, Kumagai S, Narazaki K, Chen S, Ng TP, Gao Q, Nyunt MSZ, Meguro K, Yamaguchi S, Ishii H, Lobo A, Lobo Escolar E, De la Cámara C, Brodaty H, Trollor JN, Leung Y, Lo JW, Sachdev P, for Cohort Studies of Memory in an International Consortium (COSMIC)

Abstract
BACKGROUND: We examined how the relationship between education and latelife cognitive impairment (defined as a Mini Mental State Examination score below 24) is influenced by age, sex, ethnicity, and Apolipoprotein E epsilon 4 (APOE*4).
METHODS: Participants were 30,785 dementia-free individuals aged 55-103 years, from 18 longitudinal cohort studies, with an average follow-up ranging between 2 and 10 years. Pooled hazard ratios were obtained from multilevel parametric survival analyses predicting cognitive impairment (CI) from education and its interactions with baseline age, sex, APOE*4 and ethnicity. In separate models, education was treated as continuous (years) and categorical, with participants assigned to one of four education completion levels: Incomplete Elementary; Elementary; Middle; and High School.
RESULTS: Compared to Elementary, Middle (HR = 0.645, P = 0.004) and High School (HR = 0.472, P < 0.001) education were related to reduced CI risk. The decreased risk of CI associated with Middle education weakened with older baseline age (HR = 1.029, P = 0.056) and was stronger in women than men (HR = 1.309, P = 0.001). The association between High School and lowered CI risk, however, was not moderated by sex or baseline age, but was stronger in Asians than Whites (HR = 1.047, P = 0.044), and significant among Asian (HR = 0.34, P < 0.001) and Black (HR = 0.382, P = 0.016), but not White, APOE*4 carriers.
CONCLUSION: High School completion may reduce risk of CI associated with advancing age and APOE*4. The observed ethnoregional differences in this effect are potentially due to variations in social, economic, and political outcomes associated with educational attainment, in combination with neurobiological and genetic differences, and warrant further study.

PMID: 32738518 [PubMed - in process]



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