A Multi-Functional Polymeric Carrier for Simultaneous Positron Emission Tomography Imaging and Combination Therapy.

Acta Biomater. 2018 Jun 06;:

Authors: Sun J, Sun L, Li J, Xu J, Wan Z, Ouyang Z, Liang L, Li S, Zeng D

Abstract
Multifunctional nanoplatforms offering simultaneous imaging and therapeutic functions have been recognized as a highly promising strategy for personalized nanomedicine. In this work, we synthesized a farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) based triblock copolymer POEG-b-PVBA-b-PFTS (POVF) composed of a poly(oligo(ethylene glycol) methacrylate) (POEG) hydrophilic block, a poly(FTS) hydrophobic block, and a poly(4-vinylbenzyl azide) (PVBA) middle block. The POVF polymer itself was active in inhibiting the tumor growth in vitro and in vivo. Besides, it could serve as a carrier to effectively encapsulate paclitaxel (PTX) to form stable PTX/POVF mixed micelles with a diameter around 100 nm. Meanwhile, POVF polymer provides the active azide group for incorporating a positron emission tomography (PET) imaging modality via a facile strategy based on metal-free click chemistry. This nanocarrier system could not only be used for co-delivery of PTX and FTS, but also for PET imaging guided drug delivery. In the 4T1.2 tumor bearing mice, PET imaging showed rapid uptake and slow clearance of radiolabeled PTX/POVF nanomicelles in the tumor tissues. In addition, the FTS-based multi-functional nanocarrier was able to inhibit tumor growth effectively, and the co-delivery of PTX by the carrier further improved the therapeutic effect.
STATEMENT OF SIGNIFICANCE: Due to the intrinsic heterogeneity of cancer and variability in individual patient response, personalized nanomedicine based on multi-functional carriers that integrate the functionalities of combination therapy and imaging guidance is highly demanded. Here we developed a multi-functional nanocarrier based on triblock copolymer POEG-b-PVBA-b-PFTS (POVF), which could not only be used for co-delivery of anticancer drugs PTX and Ras inhibitor FTS, but also for PET imaging guided drug delivery. The POVF carrier itself was active in inhibiting the tumor growth in vitro and in vivo. Besides, it was effective in formulating PTX with high drug loading capacity, which further enhanced the tumor inhibition effect. Meanwhile, we developed a simple and universal approach to incorporate a PET radioisotope (Zr-89 and Cu-64) into the azide-containing PTX/POVF micelles via metal-free click chemistry in aqueous solution. The radiolabeled PTX/POVF micelles exhibited excellent serum stability, rapid tumor uptake and slow clearance, which validated the feasibility of the PET image-guided delivery of PTX/POVF micelles.

PMID: 29885530 [PubMed - as supplied by publisher]

17q21 variant increases the risk of exacerbations in asthmatic children despite inhaled corticosteroids use.

Allergy. 2018 Jun 09;:

Authors: Farzan N, Vijverberg SJ, Hernandez-Pacheco N, Bel EHD, Berce V, Bønnelykke K, Bisgaard H, Burchard EG, Canino G, Celedón JC, Chew FT, Chiang WC, Cloutier MM, Forno E, Francis B, Hawcutt DB, Herrera-Luis E, Kabesch M, Karimi L, Melén E, Mukhopadhyay S, Merid SK, Palmer CN, Pino-Yanes M, Munir P, Potočnik U, Repnik K, Schieck M, Sevelsted A, Yang Yie S, Smyth RL, Soares P, Söderhäll C, Tantisira KG, Tavendale R, Sze Man T, Turner S, Verhamme KM, Maitland-van der Zee AH

PMID: 29885281 [PubMed - as supplied by publisher]

Effectiveness of half-a-tablet efavirenz plus 2 nucleos(t)ide reverse-transcriptase inhibitors as maintenance therapy with the guidance of therapeutic drug monitoring among virologically suppressed HIV-positive patients: A prospective study.

J Microbiol Immunol Infect. 2018 May 29;:

Authors: Huang SH, Lin SW, Chang SY, Lin YT, Sun HY, Liu WC, Su YC, Hung CC, Chang SC

Abstract
BACKGROUND: Optimal efavirenz (EFV) dose that minimizes adverse effects while maintaining efficacy has yet to be elucidated. With a therapeutic drug monitoring (TDM)-guided strategy, we assessed the effectiveness of half-a-tablet EFV plus 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) in HIV-infected Taiwanese who had achieved viral suppression with full-dose (600 mg) EFV.
METHODS: HIV-infected adults receiving EFV-containing regimens who had plasma mid-dose EFV concentration (C12) ≥2.0 mg/L and had plasma HIV RNA load (PVL) <200 copies/mL were enrolled in this single-arm, open-label study by reducing EFV to half-a-tablet daily. The primary endpoint was PVL <50 copies/ml in an intention-to-treat (ITT) population at week 48. The secondary endpoints were the plasma EFV C12, the proportion of patients with plasma EFV C12 <1.0 mg/L, PVL <50 copies/ml at week 96 and week 144.
RESULTS: Between April 2013 and September 2016, 203 patients (93.6% male; median age, 39.0 years) were enrolled. The median EFV C12 before switch was 2.80 mg/L (interquartile range (IQR), 2.41-3.73), which decreased to 1.59 mg/L (IQR, 1.23-2.03) after switch with a reduction of 47.4% (IQR, 38.3-55.5%). In ITT analysis, 93.6%, 92.3% and 87.3% of the patients achieved PVL <50 copies/ml at weeks 48, 96 and 144, respectively. More than 70% of the patients reported alleviation of EFV-associated adverse effects following the switch.
CONCLUSION: Under the guidance of TDM, switch to half-a-tablet EFV plus 2 NRTIs is effective in maintaining viral suppression in HIV-infected Taiwanese with EFV C12 ≥ 2.0 mg/L.

PMID: 29884449 [PubMed - as supplied by publisher]

β-cell Secretory Defects are Present in Pancreatic Insufficient Cystic Fibrosis with 1-hour OGTT Glucose ≥155 mg/dL.

Pediatr Diabetes. 2018 Jun 08;:

Authors: Nyirjesy SC, Sheikh S, Hadjiliadis D, De Leon DD, Peleckis AJ, Eiel JN, Kubrak C, Stefanovski D, Rubenstein RC, Rickels MR, Kelly A

Abstract
BACKGROUND: Patients with pancreatic insufficient cystic fibrosis (PI-CF) meeting standard criteria for normal glucose tolerance display impaired β-cell secretory capacity and early-phase insulin secretion defects. We sought evidence of impaired β-cell secretory capacity, a measure of functional β-cell mass, amongst those with early glucose intolerance (EGI), defined as 1-hour OGTT glucose ≥155mg/dL (8.6 mmol/L).
METHODS: A cross-sectional study was conducted in the Penn and CHOP Clinical & Translational Research Centers. PI-CF categorized by OGTT as normal (PI-NGT: 1-hour glucose <155 and 2-hour <140 mg/dL (7.8 mmol/L); n=13), early glucose intolerance (PI-EGI: 1-hour ≥155 and 2-hour <140 mg/dL; n=13), impaired (PI-IGT: 2-hour ≥140 and <200 mg/dL (11.1 mmol/L); n=8), and diabetic (CFRD: 2-hour ≥200 mg/dL; n=8) participated. Post-prandial glucose tolerance and insulin secretion, and β-cell secretory capacity and demand were derived from mixed-meal tolerance tests (MMTT), and glucose-potentiated arginine (GPA) tests, respectively.
RESULTS: PI-EGI had elevated post-prandial glucose with reduced early-phase insulin secretion during MMTT compared to PI-NGT (P<0.05). PI-EGI also exhibited impaired acute insulin and C-peptide responses to glucose-potentiated arginine (P<0.01 vs. PI-NGT), measures of β-cell secretory capacity. Proinsulin secretory ratios were higher under hyperglycemic clamp conditions in PI-IGT and CFRD (P<0.05 vs. PI-NGT), and correlated with 1-hour glucose in PI-CF (P<0.01).
CONCLUSIONS: PI-CF patients with 1-hour OGTT glucose ≥155 mg/dL already manifest impaired β-cell secretory capacity with associated early-phase insulin secretion defects. Avoiding hyperglycemia in patients with early glucose intolerance may be important for preventing excessive insulin demand indicated by disproportionately increased proinsulin secretion. This article is protected by copyright. All rights reserved.

PMID: 29885044 [PubMed - as supplied by publisher]

Ceftolozane/tazobactam sensitivity patterns in Pseudomonas aeruginosa isolates recovered from sputum of cystic fibrosis patients.

Diagn Microbiol Infect Dis. 2018 May 12;:

Authors: Finklea JD, Hollaway R, Lowe K, Lee F, Le J, Jain R

Abstract
Ceftolozane/tazobactam is a combination intravenous antibiotic with potentially important activity against drug-resistant Gram-negative organisms. Ceftolozane/tazobactam's in vitro activity was evaluated in 30 samples collected from 23 adult cystic fibrosis patients with extended and pan-resistant Pseudomonas aeruginosa in 2015. Testing results demonstrated that 30% of the isolates were susceptible,13% were intermediate, and 57% were resistant. This suggests that ceftolozane/tazobactam may be a useful antibiotic in carefully selected, multidrug-resistant Pseudomonas isolates.

PMID: 29884565 [PubMed - as supplied by publisher]

Interleukin-1 is associated with inflammation and structural lung disease in young children with cystic fibrosis.

J Cyst Fibros. 2018 Jun 05;:

Authors: Montgomery ST, Dittrich AS, Garratt LW, Turkovic L, Frey DL, Stick SM, Mall MA, Kicic A, AREST CF

Abstract
BACKGROUND: Little is known about the role of interleukin (IL)-1 in the pathogenesis of cystic fibrosis (CF) lung disease. This study investigated the relationship between IL-1 signalling, neutrophilic inflammation and structural lung changes in children with CF.
METHODS: Bronchoalveolar lavage fluid (BALf) from 102 children with CF were used to determine IL-1α, IL-1β, IL-8 levels and neutrophil elastase (NE) activity, which were then correlated to structural lung changes observed on chest computed tomography (CT) scans.
RESULTS: IL-1α and IL-1β were detectable in BAL in absence of infection, increased in the presence of bacterial infection and correlated with IL-8 (p < 0.0001), neutrophils (p < 0.0001) and NE activity (p < 0.01 and p < 0.001). IL-1α had the strongest association with structural lung disease (p < 0.01) in the absence of infection (uninfected: p < 0.01 vs. infected: p = 0.122).
CONCLUSION: Our data associates IL-1α with early structural lung damage in CF and suggests this pathway as a novel anti-inflammatory target.

PMID: 29884450 [PubMed - as supplied by publisher]

Whole Exome Sequencing of Patients from Multicase Families with Systemic Lupus Erythematosus Identifies Multiple Rare Variants.

Sci Rep. 2018 Jun 08;8(1):8775

Authors: Delgado-Vega AM, Martínez-Bueno M, Oparina NY, López Herráez D, Kristjansdottir H, Steinsson K, Kozyrev SV, Alarcón-Riquelme ME

Abstract
In an effort to identify rare alleles associated with SLE, we have performed whole exome sequencing of the most distantly related affected individuals from two large Icelandic multicase SLE families followed by Ta targeted genotyping of additional relatives. We identified multiple rare likely pathogenic variants in nineteen genes co-segregating with the disease through multiple generations. Gene co-expression and protein-protein interaction analysis identified a network of highly connected genes comprising several loci previously implicated in autoimmune diseases. These genes were significantly enriched for immune system development, lymphocyte activation, DNA repair, and V(D)J gene recombination GO-categories. Furthermore, we found evidence of aggregate association and enrichment of rare variants at the FAM71E1/EMC10 locus in an independent set of 4,254 European SLE-cases and 4,349 controls. Our study presents evidence supporting that multiple rare likely pathogenic variants, in newly identified genes involved in known disease pathogenic pathways, segregate with SLE at the familial and population level.

PMID: 29884787 [PubMed - in process]

Metformin induces FOXO3-dependent fetal hemoglobin production in human primary erythroid cells.

Blood. 2018 Jun 08;:

Authors: Zhang Y, Paikari A, Sumazin P, Ginter Summarell CC, Crosby JR, Boerwinkle E, Weiss MJ, Sheehan VA

Abstract
Induction of red blood cell fetal hemoglobin (HbF, α2γ2) ameliorates the pathophysiology of sickle cell disease (SCD) by reducing the concentration of sickle hemoglobin (HbS, α2βS2) to inhibit its polymerization. Hydroxyurea (HU), the only FDA-approved drug for SCD, acts in part by inducing HbF, but is not fully effective, reflecting the need for new therapies. Whole exome sequence analysis of rare genetic variants in SCD patients identified FOXO3 as a candidate regulator of RBC HbF. We validated these genomic findings through loss and gain of function studies in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation. FOXO3 gene silencing reduced γ-globin RNA levels and HbF levels in erythroblasts, while overexpression of FOXO3 produced the opposite effect. Moreover, treatment of primary CD34+ cell-derived erythroid cultures with metformin, an FDA-approved drug known to enhance FOXO3 activity in non-erythroid cells, caused dose-related, FOXO3-dependent, increases in both percentage (%) HbF protein and the fraction of HbF-immunostaining cells (F-cells). Combined HU and metformin treatment induced HbF additively and reversed the erythroid maturation arrested caused by HU treatment alone. HbF induction in erythroid precursors by metformin was dependent on FOXO3 expression and did not alter expression of BCL11A, MYB or KLF1. Collectively, our data implicate FOXO3 as a positive regulator of γ-globin expression and identify metformin as a potential therapeutic agent for SCD.

PMID: 29884740 [PubMed - as supplied by publisher]

The role of protein methyltransferases as potential novel therapeutic targets in squamous cell carcinoma of the head and neck.

Oral Oncol. 2018 Jun;81:100-108

Authors: Saloura V, Vougiouklakis T, Sievers C, Burkitt K, Nakamura Y, Hager G, van Waes C

Abstract
Squamous cell carcinoma of the head and neck is a lethal disease with suboptimal survival outcomes and standard therapies with significant comorbidities. Whole exome sequencing data recently revealed an abundance of genetic and expression alterations in a family of enzymes known as protein methyltransferases in a variety of cancer types, including squamous cell carcinoma of the head and neck. These enzymes are mostly known for their chromatin-modifying functions through methylation of various histone substrates, though evidence supports their function also through methylation of non-histone substrates. This review summarizes the current knowledge on the function of protein methyltransferases in squamous cell carcinoma of the head and neck and highlights their promising potential as the next generation of therapeutic targets in this disease.

PMID: 29884408 [PubMed - in process]

Integrated genomic characterization of oral carcinomas in post-hematopoietic stem cell transplantation survivors.

Oral Oncol. 2018 Jun;81:1-9

Authors: Hanna GJ, Kofman ER, Shazib MA, Woo SB, Reardon B, Treister NS, Haddad RI, Cutler CS, Antin JH, Van Allen EM, Uppaluri R, Soiffer RJ

Abstract
OBJECTIVES: Secondary oral squamous cell carcinoma (OSCC) is a late complication in allogeneic hematopoietic stem cell transplantation (HSCT) patients, but little is known about long-term outcomes and prognostication. Additionally, molecular alterations and immunologic insights unique to this disease remain largely unexplored.
METHODS: We present a cohort of 31 patients with post-HSCT OSCC and reported on clinicopathologic predictors of survival. Whole-exome sequencing was performed on 6 (19%) matched pairs of peripheral blood (post-conditioning, pre-HSCT) and tumor samples. The entire cohort had archival tumor available for immunoprofiling with PD-1/L1 immunohistochemistry.
RESULTS: Five-year overall survival (OS) was 57% (95% CI: 46.1-69.8) with a median disease-free survival (DFS) of 13.3 months. Advanced initial staging, a buccal or oral tongue subsite, chronic oral graft-versus-host disease (GVHD) and smoking all negatively impacted survival. High tumor mutational burden (TMB) (median 11.3 vs. 5.0) and unique mutational signatures were noted between unrelated and related donor groups - with a strong correlation between infiltrating PD-1+ lymphocytes and TMB (R = 0.98, p < 0.01). Some differences were observed when comparing commonly mutated genes among our cohort and TCGA, with a predominance of TP53 events.
CONCLUSION: Survival outcomes appear similar in HSCT survivors with OSCC compared with non-HSCT OSCC populations. We identified somatic alterations in genes with therapeutic potential unique to this subpopulation of oral cancers.

PMID: 29884406 [PubMed - in process]

Micropapillary urothelial carcinoma: evaluation of HER2 status and immunohistochemical characterization of the molecular subtype.

Hum Pathol. 2018 Jun 06;:

Authors: Zinnall U, Weyerer V, Compérat E, Camparo P, Gaisa NT, Knuechel-Clarke R, Perren A, Lugli A, Toma M, Baretton G, Kristiansen G, Wirtz RM, Cheng L, Wullich B, Stoehr R, Hartmann A, Bertz S

Abstract
Comprehensive molecular analyses of urothelial bladder cancer (UBC) have defined distinct subtypes with potential therapeutic implications. In this study, we focused on micropapillary urothelial carcinoma (MPUC), an aggressive, histomorphologically defined rare variant. Apart from genetic alterations shared with conventional UBC alterations of the HER2 gene have been reported in higher frequencies. However, only small cohorts of MPUCs have been analyzed and the real impact is still unclear. We collected a cohort of 94 MPUCs and immunohistochemically tested HER2, basal (CD44, CK5, EGFR, p63) and luminal (CD24, FOXA1, GATA3, CK20) markers to allocate MPUC to a molecular subtype. Additionally, HER2 amplification status was assigned by chromogenic in-situ-hybridization. Sanger sequencing of Exon 4 and 8 was used to test for HER2 mutations. Kruskal-Wallis test was calculated to compare marker distribution between proportions of the MPUC component. 2+/3+ HER2 staining scores were identified in 39.6% of 91 analyzed MPUCs and were not differentially distributed among the proportion of the MPUC component (P=.89). Additionally, CISH analysis revealed 30% of HER2 amplified tumors independently of the MPUC fraction. In 6/90 evaluable MPUCs a p.S310F HER2 mutation was detected. Overexpression of luminal markers was observed in the majority of MPUC. Our investigations of the largest cohort of analyzed MPUC demonstrate that HER2 overexpression and amplifications are common genetic alterations and identification of overexpressed luminal markers allows sub-classification to the luminal subtype. These findings highlight the need of histomorphological recognition of MPUC and analysis of HER2 status and the luminal molecular subtype for potential targeted therapeutic strategies.

PMID: 29885409 [PubMed - as supplied by publisher]

Are there general laws for digit evolution in squamates? The loss and re-evolution of digits in a clade of fossorial lizards (Brachymeles, Scincinae).

J Morphol. 2018 Jun 08;:

Authors: Wagner GP, Griffith OW, Bergmann PJ, Bello-Hellegouarch G, Kohlsdorf T, Bhullar A, Siler CD

Abstract
Evolutionary simplification of autopodial structures is a major theme in studies of body-form evolution. Previous studies on amniotes have supported Morse's law, that is, that the first digit reduced is Digit I, followed by Digit V. Furthermore, the question of reversibility for evolutionary digit loss and its implications for "Dollo's law" remains controversial. Here, we provide an analysis of limb and digit evolution for the skink genus Brachymeles. Employing phylogenetic, morphological, osteological, and myological data, we (a) test the hypothesis that digits have re-evolved, (b) describe patterns of morphological evolution, and (c) investigate whether patterns of digit loss are generalizable across taxa. We found strong statistical support for digit, but not limb re-evolution. The feet of pentadactyl species of Brachymeles are very similar to those of outgroup species, while the hands of these lineages are modified (2-3-3-3-2) and a have a reduced set of intrinsic hand muscles. Digit number variation suggests a more labile Digit V than Digit I, contrary to Morse's law. The observed pattern of digit variation is different from that of other scincid lizards (Lerista, Hemiergis, Carlia). Our results present the first evidence of clade-specific modes of digit reduction.

PMID: 29884998 [PubMed - as supplied by publisher]

Metallomics: The Science of Biometals and Biometalloids.

Adv Exp Med Biol. 2018;1055:1-20

Authors: Maret W

Abstract
Metallomics, a discipline integrating sciences that address the biometals and biometalloids, provides new opportunities for discoveries. As part of a systems biology approach, it draws attention to the importance of many chemical elements in biochemistry. Traditionally, biochemistry has treated life as organic chemistry, separating it from inorganic chemistry, considered a field reserved for investigating the inanimate world. However, inorganic chemistry is part of the chemistry of life, and metallomics contributes by showing the importance of a neglected fifth branch of building blocks in biochemistry. Metallomics adds chemical elements/metals to the four building blocks of biomolecules and the fields of their studies: carbohydrates (glycome), lipids (lipidome), proteins (proteome), and nucleotides (genome). The realization that non-essential elements are present in organisms in addition to essential elements represents a certain paradigm shift in our thinking, as it stipulates inquiries into the functional implications of virtually all the natural elements. This article discusses opportunities arising from metallomics for a better understanding of human biology and health. It looks at a biological periodic system of the elements as a sum of metallomes and focuses on the major roles of metals in about 30-40% of all proteins, the metalloproteomes. It emphasizes the importance of zinc and iron biology and discusses why it is important to investigate non-essential metal ions, what bioinformatics approaches can contribute to understanding metalloproteins, and why metallomics has a bright future in the many dimensions it covers.

PMID: 29884959 [PubMed - in process]

Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit.

Nat Commun. 2018 Jun 08;9(1):2227

Authors: Schott K, Fuchs NV, Derua R, Mahboubi B, Schnellbächer E, Seifried J, Tondera C, Schmitz H, Shepard C, Brandariz-Nuñez A, Diaz-Griffero F, Reuter A, Kim B, Janssens V, König R

Abstract
SAMHD1 is a critical restriction factor for HIV-1 in non-cycling cells and its antiviral activity is regulated by T592 phosphorylation. Here, we show that SAMHD1 dephosphorylation at T592 is controlled during the cell cycle, occurring during M/G1 transition in proliferating cells. Using several complementary proteomics and biochemical approaches, we identify the phosphatase PP2A-B55α responsible for rendering SAMHD1 antivirally active. SAMHD1 is specifically targeted by PP2A-B55α holoenzymes during mitotic exit, in line with observations that PP2A-B55α is a key mitotic exit phosphatase in mammalian cells. Strikingly, as HeLa or activated primary CD4+ T cells enter the G1 phase, pronounced reduction of RT products is observed upon HIV-1 infection dependent on the presence of dephosphorylated SAMHD1. Moreover, PP2A controls SAMHD1 pT592 level in non-cycling monocyte-derived macrophages (MDMs). Thus, the PP2A-B55α holoenzyme is a key regulator to switch on the antiviral activity of SAMHD1.

PMID: 29884836 [PubMed - in process]

Metformin induces FOXO3-dependent fetal hemoglobin production in human primary erythroid cells.

Blood. 2018 Jun 08;:

Authors: Zhang Y, Paikari A, Sumazin P, Ginter Summarell CC, Crosby JR, Boerwinkle E, Weiss MJ, Sheehan VA

Abstract
Induction of red blood cell fetal hemoglobin (HbF, α2γ2) ameliorates the pathophysiology of sickle cell disease (SCD) by reducing the concentration of sickle hemoglobin (HbS, α2βS2) to inhibit its polymerization. Hydroxyurea (HU), the only FDA-approved drug for SCD, acts in part by inducing HbF, but is not fully effective, reflecting the need for new therapies. Whole exome sequence analysis of rare genetic variants in SCD patients identified FOXO3 as a candidate regulator of RBC HbF. We validated these genomic findings through loss and gain of function studies in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation. FOXO3 gene silencing reduced γ-globin RNA levels and HbF levels in erythroblasts, while overexpression of FOXO3 produced the opposite effect. Moreover, treatment of primary CD34+ cell-derived erythroid cultures with metformin, an FDA-approved drug known to enhance FOXO3 activity in non-erythroid cells, caused dose-related, FOXO3-dependent, increases in both percentage (%) HbF protein and the fraction of HbF-immunostaining cells (F-cells). Combined HU and metformin treatment induced HbF additively and reversed the erythroid maturation arrested caused by HU treatment alone. HbF induction in erythroid precursors by metformin was dependent on FOXO3 expression and did not alter expression of BCL11A, MYB or KLF1. Collectively, our data implicate FOXO3 as a positive regulator of γ-globin expression and identify metformin as a potential therapeutic agent for SCD.

PMID: 29884740 [PubMed - as supplied by publisher]

PDGF-A suppresses contact inhibition during directional collective cell migration.

Development. 2018 Jun 08;:

Authors: Nagel M, Winklbauer R

Abstract
The leading edge mesendoderm (LEM) of the Xenopus gastrula moves as an aggregate by collective migration. However, LEM cells on fibronectin in vitro show contact inhibition of locomotion by quickly retracting lamellipodia upon mutual contact. We found that a fibronectin-integrin-syndecan module acts between p21-activated kinase-1 upstream and ephrinB1 downstream to promote the contact-induced collapse of lamellipodia. To function in this module, fibronectin has to be present as puncta on the surface of LEM cells. To overcome contact inhibition in LEM cell aggregates, PDGF-A deposited in the endogenous substratum of LEM migration blocks the fibronectin-integrin-syndecan module at the integrin level. This stabilizes lamellipodia preferentially in the direction of normal LEM movement and supports cell orientation and the directional migration of the coherent LEM cell mass.

PMID: 29884673 [PubMed - as supplied by publisher]