© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.Repressor/activator protein 1 (RAP1) is a highly evolutionarily conserved protein found at telomeres. Although yeast Rap1 is a key telomere capping protein preventing non-homologous end joining (NHEJ) and consequently telomere fusions, its role at mammalian telomeres in vivo is still controversial. Here, we demonstrate that RAP1 is required to protect telomeres in replicative senescent human cells. Downregulation of RAP1 in these cells, but not in young or dividing pre-senescent cells, leads to telomere uncapping and fusions. The anti-fusion effect of RAP1 was further explored in a HeLa cell line where RAP1 expression was depleted through an inducible CRISPR/Cas9 strategy. Depletion of RAP1 in these cells gives rise to telomere fusions only when telomerase is inhibited. We further show that the fusions triggered by RAP1 loss are dependent upon DNA ligase IV. We conclude that human RAP1 is specifically involved in protecting critically short telomeres. This has important implications for the functions of telomeres in senescent cells. © 2020 The Authors. Published under the terms of the CC BY 4.0 license.Ameloblastoma is a rare odontogenic benign tumor accounting for less than 1% of head and neck tumors. Advanced next generation sequencing (NGS) analyses identified high frequency of BRAF V600E and SMO L412F mutations in ameloblastoma. Despite the existence of whole genomic sequence information from patients with ameloblastoma, entire molecular signature of and the characteristics of ameloblastoma cells are still obscure. In this study, we sought to uncover the molecular basis of ameloblastoma and to determine the cellular phenotype of ameloblastoma cells with BRAF mutations. Our comparative cDNA microarray analysis and gene set enrichment analysis (GSEA) showed that ameloblastoma exhibited a distinct gene expression pattern from the normal tissues KRAS-responsive gene set is significantly activated in ameloblastoma. Importantly, insulin like growth factor 2 (IGF2), a member of KRAS-responsive genes, enhances the proliferation of an ameloblastoma cell line AMU-AM1 with BRAF mutation. In addition, Toll-like receptor 2 (TLR2) knockdown readily inactivated KRAS-responsive gene sets as well as increases caspase activities, suggesting that TLR2 signaling may mediate cell survival signaling in ameloblastoma cells. Collectively, the findings may help to further clarify the pathophysiology of ameloblastoma and lead to the development of precision medicine for patients with ameloblastoma. © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.OBJECTIVES To report the incidence of and risk factors for development of recurrent secondary septic peritonitis (RSSP) in dogs. To report the outcome of dogs treated surgically for RSSP. DESIGN Retrospective study. SETTING University teaching hospital. ANIMALS One hundred forty-nine client-owned dogs treated surgically for secondary septic peritonitis (SSP). INTERVENTIONS None. MEASUREMENTS AND RESULTS The medical records database was searched for dogs that underwent surgery to treat SSP. Of 149 dogs that met the inclusion criteria, 15 (10.1%) dogs developed RSSP following surgery and 134 (89.9%) did not. Dogs with RSSP had significantly lower albumin prior to the first surgery to treat secondary septic peritonitis (SPsx1) (median 18 g/L [1.8 g/dL] vs 22 g/L [2.2 g/dL], P = 0.005) and significantly higher PCV prior to SPsx1 (median 52% vs 45%, P = 0.028). Dogs with septic peritonitis of gastrointestinal (GI) origin were significantly more likely to develop recurrent peritonitis than those with sepsis from a non-GI source (odds ratio [OR], 4.4, 95% CI 0.95-20, P = 0.041). Of dogs with sepsis of GI origin, those with sepsis due to a foreign body were significantly more likely to develop RSSP than those with GI sepsis from a non-foreign body cause (OR, 7.2, 95% CI 1.6-43, P = 0.0018). Of the 15 dogs in the RSSP group, 8 were euthanized without further treatment. Relaparotomy was performed in the remaining 7 cases; 3 of these (42.9%) survived. CONCLUSIONS There was a 10.1% rate of RSSP following SPsx1. Preoperative albumin was significantly lower and preoperative PCV was significantly higher in dogs that developed recurrence. Dogs with GI sepsis were at increased risk of recurrence and, among dogs with GI sepsis, the presence of a foreign body was an additional risk factor for recurrence. © Veterinary Emergency and Critical Care Society 2020.BACKGROUND AND AIMS Evidence from randomized controlled trials establishes that medication treatment with methadone and buprenorphine reduces opioid use and improves treatment retention. However, little is known about the role of such medications compared with non-medication treatments in mitigating overdose risk among US patient populations receiving treatment in usual care settings. This study compared overdose mortality among those in medication versus non-medication treatments in specialty care settings. DESIGN Retrospective cohort study using state-wide treatment data linked to death records. Survival analysis was used to analyze data in a time-to-event framework. SETTING Services delivered by 757 providers in publicly funded out-patient specialty treatment programs in Maryland, USA between 1 January 2015 and 31 December 2016. PARTICIPANTS A total of 48 274 adults admitted to out-patient specialty treatment programs in 2015-16 for primary diagnosis of opioid use disorder. MEASUREMENTS Main exposure was tsubstantially elevated risks compared with periods in non-medication treatments.  https://www.selleckchem.com/products/pepstatin-a.html  CONCLUSIONS Among Maryland patients in specialty opioid treatment, periods in treatment are protective against overdose compared with periods out of care. Methadone and buprenorphine are associated with significantly lower overdose death compared with non-medication treatments during care but not after treatment is discontinued. © 2020 Society for the Study of Addiction.A divergent synthetic approach to six Ganoderma meroterpenoids, namely ganocins A-C, ganocochlearins C and D, and cochlearol T, has been developed for the first time. This synthetic route features a two-phase strategy which includes early-stage rapid construction of a common planar tricyclic intermediate followed by highly selective late-stage transformations into various Ganoderma meroterpenoids. Key to the strategy are a bioinspired intramolecular hetero-Diels-Alder reaction and Stahl-type oxidative aromatization, allowing efficient formation of the common tricyclic phenol intermediate. A nucleophilic dearomatization of the phenol unit, combined with a regioselective 1,4-reduction of the resulting dienone, enabled rapid access to ganocins B and C. Additionally, site-selective Mukaiyama hydration, followed by an intramolecular oxa-Michael addition/triflation cascade, served as a key strategic element in the chemical synthesis of ganocin A. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.