FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

\ua9 2021 by the authors. Licensee MDPI, Basel, Switzerland.FEN1 plays critical roles in long patch base excision repair (LP-BER), Okazaki fragment maturation, and rescue of stalled replication forks. In a clinical cohort, FEN1 overexpression is associated with aggressive phenotype and poor progression-free survival after platinum chemother-apy. Pre-clinically, FEN1 is induced upon cisplatin treatment, and nuclear translocation of FEN1 is dependent on physical interaction with importin β. FEN1 depletion, gene inactivation, or inhibition re-sensitizes platinum-resistant ovarian cancer cells to cisplatin. BRCA2 deficient cells exhibited synthetic lethality upon treatment with a FEN1 inhibitor. FEN1 inhibitor-resistant PEO1R cells were generated, and these reactivated BRCA2 and overexpressed the key repair proteins, POLβ and XRCC1. FEN1i treatment was selectively toxic to POLβ deficient but not XRCC1 deficient ovarian cancer cells. High throughput screening of 391,275 compounds identified several FEN1 inhibitor hits that are suitable for further drug development. We conclude that FEN1 is a valid target for ovarian cancer therapy

USE OF SPECIES OF URBAN TREES IN ENVIRONMENTAL POLLUTION BIOMONITORING

O biomonitoramento consiste na utiliza\ue7\ue3o de organismos vivos para apontar poss\uedveis polui\ue7\uf5es ambientais. Objetivou-se neste estudo avaliar a influ\ueancia da intensidade do tr\ue1fego urbano na disponibilidade de elementos e s\uf3lidos em suspens\ue3o, bem como identificar a potencialidade no ac\ufamulo e reten\ue7\ue3o das subst\ue2ncias em diferentes esp\ue9cies arb\uf3reas, utilizando suas folhas como biomonitores passivos e de acumula\ue7\ue3o. Como amostras utilizaram-se folhas de \ue1rvores coletadas em duas \ue1reas no munic\uedpio de Vit\uf3ria da Conquista - BA: com tr\ue2nsito de ve\uedculos e atividades antr\uf3picas moderadas; e em uma zona de maior tr\ue1fego e com atividades intensas. Foram determinados o material particulado (MP) depositado nas folhas pelo m\ue9todo gravim\ue9trico e os elementos Fe, Cu, Ni, Co e Cd por espectrometria de absor\ue7\ue3o at\uf4mica em forno de grafite (EAA FG). O Fe se distinguiu significativamente das demais vari\ue1veis, com concentra\ue7\uf5es superiores aos outros metais. Utilizaram-se an\ue1lises estat\uedsticas multivariadas para a interpreta\ue7\ue3o dos dados. A an\ue1lise de agrupamento hier\ue1rquico separou dois grupos de acordo com a espacialidade e a an\ue1lise de componentes principais permitiu a explica\ue7\ue3o desta tend\ueancia amostral. Um grupo foi constitu\ueddo por MP, Fe e Cd, pelo fato de serem originados do desgaste dos ve\uedculos e queima de combust\uedveis f\uf3sseis. As esp\ue9cies da fam\uedlia Fabaceae apresentaram uma maior similaridade em rela\ue7\ue3o ao elemento Cu, isto, porque a atividade metab\uf3lica do Cu tem comportamento inversamente proporcional \ue0 concentra\ue7\ue3o de nitrog\ueanio. O tr\ue2nsito de ve\uedculos influiu diretamente na disponibilidade de alguns elementos t\uf3xicos e na concentra\ue7\ue3o de part\uedculas s\uf3lidas depositadas. Conclui-se que a esp\ue9cie influi no ac\ufamulo dos elementos qu\uedmicos e apresentam diferentes potenciais de capta\ue7\ue3o. A arboriza\ue7\ue3o pode ser utilizada como biomonitora passiva de acumula\ue7\ue3o.Biomonitoring is the use of living organisms to identify possible environmental pollution. The objective of this study was to evaluate the influence of intensity of urban traffic in the availability of elements and suspended solids as well as identify the potential in the accumulation and retention of substances in different tree species using its leaves as passive biomonitors and for accumulation. As samples we used tree leaves collected from two areas in the municipality of Vitoria da Conquista (BA state), with transit vehicles and moderate human activities, and in a zone of increased traffic and intense activities. We determined the particulate matter (MP) deposited in the leaves by the gravimetric method and the elements Fe, Cu, Ni, Co and Cd by atomic absorption spectrometry with graphite furnace (GF AAS). Fe was significantly distinguished from other variables, with higher concentrations than other metals. The data was interpreted by multivariate analysis. Cluster analysis separated two groups, one consisting of MP, Fe and Cd, because they are originated from the wear and tear of vehicles and burning fossil fuels. The species of the family Fabaceae showed greater similarity to Cu element, namely, because the Cu metabolic activity is inversely proportional to the concentration of nitrogen behavior. The vehicle traffic directly influenced the availability of some toxic elements and the concentration of the deposited solid particles. It is concluded that the species influences the accumulation of chemical elements and have different catchment potentials. The trees can be utilized as biomonitors which are passive of accumulation

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A polymorphic microsatellite from the Squalius alburnoides complex (Osteichthyes, Cyprinidae) cloned by serendipity can be useful in genetic analysis of polyploids

A new microsatellite locus (SAS1) for Squalius alburnoides was obtained through cloning by serendipity. The possible usefulness of this new species-specific microsatellite in genetic studies of this hybrid-species complex, was explored. The polymorphism exhibited by SAS1 microsatellite is an important addition to the set of microsatellites previously used in genetic studies in S. alburnoides complex, that mostly relied in markers described for other species. Moreover, the SAS1 microsatellite could be used to identify the parental genomes of the complex, complementing other methods recently described for the same purpose.

Habitat Fragmentation, Variable Edge Effects, and the Landscape-Divergence Hypothesis

Edge effects are major drivers of change in many fragmented landscapes, but are often highly variable in space and time. Here we assess variability in edge effects altering Amazon forest dynamics, plant community composition, invading species, and carbon storage, in the world's largest and longest-running experimental study of habitat fragmentation. Despite detailed knowledge of local landscape conditions, spatial variability in edge effects was only partially foreseeable: relatively predictable effects were caused by the differing proximity of plots to forest edge and varying matrix vegetation, but windstorms generated much random variability. Temporal variability in edge phenomena was also only partially predictable: forest dynamics varied somewhat with fragment age, but also fluctuated markedly over time, evidently because of sporadic droughts and windstorms. Given the acute sensitivity of habitat fragments to local landscape and weather dynamics, we predict that fragments within the same landscape will tend to converge in species composition, whereas those in different landscapes will diverge in composition. This ‘landscape-divergence hypothesis’, if generally valid, will have key implications for biodiversity-conservation strategies and for understanding the dynamics of fragmented ecosystems