bluuebunny/crossref_metadata_2025_split huggingface dataset:
Staphylococcus aureus Preferentially Liberates Inorganic Phosphate from Organophosphates in Environments where This Nutrient Is Limiting
Authors: Kelliher Jessica L. , Leder Macek Aleeza J. , Grudzinski Kevin M. , Radin Jana N. , Kehl-Fie Thomas E. 
Published: September 2020

ABSTRACT
Phosphate is an essential nutrient that Staphylococcus aureus and other pathogens must acquire from the host during infection. While inorganic monophosphate (Pi) is the preferred source of this nutrient, bacteria can also obtain it from phosphate-containing organic molecules. The Pi-responsive regulator PhoPR is necessary for S. aureus to cause infection, suggesting that Pi is not freely available during infection and that this nutrient must be obtained from other sources. However, the organophosphates from which S. aureus can obtain phosphate are unknown. We evaluated the ability of 58 phosphorus-containing molecules to serve as phosphate sources for S. aureus. Forty-six of these compounds, including phosphorylated amino acids, sugars, and nucleotides, supported growth. Among the organophosphate sources was glycerol-3-phosphate (G3P), which is commonly found in the mammalian host. Differing from the model organism Escherichia coli, S. aureus does not import G3P intact to obtain Pi. Instead, S. aureus relies on the phosphatase PhoB to release Pi from G3P, which is subsequently imported by Pi transporters. To determine if this strategy is used by S. aureus to extract phosphate from other phosphate sources, we assessed the ability of PhoB- and Pi transporter-deficient strains to grow on the same library of phosphorus-containing molecules. Sixty percent of the substrates (28/46) relied on the PhoB/Pi transporter pathway, and an additional 10/46 (22%) were PhoB independent but still required Pi transport through the Pi transporters. Cumulatively, these results suggest that in Pi-limited environments, S. aureus preferentially generates Pi from organophosphates and then relies on Pi transporters to import this nutrient.
IMPORTANCE For bacteria, the preferred form of the essential nutrient phosphate is inorganic monophosphate (Pi), but phosphate can also be extracted from a variety of phosphocompounds. Pathogens, including Staphylococcus aureus, experience Pi limitation within the host, suggesting that the use of alternative phosphate sources is important during infection. However, the alternative phosphate sources that can be used by S. aureus and others remain largely unexplored. We screened a library of phosphorus-containing compounds for the ability to support growth as a phosphate source. S. aureus could use a variety of phosphocompounds, including nucleotides, phosphosugars, and phosphoamino acids. Subsequent genetic analysis determined that a majority of these alternative phosphate sources are first processed extracellularly to liberate Pi, which is then imported through Pi transporters.
Reprogramming of Differentiated Mammalian and Human Retinal Pigment Epithelium: Current Achievements and Prospects
Authors: Rzhanova L. A. , Kuznetsova A. V. , Aleksandrova M. A. 
Published: September 2020

AbstractImpairment of the homeostatic and functional integrity of the retina and retinal pigment epithelium (RPE) is the main cause of some degenerative diseases of the human eye, which are accompanied by loss of eyesight. Despite the significant progress made over the past decades in the development of new methods for treatment for this pathology, there are still several complications when using surgical methods for correction of eyesight and so far insurmountable limitations in the applications of modern approaches, such as gene therapy and genetic engineering. One of the promising approaches to the treatment of degenerative diseases of the retina may be an approach based on the application of regenerative capacities of its endogenous cells with high plasticity, in particular, of RPE cells and Müller glia. Currently, vertebrate RPE cells are of great interest as a source of new photoreceptors and other neurons in the degrading retina in vivo.In this regard, the possibilities of their direct reprogramming by genetic, epigenetic, and chemical methods and their combination are being investigated. This review focuses on research in gene-directed reprogramming of vertebrate RPE cells into retinal neurons, with detailed analysis of the genes used as the main reprogramming factors, comparative analysis, and extrapolation of experimental data from animals to humans. Also, this review covers studies on the application of alternative approaches to gene-directed reprogramming, such as chemical-mediated reprogramming with the use of cocktails of therapeutic low-molecular-weight compounds and microRNAs. In general, the research results indicate the complexity of the process for direct reprogramming of human RPE cells into retinal neurons. However, taking into account the results of direct reprogramming of vertebrate cells and the accessibility of human RPE cells for various vectors that deliver a variety of molecules to cells, such as transcription factors, chimeric endonucleases, recombinant proteins, and low-weight molecular compounds, the most optimal combination of factors for the successful conversion of human RPE cells to retinal neurons can be suggested.
Off-shell renormalization in the presence of dimension 6 derivative operators. II. Ultraviolet coefficients
Authors: Binosi D. , Quadri A. 
Published: September 2020

AbstractThe full off-shell one loop renormalization for all divergent amplitudes up to dimension 6 in the Abelian Higgs-Kibble model, supplemented with a maximally power counting violating higher-dimensional gauge-invariant derivative interaction $$\sim g ~ \phi ^\dagger \phi (D^\mu \phi )^\dagger D_\mu \phi $$

∼
g

ϕ
†

ϕ

(

D
μ

ϕ
)

†

D
μ

ϕ

, is presented. This allows one to perform the complete renormalization of radiatively generated dimension 6 operators in the model at hand. We describe in details the technical tools required in order to disentangle the contribution to ultraviolet divergences parameterized by (generalized) non-polynomial field redefinitions. We also discuss how to extract the dependence of the $$\beta $$
β
-function coefficients on the non-renormalizable coupling g in one loop approximation, as well as the cohomological techniques (contractible pairs) required to efficiently separate the mixing of contributions associated to different higher-dimensional operators in a spontaneously broken effective field theory.
Heterotic orbifolds, reduced rank and SO(2n + 1) characters
Authors: Partouche Hervé , de Vaulchier Balthazar 
Published: September 2020

The moduli space of the maximally supersymmetric heterotic string in [Formula: see text]-dimensional Minkowski space contains various components characterized by the rank of the gauge symmetries of the vacua they parametrize. We develop an approach for describing in a unified way continuous Wilson lines which parametrize a component of the moduli space, together with discrete deformations responsible for the switch from one component to the other. Applied to a component that contains vacua with [Formula: see text] gauge-symmetry factors, our approach yields a description of all backgrounds of the component in terms of free-orbifold models. The orbifold generators turn out to act symmetrically or asymmetrically on the internal space, with or without discrete torsion. Our derivations use extensively affine characters of [Formula: see text]. As a by-product, we find a peculiar orbifold description of the heterotic string in 10 dimensions, where all gauge degrees of freedom arise as twisted states, while the untwisted sector reduces to the gravitational degrees of freedom.
Automating Resolution is NP-Hard
Authors: Atserias Albert , Müller Moritz 
Published: September 2020

We show that the problem of finding a Resolution refutation that is at most polynomially longer than a shortest one is NP-hard. In the parlance of proof complexity, Resolution is not automatable unless P = NP. Indeed, we show that it is NP-hard to distinguish between formulas that have Resolution refutations of polynomial length and those that do not have subexponential length refutations. This also implies that Resolution is not automatable in subexponential time or quasi-polynomial time unless NP is included in SUBEXP or QP, respectively.
Hypoxia Induces Resistance to EGFR Inhibitors in Lung Cancer Cells via Upregulation of FGFR1 and the MAPK Pathway
Authors: Lu Yuhong , Liu Yanfeng , Oeck Sebastian , Zhang Gary J. , Schramm Alexander , Glazer Peter M. 
Published: September 2020

Abstract

Development of resistance remains the key obstacle to the clinical efficacy of EGFR tyrosine kinase inhibitors (TKI). Hypoxia is a key microenvironmental stress in solid tumors associated with acquired resistance to conventional therapy. Consistent with our previous studies, we show here that long-term, moderate hypoxia promotes resistance to the EGFR TKI osimertinib (AZD9291) in the non–small cell lung cancer (NSCLC) cell line H1975, which harbors two EGFR mutations including T790M. Hypoxia-induced resistance was associated with development of epithelial–mesenchymal transition (EMT) coordinated by increased expression of ZEB-1, an EMT activator. Hypoxia induced increased fibroblast growth factor receptor 1 (FGFR1) expression in NSCLC cell lines H1975, HCC827, and YLR086, and knockdown of FGFR1 attenuated hypoxia-induced EGFR TKI resistance in each line. Upregulated expression of FGFR1 by hypoxia was mediated through the MAPK pathway and attenuated induction of the proapoptotic factor BIM. Consistent with this, inhibition of FGFR1 function by the selective small-molecule inhibitor BGJ398 enhanced EGFR TKI sensitivity and promoted upregulation of BIM levels. Furthermore, inhibition of MEK activity by trametinib showed similar effects. In tumor xenografts in mice, treatment with either BGJ398 or trametinib enhanced response to AZD9291 and improved survival. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased expression of FGFR1. The combination of EGFR TKI and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLC.

Significance:
Hypoxia-induced resistance to EGFR TKI is driven by overexpression of FGFR1 to sustain ERK signaling, where a subsequent combination of EGFR TKI with FGFR1 inhibitors or MEK inhibitors reverses this resistance.
Phosphorylation Control of p53 DNA-Binding Cooperativity Balances Tumorigenesis and Aging
Authors: Timofeev Oleg , Koch Lukas , Niederau Constantin , Tscherne Alina , Schneikert Jean , Klimovich Maria , Elmshäuser Sabrina , Zeitlinger Marie , Mernberger Marco , Nist Andrea , Osterburg Christian , Dötsch Volker , Hrabé de Angelis Martin , Stiewe Thorsten 
Published: September 2020

Abstract

Posttranslational modifications are essential for regulating the transcription factor p53, which binds DNA in a highly cooperative manner to control expression of a plethora of tumor-suppressive programs. Here we show at the biochemical, cellular, and organismal level that the cooperative nature of DNA binding is reduced by phosphorylation of highly conserved serine residues (human S183/S185, mouse S180) in the DNA-binding domain. To explore the role of this inhibitory phosphorylation in vivo, new phosphorylation-deficient p53-S180A knock-in mice were generated. Chromatin immunoprecipitation sequencing and RNA sequencing studies of S180A knock-in cells demonstrated enhanced DNA binding and increased target gene expression. In vivo, this translated into a tissue-specific vulnerability of the bone marrow that caused depletion of hematopoietic stem cells and impaired proper regeneration of hematopoiesis after DNA damage. Median lifespan was significantly reduced by 20% from 709 days in wild type to only 568 days in S180A littermates. Importantly, lifespan was reduced by a loss of general fitness and increased susceptibility to age-related diseases, not by increased cancer incidence as often seen in other p53-mutant mouse models. For example, S180A knock-in mice showed markedly reduced spontaneous tumorigenesis and increased resistance to Myc-driven lymphoma and Eml4–Alk-driven lung cancer. Preventing phosphorylation of S183/S185 in human cells boosted p53 activity and allowed tumor cells to be killed more efficiently. Together, our data identify p53 DNA-binding domain phosphorylation as a druggable mechanism that balances tumorigenesis and aging.

Significance:
These findings demonstrate that p53 tumor suppressor activity is reduced by DNA-binding domain phosphorylation to prevent aging and identify this phosphorylation as a potential target for cancer therapy.
See related commentary by Horikawa, p. 5164
Copy-Number Alteration Burden Differentially Impacts Immune Profiles and Molecular Features of Hepatocellular Carcinoma
Authors: Bassaganyas Laia , Pinyol Roser , Esteban-Fabró Roger , Torrens Laura , Torrecilla Sara , Willoughby Catherine E. , Franch-Expósito Sebastià , Vila-Casadesús Maria , Salaverria Itziar , Montal Robert , Mazzaferro Vincenzo , Camps Jordi , Sia Daniela , Llovet Josep M. 
Published: September 2020

Abstract

Purpose:
Chromosomal instability is a hallmark of cancer that results in broad and focal copy-number alterations (CNAs), two events associated with distinct molecular, immunologic, and clinical features. In hepatocellular carcinoma (HCC), the role of CNAs has not been thoroughly assessed. Thus, we dissected the impact of CNA burdens on HCC molecular and immune features.

Experimental Design:
We analyzed SNP array data from 452 paired tumor/adjacent resected HCCs and 25 dysplastic nodules. For each sample, broad and focal CNA burdens were quantified using CNApp, and the resulting broad scores (BS) and focal scores (FS) were correlated with transcriptomic, mutational, and methylation profiles, tumor immune composition, and clinicopathologic data.

Results:
HCCs with low broad CNA burdens (defined as BS ≤ 4; 17%) presented high inflammation, active infiltrate signaling, high cytolytic activity, and enrichment of the “HCC immune class” and gene signatures related to antigen presentation. Conversely, tumors with chromosomal instability (high broad CNA loads, BS ≥ 11; 40%), displayed immune-excluded traits and were linked to proliferation, TP53 dysfunction, and DNA repair. Candidate determinants of the low cytotoxicity and immune exclusion features of high-BS tumors included alterations in antigen-presenting machinery (i.e., HLA), widespread hypomethylation, and decreased rates of observed/expected neoantigenic mutations. High FSs were independent of tumor immune features, but were related to proliferation, TP53 dysfunction, and progenitor cell traits.

Conclusions:
HCCs with high chromosomal instability exhibit features of immune exclusion, whereas tumors displaying low burdens of broad CNAs present an immune active profile. These CNA scores can be tested to predict response to immunotherapies.
Long-term Outcomes of Oral Vinorelbine in Advanced, Progressive Desmoid Fibromatosis and Influence of CTNNB1 Mutational Status
Authors: Mir Olivier , Honoré Charles , Chamseddine Ali N. , Dômont Julien , Dumont Sarah N. , Cavalcanti Andrea , Faron Matthieu , Rimareix Françoise , Haddag-Miliani Leila , Le Péchoux Cécile , Levy Antonin , Court Charles , Briand Sylvain , Fadel Elie , Mercier Olaf , Bayle Arnaud , Brunet Anaïs , Ngo Carine , Rouleau Etienne , Adam Julien , Le Cesne Axel 
Published: September 2020

Abstract

Purpose:
Desmoid-type fibromatosis (DF) are locally aggressive neoplasms, with a need for effective systemic treatment in case of progression to avoid the short- and long-term complications of local treatments.

Experimental Design:
We retrospectively analyzed the outcomes of adult patients with DF treated with oral vinorelbine (90 mg once weekly) at Gustave Roussy Cancer Institute (Villejuif, Paris, France). Only patients with documented progressive disease according to RECIST v1.1 for more than 3 months (±2 weeks) before treatment initiation were included.

Results:
From 2009 to 2019, 90 out of 438 patients with DF were eligible for this analysis. Vinorelbine was given alone in 56 patients (62%), or concomitantly with endocrine therapy in 34 patients, for a median duration of 6.7 months. A partial response was observed in 29% and stable disease in another 57%. With a median follow-up of 52.4 months, the median time to treatment failure (TTF) was not reached. Progression-free rates at 6 and 12 months were 88.7% and 77.5%, respectively. Concomitant endocrine therapy was associated with longer TTF in women [HR, 2.16; 95% confidence interval (CI), 1.06–4.37; P = 0.03). Among 64 patients with documented CTNNB1 mutational status, p.S45F or p.S45P mutations were associated with longer TTF compared with p.T41A or wild-type tumors (HR, 2.78; 95% CI, 1.23–6.27; P = 0.04). Toxicity profile was favorable, without grade 3–4 toxicity, except for one grade 3 neutropenia.

Conclusions:
Oral vinorelbine is an effective, affordable, and well-tolerated regimen in patients with advanced, progressive DF. Prolonged activity was observed in patients with tumors harboring CTNNB1 p.S45F or p.S45P mutations.
Abstract A006: Multi-modal estimation of causal influences of environmental agents on colorectal cancer in an understudied population
Authors: Galadima Hadiza , Adunlin Georges , Blando James 
Published: September 2020

Abstract
Background: While there is a well-established causal relationship between several individual factors and contextual socioeconomic status with colorectal cancer, there is still a lack of strong evidence that the prevalence of environmental agents is independently associated with colorectal cancer in various geographical areas. Population-based studies assessing the causal relationship between environmental agents and colorectal cancer are limited by the scarcity of comprehensive data. Most previous studies have relied on the recall of self-reported exposures. Objective: In this study, we provide new and important insights by integrating publicly available ‘big data’ resources with hospital data to identify causal influences on colorectal cancer in an understudied rural population in Virginia. Methods: Data linkage was achieved by geocoding patients zip codes at diagnosis and spatially assigning contextual and environmental data to the hospital cancer records. Machine learning imputation methods were used to fill in the missing values that resulted from the linkage. A “Big Data” science approach was used to develop a multi-scale modeling of individual and contextual data with national and local exposomes from environmental exposures sources. The methodology is based on training a Bayesian causal network to better understand the causal inference from individual and contextual level data, as well as environmental exposures data on the outcomes of colorectal cancer. The primary source of data for this project is the Sentara Cancer Registry (SCR). The SCR collects data on cancer cases from eight Sentara hospitals. The information collected by SCR includes patient characteristics and clinical outcomes. The secondary source of data come from the U.S. Census Bureau (Census 2010). This data source is used to determine zip-code level socioeconomic status of each colorectal cancer case. Environmental data such as water quality, Superfund site locations, toxic release sites, and heavy metals were obtained from the Virginia Department of Environmental Quality. Environmental data was supplemented with Toxics Release Inventory (TRI) database, considered to be the most comprehensive data source on industrial toxic emissions in the US. Conclusion: This study contributed to the scientific innovation of leveraging mixed-methods data collection by building a comprehensive database for cancer research in an understudied population.
Citation Format: Hadiza Galadima, Georges Adunlin, James Blando. Multi-modal estimation of causal influences of environmental agents on colorectal cancer in an understudied population [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A006.
Abstract C081: Introduction of a randomized controlled trial on areca nut/betel quid cessation: The Betel Nut Intervention Trial (BENIT)
Authors: Paulino Yvette C , Wilkens Lynne R , Sotto Patrick P , Franke Adrian A , Kawamoto Crissy T , Chennaux Jade SN , Mendez Ana J , Tenorio Lynette F , Badowski Grazyna , Pokhrel Pallav , Herzog Thaddeus A 
Published: September 2020

Abstract
Areca nut, the seed of the Areca catechu L. palm evaluated to be a Group 1 carcinogen, is still chewed by 10-20% of the world population. It is often chewed with Piper betle L. leaf and other ingredients such as slaked lime and tobacco, to form a betel quid. Globally, areca nut/betel quid is the fourth most commonly used psychoactive substance after tobacco, alcohol, and caffeine. Unlike tobacco cessation, systematic research on areca nut/betel quid cessation is rare. The negative health effects associated with areca nut/betel quid consumption warrant the need for an evidence-based cessation program. Consequently, the Betel Nut Intervention Trial (BENIT) was initiated in August 2016. The BENIT is a randomized, controlled, superiority trial designed to test the efficacy of an intensive areca nut/betel quid cessation program, and to quantify the efficacy through bio-verification. The trial is ongoing in Guam and Saipan in the Mariana Islands. Adult areca nut/betel quid chewers, 18 years and older who include tobacco in their betel quid, are being enrolled into the trial. Those enrolled are assessed for the primary outcome (chewing status) and the secondary outcome (saliva bio-verification) at baseline, at 22 days, and at 6 months. The areca nut/betel quid chewers randomized into the control arm receive an educational booklet only. The areca nut/betel quid chewers randomized into the intervention arm receive the educational booklet and a 22-day cessation program modeled after a smoking cessation program and led by trained facilitators. To date, 224 chewers have been enrolled into the BENIT. The current quit percentages are 18% in the experimental group and 8% in the control group, though these results may change as the trial progresses. The BENIT is designed to provide evidence of the efficacy of a cessation program to help areca nut/betel quid with tobacco chewers to quit chewing. Although the current intervention trial focuses on Guam and Saipan, it has the potential for greater regional and global importance. TRIAL REGISTRATION: Clinical Trial # NCT02942745.
Citation Format: Yvette C Paulino, Lynne R Wilkens, Patrick P Sotto, Adrian A Franke, Crissy T Kawamoto, Jade SN Chennaux, Ana J Mendez, Lynette F Tenorio, Grazyna Badowski, Pallav Pokhrel, Thaddeus A Herzog. Introduction of a randomized controlled trial on areca nut/betel quid cessation: The Betel Nut Intervention Trial (BENIT) [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C081.