PTEN as a Prognostic and Predictive Marker in Postoperative Radiotherapy for Squamous Cell Cancer of the Head and Neck

BACKGROUND: Tumor suppressor PTEN is known to control a variety of processes related to cell survival, proliferation, and growth. PTEN expression is considered as a prognostic factor in some human neoplasms like breast, prostate, and thyroid cancer. METHODOLOGY/PRINCIPAL FINDINGS: In this study we analyzed the influence of PTEN expression on the outcome of a randomized clinical trial of conventional versus 7-days-a-week postoperative radiotherapy for squamous cell cancer of the head and neck. The patients with cancer of the oral cavity, oropharynx, and larynx were randomized to receive 63 Gy in fractions of 1.8 Gy given 5 days a week (CF) or 7 days a week (p-CAIR). Out of 279 patients enrolled in the study, 147 paraffin blocks were available for an immunohistochemical assessment of PTEN. To evaluate the prognostic value of PTEN expression and the effect of fractionation relative to PTEN, the data on the outcome of a randomized clinical trial were analyzed. Tumors with a high intensity of PTEN staining had significant gain in the loco-regional control (LRC) from p-CAIR (5-year LRC 92.7% vs. 70.8%, for p-CAIR vs. CF, p = 0.016, RR = 0.26). By contrast, tumors with low intensity of PTEN did not gain from p-CAIR (5-year LRC 56.2% vs. 47.2%, p = 0.49, RR = 0.94). The intensity of PTEN highly affected the LRC in a whole group of 147 patients (5-year LRC 80.9% vs. 52.3% for high vs. low PTEN, p = 0.0007, RR = 0.32). In multivariate Cox analysis, including neck node involvement, EGFR, nm23, Ki-67, p53, cyclin D1, tumor site and margins, PTEN remained an independent predictor of LRC (RR = 2.8 p = 0.004). CONCLUSIONS/SIGNIFICANCE: These results suggest that PTEN may serve as a potent prognostic and predictive marker in postoperative radiotherapy for high-risk squamous cell cancer of the head and neck

On the Electronic Structure of mer,trans−[RuCl3(1H−indazole)2(NO)]mer,trans-[RuCl_{3}(1 H -indazole)_{2}(NO)], a Hypothetical Metabolite of the Antitumor Drug Candidate KP1019: An Experimental and DFT Study

The study reported herein focused on the electronic structure of the {Ru(NO)}6 fragment and characterization of the oxidation state of ruthenium in mer,trans-[RuCl3(Hind)2(NO)] (1; Hind = 1H-indazole) resulting from the reaction of mer,trans-[RuCl3(H2O)(Hind)2] (2) with NO in acetone or solid-state Anderson rearrangement of (H2ind)2[RuCl5(NO)] at 180 °C. The results of X-ray diffraction, 1H, 13C, and 15N NMR, EPR, IR, and UV/Vis spectroscopy, cyclic voltammetry, magnetic susceptibility, and XANES/EXAFS as well as theoretical data have been critically analyzed. The localized orbitals, domain-averaged Fermi holes, frontier orbitals, Mulliken population, and quantum theory of atoms-in-molecules (QTAIM) analyses are presented. In addition, mer,trans-[RuIIICl3(H2O)(Hind)2] (2) and trans-[RuIICl2(Hind)4] (3) were experimentally and theoretically investigated as reference compounds. A complete active space SCF calculation was performed to estimate the extent of antiferromagnetic spin–spin coupling in 1. We found that the closed-shell structure {RuIII(NO)0}6 fits better to the physical/spectroscopic properties of 1, although {RuII(NO)+}6 is formally still suitable for describing the oxidation state of Ru in this entit

Associations between antimicrobial use and the faecal resistome on broiler farms from nine European countries

Objectives: To determine associations between farm-and flock-level antimicrobial usage (AMU), farmbiosecurity status and the abundance of faecal antimicrobial resistance genes (ARGs) on broiler farms. Methods: In the cross-sectional pan-European EFFORT study, conventional broiler farms were visited and faeces, AMU information and biosecurity records were collected. The resistomes of pooled faecal samples were determined by metagenomic analysis for 176 farms. A meta-analysis approach was used to relate total and classspecific ARGs (expressed as fragments per kb reference per million bacterial fragments, FPKM) to AMU (treatment incidence per DDD, TIDDDvet) per country and subsequently across all countries. In a similar way, the association between biosecurity status (Biocheck. UGent) and the resistome was explored. Results: Sixty-six (38%) flocks did not report group treatments but showed a similar resistome composition and roughly similar ARG levels to antimicrobial-treated flocks. Nevertheless, we found significant positive associations between beta-lactam, tetracycline, macrolide and lincosamide, trimethoprim and aminoglycoside antimicrobial flock treatments and ARG clusters conferring resistance to the same class. Similar associations were found with purchased products. In gene-level analysis for beta-lactams and macrolides, lincosamides and streptogramins, a significant positive association was found with the most abundant gene clusters blaTEM and erm(B). Little evidence was found for associations with biosecurity. Conclusions: The faecal microbiome in European broilers contains a high diversity of ARGs, even in the absence of current antimicrobial selection pressure. Despite this, the relative abundance of genes and the composition of the resistome is positively related to AMU in European broiler farms for several antimicrobial classes

Erratum to: Abundance and diversity of the faecal resistome in slaughter pigs and broilers in nine European countries (Nature Microbiology, (2018), 3, 8, (898-908), 10.1038/s41564-018-0192-9)

In the version of this Article originally published, the surname of author Oksana Lukjancenko was spelt incorrectly as ‘Lukjacenko’. This has now been corrected

Abundance and diversity of the faecal resistome in slaughter pigs and broilers in nine European countries

Antimicrobial resistance (AMR) in bacteria and associated human morbidity and mortality is increasing. The use of antimicrobials in livestock selects for AMR that can subsequently be transferred to humans. This flow of AMR between reservoirs demands surveillance in livestock and in humans. We quantified and characterized the acquired resistance gene pools (resistomes) of 181 pig and 178 poultry farms from nine European countries, sequencing more than 5,000 Gb of DNA using shotgun metagenomics. We quantified acquired AMR using the ResFinder database and a second database constructed for this study, consisting of AMR genes identified through screening environmental DNA. The pig and poultry resistomes were very different in abundance and composition. There was a significant country effect on the resistomes, more so in pigs than in poultry. We found higher AMR loads in pigs, whereas poultry resistomes were more diverse. We detected several recently described, critical AMR genes, including mcr-1 and optrA, the abundance of which differed both between host species and between countries. We found that the total acquired AMR level was associated with the overall country-specific antimicrobial usage in livestock and that countries with comparable usage patterns had similar resistomes. However, functionally determined AMR genes were not associated with total drug use

Antimicrobial resistance genes aph(3′)-III, erm(B), sul2 and tet(W) abundance in animal faeces, meat, production environments and human faeces in Europe

Background: Real-Time quantitative PCR (qPCR) is an affordable method to quantify antimicrobial resistance gene (ARG) targets, allowing comparisons of ARG abundance along animal production chains. Objectives: We present a comparison of ARG abundance across various animal species, production environments and humans in Europe. AMR variation sources were quantified. The correlation of ARG abundance between qPCR data and previously published metagenomic data was assessed. Methods: A cross-sectional study was conducted in nine European countries, comprising 9572 samples. qPCR was used to quantify abundance of ARGs [aph(3′)-III, erm(B), sul2, tet(W)] and 16S rRNA. Variance component analysis was conducted to explore AMR variation sources. Spearman's rank correlation of ARG abundance values was evaluated between pooled qPCR data and earlier published pooled metagenomic data. Results: ARG abundance varied strongly among animal species, environments and humans. This variation was dominated by between-farm variation (pigs) or within-farm variation (broilers, veal calves and turkeys). A decrease in ARG abundance along pig and broiler production chains ('farm to fork') was observed. ARG abundance was higher in farmers than in slaughterhouse workers, and lowest in control subjects. ARG abundance showed a high correlation (Spearman's ρ>0.7) between qPCR data and metagenomic data of pooled samples. Conclusions: qPCR analysis is a valuable tool to assess ARG abundance in a large collection of livestock-Associated samples. The between-country and between-farm variation of ARG abundance could partially be explained by antimicrobial use and farm biosecurity levels. ARG abundance in human faeces was related to livestock antimicrobial resistance exposure

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Author Correction: Abundance and diversity of the faecal resistome in slaughter pigs and broilers in nine European countries

In the version of this Article originally published, the surname of author Oksana Lukjancenko was spelt incorrectly as ‘Lukjacenko’. This has now been corrected.</p