Targeting of the human ribosome is an unprecedented therapeutic modality with a genome‐wide selectivity challenge. A liver‐targeted drug candidate is described that inhibits ribosomal synthesis of ...PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell‐free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18F‐isotopologue validated our liver‐targeting approach.
A liver‐targeting strategy was developed for a small‐molecule drug candidate that inhibits PCSK9 synthesis at the human ribosome. Chemistry enabling the synthesis of N1 tetrazole prodrugs and a companion PET tracer were essential to validating the approach.
The Jet Experiments in Nuclear Structure and Astrophysics (JENSA) gas-jet target was used to perform spectroscopic studies of 20Ne+p reactions. Levels in 19Ne were probed via the 20Ne(p,d)19Ne ...reaction to constrain the astrophysical rate of the 18F(p,a)15O reaction. Additionally, the first spectroscopic study of the 20Ne(p,3He)18F reaction was performed. Angular distribution data were used to determine or confirm the spins of several previously observed levels, and the existence of a strong subthreshold 18F(p,a)15O resonance was verified.
Peer Reviewed
The present study investigates the role of nitric oxide and the involvement of nitric oxide synthase II isoform on the invasion of human colorectal adenocarcinoma cell lines HRT-18 and HT-29. HRT-18 ...cells, which constitutively express nitric oxide synthase II mRNA were three-fold more invasive in a Matrigel invasion assay than nitric oxide synthase II mRNA negative HT-29 cells. Treatment of HT-29 cells with the nitric oxide donor Deta NONOate (50 nM) as well as induction of nitric oxide synthase II mRNA and production of endogenous nitric oxide by inflammatory cytokines (IFN-gamma and IL-1alpha) increased the invasiveness of HT-29 cells by approximately 40% and 75%, respectively. In HT-29 cells nitric oxide synthase II mRNA was also induced in co-culture with human monocytes. The invasiveness of HRT-18 cells and stimulated HT-29 cells was partly inhibited by the nitric oxide synthase II inhibitor 1400 W. These results show that nitric oxide increases the invasion of human colorectal adenocarcinoma cell lines HRT-18 and HT-29, and the involvement of nitric oxide synthase II isoform in tumour cell invasion. Therefore, the production of nitric oxide and secretion of pro-inflammatory cytokines by tumour-associated macrophages, which in turn induce nitric oxide synthase II isoform in tumour cells, promotes tumour cell invasiveness.
To determine whether endogenous opioids contribute to the pruritus of cholestasis by studying the effect of the opiate antagonist naloxone on the perception of pruritus and on scratching activity in ...patients with this form of pruritus.
Double-blind, placebo-controlled, crossover trial with four periods.
Clinical research referral center.
29 pruritic patients with liver diseases of various causes.
Each patient received as many as two naloxone and two placebo solution infusions consecutively in random order. Each infusion lasted 24 hours.
During the infusions, visual analog scores of pruritus were recorded every 4 hours while patients were awake; scratching activity independent of limb movements was recorded continuously.
One patient had a mild reaction consistent with a naloxone-precipitated syndrome similar to opiate withdrawal. A significant 24-hour rhythm of scratching activity was seen in 7 of 11 patients for whom complete 96-hour data were collected. The mean of a visual analog score of the perception of pruritus (maximum, 10.0) recorded during naloxone infusions was 0.582 lower than that recorded during placebo infusions (95% CI, 0.176 to 0.988; P < 0.01). Furthermore, the ratio of the geometric mean hourly scratching activity during naloxone infusions to that during placebo infusions was 0.727 (CI, 0.612 to 0.842; P < 0.001) and was greater than 1.0 in only five patients.
Naloxone administration is associated with amelioration of the perception of pruritus and reduction of scratching activity in cholestatic patients. Because of the opioid receptor specificity of the action of naloxone, these findings support the hypothesis that a mechanism underlying the pruritus of cholestasis is modulated by endogenous opioids and suggest that opiate antagonists may have a role in the management of this complication of cholestasis.
Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the ...development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.
A
bstract
Evidence for Higgs boson decay to a pair of muons is presented. This result combines searches in four exclusive categories targeting the production of the Higgs boson via gluon fusion, via ...vector boson fusion, in association with a vector boson, and in association with a top quark-antiquark pair. The analysis is performed using proton-proton collision data at
s
= 13 TeV, corresponding to an integrated luminosity of 137 fb
−
1
, recorded by the CMS experiment at the CERN LHC. An excess of events over the back- ground expectation is observed in data with a significance of 3.0 standard deviations, where the expectation for the standard model (SM) Higgs boson with mass of 125.38 GeV is 2.5. The combination of this result with that from data recorded at
s
= 7 and 8 TeV, corresponding to integrated luminosities of 5.1 and 19.7 fb
−
1
, respectively, increases both the expected and observed significances by 1%. The measured signal strength, relative to the SM prediction, is
1.19
−
0.39
+
0.40
stat
−
0.14
+
0.15
syst
. This result constitutes the first evidence for the decay of the Higgs boson to second generation fermions and is the most precise measurement of the Higgs boson coupling to muons reported to date.
The Galactic 1.809-MeV gamma -ray signature from the beta decay of Al26g is a dominant target of gamma -ray astronomy, of which a significant component is understood to originate from massive stars. ...The Al26g(p, gamma ) Si27 reaction is a major destruction pathway for Al26g at stellar temperatures, but the reaction rate is poorly constrained due to uncertainties in the strengths of low-lying resonances in Si27. The Al26g(d,p)Al27 reaction has been employed in inverse kinematics to determine the spectroscopic factors, and hence resonance strengths, of proton resonances in Si27 via mirror symmetry. The strength of the 127-keV resonance is found to be a factor of 4 higher than the previously adopted upper limit, and the upper limit for the 68-keV resonance has been reduced by an order of magnitude, considerably constraining the Al26g destruction rate at stellar temperatures.
The Galactic 1.809-MeV γ-ray signature from the β decay of ^{26g}Al is a dominant target of γ-ray astronomy, of which a significant component is understood to originate from massive stars. The ...^{26g}Al(p,γ)^{27}Si reaction is a major destruction pathway for ^{26g}Al at stellar temperatures, but the reaction rate is poorly constrained due to uncertainties in the strengths of low-lying resonances in ^{27}Si. The ^{26g}Al(d,p)^{27}Al reaction has been employed in inverse kinematics to determine the spectroscopic factors, and hence resonance strengths, of proton resonances in ^{27}Si via mirror symmetry. The strength of the 127-keV resonance is found to be a factor of 4 higher than the previously adopted upper limit, and the upper limit for the 68-keV resonance has been reduced by an order of magnitude, considerably constraining the ^{26g}Al destruction rate at stellar temperatures.
Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM ...staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms.
The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided.
Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio HR of death = 16.23, 95% confidence interval CI = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability.
Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.
Zusammenfassung
Hintergrund
Der Artikel gibt eine Übersicht über die Diagnostik des Ovarialkarzinoms, eine seltene, aber häufig letale Erkrankung. Die jüngste Entwicklung auf dem Gebiet hat gezeigt, ...dass es sich beim Ovarialkarzinom tumorbiologisch nicht um eine Erkrankung, sondern vielmehr um verschiedene Subtypen mit jeweils spezifischer Pathogenese, Morphologie, Molekularpathologie und Prognose handelt.
Methode
Der Artikel basiert auf selektiver Literaturrecherche in PubMed und gängigen pathologischen Standardwerken sowie eigener Erfahrung in Diagnostik und konsiliarpathologischer Tätigkeit am Institut für Pathologie – Charité – Universitätsmedizin Berlin.
Ergebnisse
Der häufigste histologische Subtyp ist das seröse High-grade-Ovarialkarzinom; daneben gibt es die selteneren serösen Low-grade- sowie die endometrioiden, klarzelligen und muzinösen Ovarialkarzinome. Das seröse High-grade-Adenokarzinom entsteht nach aktueller Lehrmeinung auf dem Boden eines serösen tubaren intraepithelialen Karzinoms (STIC) und ist durch eine hohe Rate an p53-Mutationen und Defekte in der homologen Rekombination gekennzeichnet.
Das seröse Low-grade-Adenokarzinom entsteht hingegen über ein Borderline-Karzinom-Kontinuum und ist molekular durch pathologische Genmutationen von
KRAS
oder
BRAF
charakterisiert. Endometrioide und klarzellige Adenokarzinome entstehen am ehesten in Zusammenhang mit einer Endometriose und weisen daher entsprechende molekulare Aberrationen der Gene wie
PI3KCA, CTNNB1
und
ARID1A
auf. Weiterhin ist das endometrioide Adenokarzinom mit einer Mikrosatelliteninstabilität assoziiert. Der Ursprung muzinöser Ovarialtumoren ist weitestgehend unbekannt. Auch wenn ein Primarius im Gastrointestinaltrakt ausgeschlossen wird, ähneln sie morphologisch und molekular den kolorektalen Karzinomen.
Schlussfolgerung
Die molekularen Eigenheiten beeinflussen entscheidend die Prognose, den klinischen Verlauf, die Chemosensititvität und die Rezidivneigung. Translationale und klinische Studien dieses spannenden Gebiets sind notwendig, um tumorbiologische Besonderheiten herauszukristallisieren und multimodale innovative Therapiestrategien zu entwickeln.
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