Ras proteins are of importance in cell proliferation, and hence their mutated forms play causative roles in many kinds of cancer in different tissues. Inhibition of the Ras‐depalmitoylating enzyme ...acyl protein thioesterases APT1 and ‐2 is a new approach to modulating the Ras cycle. Here we present boronic and borinic acid derivatives as a new class of potent and nontoxic APT inhibitors. These compounds were detected by extensive library screening using chemical arrays and turned out to inhibit human APT1 and ‐2 in a competitive mode. Furthermore, one of the molecules was demonstrated to inhibit Erk1/2 phosphorylation significantly.
Ras depalmitoylation inhibitors: Different boronic and boronic acid inhibitors were found to target acyl protein thioesterases on a microarray screening chip. Individual inhibitors also display appreciable isoenzymatic specificity for APT2; this makes these boronic acids a class of APT inhibitors with specificity for one of the APTs.
Previous studies have indicated an association between coronavirus disease 2019 (COVID-19) and acute kidney injury (AKI) but lacked a control group. The prospective observational COronaVIrus-surviVAl ...(COVIVA) study performed at the University Hospital, Basel, Switzerland consecutively enrolled patients with symptoms suggestive of COVID-19. We compared patients who tested positive for SARS-CoV-2 with patients who tested negative but with an adjudicated diagnosis of a respiratory tract infection, including pneumonia. The primary outcome measure was death at 30 days, and the secondary outcomes were AKI incidence and a composite endpoint of death, intensive care treatment or rehospitalization at 30 days. Five hundred and seven patients were diagnosed with respiratory tract infections, and of those, 183 (36%) had a positive PCR swab test for SARS-CoV-2. The incidence of AKI was higher in patients with COVID-19 (30% versus 12%,
< 0.001), more severe (KDIGO stage 3, 22% versus 13%,
= 0.009) and more often required renal replacement therapy (4.4% versus 0.93%;
= 0.03). The risk of 30-day mortality and a composite endpoint was higher in patients with COVID-19-associated AKI (adjusted hazard ratio (aHR) mortality 3.98, 95% confidence interval (CI) 1.10-14.46,
= 0.036; composite endpoint aHR 1.84, 95% CI 1.02-3.31,
= 0.042). The mortality risk was attenuated when adjusting for disease severity (aHR 3.60, 95% CI 0.93-13.96,
= 0.062). AKI occurs more frequently and with a higher severity in patients with COVID-19 and is associated with worse outcomes.
Inhibitors of DNA topoisomerase I (TOP1), an enzyme relieving torsional stress of DNA by generating transient single-strand breaks, are clinically used to treat ovarian, small cell lung and cervical ...cancer. As torsional stress is generated during transcription by progression of RNA polymerase II through the transcribed gene, we tested the effects of camptothecin and of the approved TOP1 inhibitors Topotecan and SN-38 on TNFα-induced gene expression. RNA-seq experiments showed that inhibition of TOP1 but not of TOP2 activity suppressed the vast majority of TNFα-triggered genes. The TOP1 effects were fully reversible and preferentially affected long genes. TNFα stimulation led to inducible recruitment of TOP1 to the gene body of
, where its inhibition by camptothecin reduced transcription elongation and also led to altered histone H3 acetylation. Together, these data show that TOP1 inhibitors potently suppress expression of proinflammatory cytokines, a feature that may contribute to the increased infection risk occurring in tumor patients treated with these agents. On the other hand, TOP1 inhibitors could also be considered as a therapeutic option in order to interfere with exaggerated cytokine expression seen in several inflammatory diseases.
Aims
The aim of this study was to investigate the diagnostic and prognostic utility of the QRS‐T angle, an electrocardiogram (ECG) marker quantifying depolarization–repolarization heterogeneity, in ...patients with suspected acute decompensated heart failure (ADHF).
Methods and results
We prospectively enrolled unselected patients presenting to the emergency department with symptoms suggestive of ADHF. The QRS‐T angle was automatically derived from a standard 12‐lead ECG recorded at presentation. The primary diagnostic endpoint was a final adjudicated diagnosis of ADHF. The primary prognostic endpoint was all‐cause mortality during 2 years of follow‐up. Among the 1915 patients enrolled, those with higher QRS‐T angles were older, were more commonly male, and had a higher rate of co‐morbidities such as arterial hypertension, coronary artery disease, or chronic kidney disease. ADHF was the final adjudicated diagnosis in 1140 (60%) patients. The QRS‐T angle in patients with ADHF was significantly larger than in patients with non‐cardiac causes of dyspnoea {median 110° inter‐quartile range (IQR) 46–156° vs. median 33° IQR 15–57°, P < 0.001}. The diagnostic accuracy of the QRS‐T angle as quantified by the area under the receiver operating characteristic curve (AUC) was 0.75 95% confidence interval (CI) 0.73–0.77, P < 0.001, which was inferior to N‐terminal pro‐B‐type natriuretic peptide (AUC 0.93, 95% CI 0.92–0.94, P < 0.001), but similar to that of high‐sensitivity troponin T (AUC 0.78, 95% CI 0.76–0.80, P = 0.09). The AUC of the QRS‐T angle for discrimination between ADHF and non‐cardiac dyspnoea remained similarly high in subgroups of patients known to be diagnostically challenging, including patients older than 75 years 0.71 (95% CI 0.67–0.74), renal failure 0.79 (95% CI 0.71–0.87), and atrial fibrillation at presentation 0.68 (95% CI 0.60–0.76). Mortality rates according to QRS‐T angle tertiles were 4%, 6%, and 10% after 30 days (P < 0.001) and 24%, 31%, and 43% after 2 years (P < 0.001). After adjustment for clinical, laboratory, and ECG parameters, the QRS‐T angle remained an independent predictor for 2 year mortality with a 4% increase in mortality for every 20° increase in QRS‐T angle (P = 0.02).
Conclusions
The QRS‐T angle is a readily available and inexpensive marker that can assist in the discrimination between ADHF and non‐cardiac causes of acute dyspnoea and may aid in the risk stratification of these patients.
We observe the fluorescence of pristine diamondoids in the gas phase, excited using narrow band ultraviolet laser light. The emission spectra show well-defined features, which can be attributed to ...transitions from the excited electronic state into different vibrational modes of the electronic ground state. We assign the normal modes responsible for the vibrational bands, and determine the geometry of the excited states. Calculations indicate that for large diamondoids, the spectral bands do not result from progressions of single modes, but rather from combination bands composed of a large number of Δ
v
= 1 transitions. The vibrational modes determining the spectral envelope can mainly be assigned to wagging and twisting modes of the surface atoms. We conclude that our theoretical approach accurately describes the photophysics in diamondoids and possibly other hydrocarbons in general.
We report on the laser-induced fluorescence of diamondoids in the gas phase. The spectra show well defined vibrational structure, whose complex nature is assigned with the help of TDDFT computations.
The authors then present Figure 4 of their paper as a plot of the “Hazard ratio of mortality as a function of first measured mixed venous oxygen saturation … and first measured cardiac index … values ...during intensive care after cardiac arrest.” Availability of data and materials The Mayo Clinic Primary Biliary Cholangitis Dataset used to create the example of a dose–response hazard ratio plot is part of the R “survival” package (https://rdrr.io/cran/survival/man/pbc.html) 6. Serial assessments of cardiac output and mixed venous oxygen saturation in comatose patients after out-of-hospital cardiac arrest.
Aims
Concern has been raised that treatment with angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers may increase the expression of angiotensin‐converting enzyme 2 (ACE2), ...which acts as the entry receptor for SARS‐CoV‐2, and lead to an increased risk of death from SARS‐CoV‐2. We aimed to address this concern by evaluating the in vivo relationship of treatment with ACE inhibitors and angiotensin receptor blockers (ARB) with circulating plasma concentrations of ACE2 in a large cohort of patients with established cardiovascular disease (n = 1864) or cardiovascular risk factors (n = 2144) but without a history of heart failure.
Methods and results
Angiotensin‐converting enzyme 2 was measured in 4008 patients (median age 68, 33% women, 31% on ACE‐inhibitors, 31% on ARB) using the SOMAscan proteomic platform (SomaLogic Inc, Colorado, USA). Plasma concentration of ACE2 was comparable in 1250 patients on ACE inhibitors (mean 5.99) versus patients without ACE inhibitors (mean 5.98, P = 0.54). Similarly, plasma concentration of ACE2 was comparable in 1260 patients on ARB (mean 5.99) versus patients without ARB (mean 5.98, P = 0.50). Plasma concentration of ACE2 was comparable in 2474 patients on either ACE inhibitors or ARB (mean 5.99) versus patients without ACE inhibitors or ARB (mean 5.98, P = 0.31). Multivariable quantile regression model analysis confirmed the lack of association between treatment with ACE inhibitors or ARB and ACE2 concentrations. Body mass index showed the only positive association with ACE2 plasma concentration (effect 0.015, 95% confidence interval 0.002 to 0.028, P = 0.024).
Conclusions
In a large cohort of patients with established cardiovascular disease or cardiovascular risk factors but without heart failure, ACE inhibitors and ARB were not associated with higher plasma concentrations of ACE2.
The leakage flow across the shroud of turbine blades causes substantial aerodynamic losses as it mixes with the freestream flow within the main annulus. The present paper shows the measurement ...results of two different rotor sealing designs in turbo machines in combination with tangential end wall contouring. Tests are conducted at 2-stage turbine integrated in an air cycle, located at the Institute of Power Plant Technology, Steam and Gas Turbines, RWTH Aachen University. Two operating points characterized by the stage loading coefficient at design and overload conditions are analyzed. Constant section shrouded airfoils are sealed by means of labyrinth seals as well as combined labyrinth- and brush seals. The investigations show the impact of the brush seal to the efficiency and respectively to the secondary flow. The pressure level within each cavity chamber is measured, which allows the analysis of the seal’s pressure drop and the corresponding mass flow that passes through the flow path above the shroud in detail. The flow profiles in several measurement planes are recorded along the radial height of the annulus thus the thermodynamic parameters as well as the flow direction are determined precisely. Therefore the impact of the different sealing types to the main flow can be visualized. Additionally the pressure distribution of one stator vane at the second stage is measured on two radial positions to detect changes of blade loading due to the brush seal application. The investigation turns out that the leakage flow is blocked for the configuration with brush seal thus mixing effects are inhibited however rotor – stator interaction is considered. It is also shown that the reduced leakage flow supports the impact of the end wall contouring which leads to significant benefits in off design operation.
Zearalenone analogue
5 turned out to be an inhibitor of human carbonyl reductase 1 (CBR1).
In order to extend the chemical diversity available for organic polyketide synthesis, the concept of ...propionate scanning was developed. We observed that naturally occurring polyketides frequently comprise not only acetate, but also some propionate as building blocks. Therefore our approach consists of a systematic replacement of some of the acetate building blocks during synthesis by propionate moieties, resulting in additional methyl groups that may give rise to different properties of the polyketides. Here we present the results of a first ‘proof of concept’ study where a novel zearalenone analogue
5 was prepared that comprises an additional methyl group at C5′. Key steps in the synthesis of
5 include a Marshall–Tamaru reaction, a Suzuki cross-coupling reaction, and a Mitsunobu lactonization. Compared to the parent zearalenone (
1), analogue
5 showed reduced binding to a panel of human protein kinases and no binding to human Hsp90. On the other hand, however,
5 turned out to be a potent (IC
50
=
210
nM) inhibitor of human carbonyl reductase 1 (CBR1).
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