Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, ...switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency, and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.
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•Functional and structural characterization of covalent KRAS G12C inhibitors•An amino amide substituent enhances the potency and selectivity of inhibitors•Develop key assays for characterization and discovery of new KRAS inhibitors
Zeng et al. demonstrate that introduction of an amino amide substituent to the quinazoline scaffold remarkably increases the labeling efficiency and rates, potency, and selectivity of KRAS G12C inhibitors. This is supported by structural evidence that amide side chain allows additional interactions with KRAS G12C.
A picosecond Kerr-gated time-resolved resonance Raman examination of the 2-fluorenylnitrene and 4-methoxyphenylnitrene reactions with water to form the singlet 2-fluorenylnitrenium and ...4-methoxyphenylnitrenium ions, respectively, is given. Photolysis of 2-fluorenyl azide and 4-methoxyphenyl azide in mixed water/acetonitrile solvents both led to formation of transient species within a few picoseconds, and these were tentatively assigned to the 2-fluorenylnitrene and 4-methoxyphenylnitrene species, respectively. These arylnitrenes were observed to directly react with water to produce their respective singlet arylnitrenium ions. The decay of the 4-methoxyphenylnitrene species and its accompanying growth of the 4-methoxyphenylnitrenium ion were found to be much faster than the decay of the 2-fluorenylnitrene and its accompanying growth of its 2-fluorenylnitrenium ion, indicating these two different arylnitrenes have noticeably different chemical reactivity toward water. The 4-methoxyphenylnitrene species spectra displayed noticeable changes in its time-resolved Raman spectra as the solvent system is changed from pure acetonitrile to a mixed water/acetonitrile solvent whereas the 2-fluorenylnitrene spectra displayed very little if any change. These results suggest hydrogen bonding with the methoxy moiety.
This study presents two methods for estimating methane emissions from a waste water treatment plant (WWTP) along with results from a measurement campaign at a WWTP in Valence, France. These methods, ...chamber measurements and tracer release, rely on Fourier transform infrared spectroscopy and cavity ring-down spectroscopy instruments. We show that the tracer release method is suitable for quantifying facility- and some process-scale emissions, while the chamber measurements provide insight into individual process emissions. Uncertainties for the two methods are described and discussed. Applying the methods to CH4 emissions of the WWTP, we confirm that the open basins are not a major source of CH4 on the WWTP (about 10 % of the total emissions), but that the pretreatment and sludge treatment are the main emitters. Overall, the waste water treatment plant is representative of an average French WWTP.
GaAs(100) and InP(100) samples were cleaved in UHV to give (110) surface in order to investigate their energy band changes using high resolution x-ray photoelectron spectroscopy (XPS) measurement. It ...was revealed that the surface band of a heavy doped n-GaAs(110) sample bent upward 0.4 eV and that of a heavy doped p-GaAs(110) bent downward 0.3 eV to the midgap after cleavage whereas the surface band of a heavy doped n-InP(110) sample bent upward 0.1 eV and that of a heavy doped p-InP(110) bent downward 0.65 eV to the midgap. As for the causes of band bending, we excluded the possibility of surface charging, X-Ray radiation damage and the effect of residual gas in UHV during XPS measurement. The experimental results strongly suggest that the band bending process was caused by the surface lattice relaxation after cleavage.
In this Letter, we describe quantitative magnetic imaging of superconducting vortices in RbEuFe4As4 in order to investigate the unique interplay between the magnetic and superconducting sublattices. ...Our scanning Hall microscopy data reveal a pronounced suppression of the superfluid density near the magnetic ordering temperature in good qualitative agreement with a recently developed model describing the suppression of superconductivity by correlated magnetic fluctuations. These results indicate a pronounced exchange interaction between the superconducting and magnetic subsystems in RbEuFe4As4, with important implications for future investigations of physical phenomena arising from the interplay between them.
Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive ...therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients.
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•Loss of EGFR signaling leads to senescence-like dormancy in EGFR-mutant lung cancer•YAP promotes survival and dormancy in the absence of EGFR downstream signaling•YAP/TEAD/SLUG suppress apoptosis through transcriptional repression of BMF•A TEAD inhibitor enhances EGFR inhibitor-mediated apoptosis and prevents dormancy
Kurppa et al. show that YAP activation mediates resistance to combined EGFR/MEK inhibition by inducing dormancy in non-small-cell lung cancer cells. Targeting the YAP pathway, in part by using a newly developed covalent TEAD inhibitor, promotes apoptosis of the dormant therapy-resistant cancer cells.
Background There is a significant incidence of unrecognized postextubation dysphagia in trauma patients. The purpose of this study was to evaluate the incidence, ascertain the risk factors, and ...identify patients with postextubation dysphagia who will require clinical swallow evaluation. Methods A prospective observational study was performed on 270 trauma patients. Bedside clinical swallow evaluation was done within 24 hours of extubation. Logistic regression analysis was used to adjust for confounding variables. Results The incidence of oropharyngeal dysphagia (OD) in our study was 42%. Ventilator days was the strongest independent risk factor for OD (3.6 vs 8.0, P < .001). The odds ratio showed a 25% risk for OD for each additional ventilator day. Silent aspiration was found in 37% of patients with OD. Conclusions Trauma patients requiring mechanical ventilation for ≥2 days are at increased risk for dysphagia and should undergo routine swallow evaluations after extubation.
Mass-separated polyatomic ions, including CH
3
+, CF
+,
CF
2
+ and OH
+, have been delivered to an ultrahigh vacuum chamber in the energy range of 2–100 eV for the studies of surface reaction ...mechanisms induced by such ion arrivals as a function of impact energy, with a particular reference to reactive ion etching of semiconductors for CH
3
+, CF
+, and CF
2
+, and surface modification of polymers for OH
+. It was found that at the low end of the energy range, these polyatomic ions could survive from molecular dissociation at impact and react with a target surface as hyperthermal molecules. For example, 3 eV CH
3
+ was successfully used for etching InP in a reversed organometallic chemical vapor deposition approach, and 10 eV OH
+ for adding a single functionality of COH to polystyrene. However, when the ion arrival energy is higher than 10–20 eV, impact dissociation of the arriving reactant switches the reaction to those associated with the dissociation fragments instead of the parent reactant. At even higher arrival energies, the atomic fragments from the impact dissociation possess enough energy to penetrate into the sub-surface region, and reactions involving these atomic species are driven by the relevant local chemical potentials inside the substrate. For example, 20 eV CH
3
+/InP showed no effective etching of InP but deposition of a carbon film, and 20 eV OH
+/ polystyrene gave a mixture of oxygen containing functionalities. In the study of reactive ion etching of Si and SiO
2, it was found that CF
+ arrivals on Si gave simple CF accumulation at an arrival energy of 2 eV, a mixture of CF, CF
2 and CF
3, species at 20 eV, and no fluorocarbon but silicon carbide at 100 eV. Etching of SiO
2 was observed with 100 eV CF
2
+, the mechanism of which can be attributed to the release of a sufficiently high concentration of fluorine in the near surface region. Hence, unlike the CH
3
+/InP reaction system, the CF
x
+/SiO
2 system switches from overlayer deposition to etching when the impact energy is high enough for effective impact dissociation.
Background. Several studies have documented the substantial health and economic burdens associated with sarcopenia among the elderly, but there has been no systematic study among Asians. A ...cross-sectional survey of elderly community-dwelling Chinese volunteers (262 men and 265 women), aged 70 years and older, was undertaken in Hong Kong. The purposes of this study were to evaluate the prevalence of and risk factors for sarcopenia in elderly Chinese, and to compare these observations with those in white persons. Methods. Muscle mass was estimated by dual-energy X-ray absorptiometry. In this study, sarcopenia was defined as a total adjusted skeletal muscle mass two standard deviations or more below the normal mean for young Asian men and women in this study. The relationship between risk factors (alcohol consumption, cigarette smoking, regular exercise, body mass index, medical conditions) and sarcopenia was studied by multiple logistic regression. Results. The prevalence of sarcopenia was 12.3% in Chinese men and 7.6% in Chinese women aged 70 years and older, which was slightly lower than figures observed in white persons. Being underweight was a significant risk factor in both men (odds ratio, 39.1; 95% confidence interval, 11.3 to 134.6) and women (odds ratio, 9.7; 95% confidence interval, 2.8 to 33.8). No other risk factors were found in Chinese men or women. Conclusions. Sarcopenia exists among elderly Chinese men and women, albeit at a lower rate than in white persons. This may be due to the lower muscle mass among young men and women or to an attenuated rate of loss in muscle mass with aging in the Chinese elderly. Being underweight is a major risk factor for sarcopenia in both sexes.
Purpose
Thyroid dysfunction in COVID-19 carries clinical and prognostic implications. In this study, we developed a prediction score (ThyroCOVID) for abnormal thyroid function (TFT) on admission ...amongst COVID-19 patients.
Methods
Consecutive COVID-19 patients admitted to Queen Mary Hospital were prospectively recruited during July 2020–May 2021. Thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) were measured on admission. Multivariable logistic regression analysis was performed to identify independent determinants of abnormal TFTs. ThyroCOVID was developed based on a clinical model with the lowest Akaike information criteria.
Results
Five hundred and forty six COVID-19 patients were recruited (median age 50 years, 45.4% men, 72.9% mild disease on admission). 84 patients (15.4%) had abnormal TFTs on admission. Patients with abnormal TFTs were more likely to be older, have more comorbidities, symptomatic, have worse COVID-19 severity, higher SARS-CoV-2 viral loads and more adverse profile of acute-phase reactants, haematological and biochemical parameters. ThyroCOVID consisted of five parameters: symptoms (malaise), comorbidities (ischaemic heart disease/congestive heart failure) and laboratory parameters (lymphocyte count, C-reactive protein, and SARS-CoV-2 cycle threshold values). It was able to identify abnormal TFT on admission with an AUROC of 0.73 (95% CI 0.67–0.79). The optimal cut-off of 0.15 had a sensitivity of 75.0%, specificity of 65.2%, negative predictive value of 93.5% and positive predictive value of 28.1% in identifying abnormal TFTs on admission amongst COVID-19 patients.
Conclusion
ThyroCOVID, a prediction score to identify COVID-19 patients at risk of having abnormal TFT on admission, was developed based on a cohort of predominantly non-severe COVID-19 patients.
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