Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the ...acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR. PUBLICATION ABSTRACT
Transforming growth factor-beta1 (TGF-beta1) belongs to a family of multifunctional cytokines that regulate a variety of biological processes, including cell differentiation, proliferation, and ...apoptosis. The effects of TGF-beta1 are cell context and cell cycle specific and may be signaled through several pathways. We examined the effect of TGF-beta1 on apoptosis of primary human central airway epithelial cells and cell lines. TGF-beta1 protected human airway epithelial cells from apoptosis induced by either activation of the Fas death receptor (CD95) or by corticosteroids. This protective effect was blocked by inhibition of the Smad pathway via overexpression of inhibitory Smad7. The protective effect is associated with an increase in the cyclin-dependent kinase inhibitor p21 and was blocked by the overexpression of key gatekeeper cyclins for the G1/S interface, cyclins D1 and E. Blockade of the Smad pathway by overexpression of the inhibitory Smad7 permitted demonstration of a TGF-beta-mediated proapoptotic pathway. This proapoptotic effect was blocked by inhibition of the p38 MAPK kinase signaling with the inhibitor SB-203580 and was associated with an increase in p38 activity as measured by a kinase assay. Here we demonstrate dual signaling pathways involving TGF-beta1, an antiapoptotic pathway mediated by the Smad pathway involving p21, and an apoptosis-permissive pathway mediated in part by p38 MAPK.
The LOFAR Two-metre Sky Survey (LoTSS) will map the complete Northern sky and provide an excellent opportunity to study the distribution and evolution of the large-scale structure of the Universe. We ...study the completeness of the LoTSS first data release (DR1) and find a point-source completeness of 99 % above flux densities of 0.8 mJy and define a suite of quality cuts. We determine the count-in-cell statistics and differential source counts statistic and measure the angular two-point correlation function of the LoTSS radio sources. The counts-in-cell statistic reveals that the distribution of radio sources cannot be described by a spatial Poisson process. Instead, a good fit is provided by a compound Poisson distribution. The differential source counts are in good agreement with previous findings in deep fields at low radio frequencies and with simulated catalogues from the SKA design study sky and the Tiered Radio Extragalactic Continuum Simulation. The angular two-point correlation is \(<10^{-2}\) at angular scales \(> 1\) deg. Restricting the value added source catalogue to low-noise regions and a flux density threshold of 2 mJy provides our most reliable estimate of the angular two-point correlation. For smaller flux density thresholds systematic issues are identified, most likely related to the flux density calibration of the individual pointings. Based on the distribution of photometric redshifts of LoTSS sources and the Planck 2018 best-fit cosmological model, the theoretically predicted angular two-point correlation between 0.1 deg and 6 deg agrees with the measured clustering for a subsample of radio sources with redshift information. We find agreement with the expectation of large-scale statistical isotropy of the radio sky at the per cent level. The angular two-point correlation agrees well with the expectation of the cosmological standard model. (abbreviated)
The etiology of Kawasaki syndrome remains unestablished, although a possible role has been suggested for exposure to the application of carpet shampoo, house dust mites, and rickettsial infection. ...During an outbreak of 20 cases of Kawasaki syndrome that occurred in southeastern Wisconsin from November 1982 through March 1983, a case-control study was done of 15 cases and 30 matched controls. The study included questionnaire administration, dust collection from homes, and serum specimen collection. Only one patient had been exposed to a shampooed carpet within 30 days before onset of illness. No differences were noted between cases and controls in the degree of exposure to house dust mite-associated factors in the home, nor in the occurrence, density and species-specific prevalence of house dust mites in the home. Meadow voles exposed to house dust mites from the homes of patients did not develop serologic or pathologic evidence of infection due to rickettsiae in the spotted fever and typhus groups or Coxiella burnetii. Anti-mite-specific immunoglobulin E was not detected in serum specimens from cases or controls. Results from this study do not support hypotheses suggesting that the development of Kawasaki syndrome is associated with exposure to application of carpet shampoo, house dust mites, or rickettsial infection.
Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a novel anticonvulsant substance whose mechanism of action is not clearly understood. The present investigation examined its ability to modulate ...the strychnine-insensitive glycine receptor associated with the
N-methyl-
d-aspartate (NMDA) receptor. Felbamate decreased the magnitude of glycine (100 μM)-enhanced NMDA (100 μM)-induced intracellular calcium (Ca
2+
i) transients in mouse cerebellar granule cells which had been loaded with the Ca
2+-sensitive fluorescent probe indo-1 acetoxymethyl ester (indo-1/AM). This effect of felbamate was concentration dependent, with a maximal effect observed at 300 μM (65 ± 4% of control). In the Frings audiogenic seizure-susceptible mouse model of reflex epilepsy, the glycine agonist
d-serine (150 nmol, i.c.v.) completely blocked the anticonvulsant activity of a maximally effective dose of felbamate (19 mg/kg, i.p.). This effect of
d-serine could be reversed by increasing the administered dose of felbamate to 29 mg/kg. Furthermore, administration of
d-serine (300 nmol, i.c.v.) to felbamate-treated Frings mice produced a parallel right shift in felbamate's anticonvulsant dose-response curve (ED
50s: 9.4 mg/kg for felbamate vs. 17.7 mg/kg for felbamate +
d-serine). The results obtained in this investigation suggest that the ability of felbamate to modulate the strychnine-insensitive glycine receptor may be physiologically and behaviorally relevant to its anticonvulsant mechanism of action.
Deepening and broadening our understanding of what it means to teach in times of trauma, writing teachers analyze their own responses to national traumas ranging from the Japanese attack on Pearl ...Harbor to the various appropriations of 9/11. Offering personal, historical, and cultural perspectives, they question both the purposes and pedagogies of teaching writing.
1 Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois 60637; and 2 McDonald Research Laboratories and the iCAPTURE Centre, University of British Columbia, ...Vancouver, British Columbia, Canada V6Z 1Y6
Submitted 11 February 2004
; accepted in final form 4 May 2004
Transforming growth factor- 1 (TGF- 1) belongs to a family of multifunctional cytokines that regulate a variety of biological processes, including cell differentiation, proliferation, and apoptosis. The effects of TGF- 1 are cell context and cell cycle specific and may be signaled through several pathways. We examined the effect of TGF- 1 on apoptosis of primary human central airway epithelial cells and cell lines. TGF- 1 protected human airway epithelial cells from apoptosis induced by either activation of the Fas death receptor (CD95) or by corticosteroids. This protective effect was blocked by inhibition of the Smad pathway via overexpression of inhibitory Smad7. The protective effect is associated with an increase in the cyclin-dependent kinase inhibitor p21 and was blocked by the overexpression of key gatekeeper cyclins for the G 1 /S interface, cyclins D1 and E. Blockade of the Smad pathway by overexpression of the inhibitory Smad7 permitted demonstration of a TGF- -mediated proapoptotic pathway. This proapoptotic effect was blocked by inhibition of the p38 MAPK kinase signaling with the inhibitor SB-203580 and was associated with an increase in p38 activity as measured by a kinase assay. Here we demonstrate dual signaling pathways involving TGF- 1, an antiapoptotic pathway mediated by the Smad pathway involving p21, and an apoptosis-permissive pathway mediated in part by p38 MAPK.
cyclin-dependent kinase; cyclin-dependent kinase inhibitor; extracellular regulated kinase; transforming growth factor- receptor; airway epithelium; apoptosis
Address for reprint requests and other correspondence: S. R. White, Univ. of Chicago, Sect. of Pulmonary and Critical Care Medicine, 5841 S. Maryland Ave., MC 6076, Chicago, IL 60637 (E-mail: swhite{at}medicine.bsd.uchicago.edu )
Hypertensive disorders of pregnancy (HDP) are associated with increased risks for cardiovascular disease later in life. The HDP incidence is commonly assessed using diagnostic codes, which are not ...reliable; and typically are expressed per-pregnancy, which may underestimate the number of women with an HDP history after their reproductive years.
This study sought to determine the incidence of HDP expressed as both per-pregnancy and per-woman, and to establish their associations with future chronic conditions and multimorbidity, a measure of accelerated aging, in a population-based cohort study.
Using the Rochester Epidemiology Project medical record-linkage system, the authors identified residents of Olmsted County, Minnesota, who delivered between 1976 and 1982. The authors classified pregnancies into normotensive, gestational hypertension, pre-eclampsia, eclampsia, pre-eclampsia superimposed on chronic hypertension, and chronic hypertension using a validated electronic algorithm, and calculated the incidence of HDP both per-pregnancy and per-woman. The risk of chronic conditions between women with versus those without a history of HDP (age and parity 1:2 matched) was quantified using the hazard ratio and corresponding 95% confidence interval estimated from a Cox model.
Among 9,862 pregnancies, we identified 719 (7.3%) with HDP and 324 (3.3%) with pre-eclampsia. The incidence of HDP and pre-eclampsia doubled when assessed on a per-woman basis: 15.3% (281 of 1,839) and 7.5% (138 of 1,839), respectively. Women with a history of HDP were at increased risk for subsequent diagnoses of stroke (hazard ratio HR: 2.27; 95% confidence interval CI: 1.37 to 3.76), coronary artery disease (HR: 1.89; 95% CI: 1.26 to 2.82), cardiac arrhythmias (HR: 1.62; 95% CI: 1.28 to 2.05), chronic kidney disease (HR: 2.41; 95% CI: 1.54 to 3.78), and multimorbidity (HR: 1.25; 95% CI: 1.15 to 1.35).
The HDP population-based incidence expressed per-pregnancy underestimates the number of women affected by this condition during their reproductive years. A history of HDP confers significant increase in risks for future chronic conditions and multimorbidity.
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Objective
Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic ...lupus erythematosus (SLE). In the present study, we evaluated the ability of anifrolumab, a type I IFN receptor–blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo.
Methods
Study subjects comprised patients with moderate‐to‐severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI‐546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10–20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21‐gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma.
Results
Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin‐10 (IL‐10) were correlated with extent of type I IFN pathway activity. NET complexes and IL‐10 levels were up‐regulated in SLE patients compared to healthy controls (P < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (P < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (P < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL‐10 were reduced with anifrolumab compared to placebo (P < 0.05).
Conclusion
These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE.
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