Glioblastoma is an aggressive primary tumor of the central nervous system (CNS). Is the most aggressive among infiltrative gliomas arising from the CNS. This tumor has low patient survival rate and ...several studies aiming at developing new drugs have increased. Patients with this cancer type face significant morbidity and mortality. This study evaluated the antineoplastic activity of synthetic chalcones (3a-3f) using in vitro glioblastoma models and molecular modeling. Cytotoxicity assay showed that Astrocitoma Hospital Ofir Loyola No 1 (AHOL1) and Uppsala 87 neoplastic glioblastoma lines (U87) cellular viability were significantly reduced compared to Healthy human fibroblasts cell lines (AN27) when exposed to chalcones. Interaction with the serine amino acid was present in the most promising and the reference binder docking, suggesting its importance inhibiting cell growth. Comparative analysis between the reference ligands and the molecules showed that the amino acid LYS352 present in all fittings, suggesting that this is the main amino acid for interaction with tubulin and are consistent with those in cytotoxicity assay, suggesting antineoplastic potential in glioblastoma. Long trajectory molecular dynamics studies were also carried out in order to investigate stability and conformations amongst the chalcones bound tubulin as well, in comparison to doxorubicin (here used as control), however future studies are needed to further assess the mechanism of inhibition of chalcones used in this investigation.
Communicated by Ramaswamy H. Sarma
Adenosine A
2A
receptor (A
2A
R) is the predominant receptor in immune cells, where its activation triggers cAMP-mediated immunosuppressive signaling and the underlying inhibition of T cells ...activation and T cells-induced effects mediated by cAMP-dependent kinase proteins mechanisms. In this study, were used ADME/Tox, molecular docking and molecular dynamics simulations to investigate selective adenosine A
2A
R agonists as potential anti-inflammatory drugs. As a result, we obtained two promising compounds (A and B) that have satisfactory pharmacokinetic and toxicological properties and were able to interact with important residues of the A
2A
R binding cavity and during the molecular dynamics simulations were able to keep the enzyme complexed.
Communicated by Ramaswamy H. Sarma
We have used docking (GLIDE), pharmacophore modeling (Discovery Studio), long trajectory molecular dynamics (Discovery Studio) and ADMET/Tox (QikProp and DEREK) to investigate PAD4 in order to ...determine potential novel inhibitors and hits. We have carried out virtual screening in the ZINC natural compounds database. Pharmacokinetics and Toxicity of the best hits were assessed using databases implemented in softwares that create models based on chemical structures taking into account consideration about the toxicophoric groups. A wide variety of pharmaceutical relevant properties are determined in order to make decisions about molecular suitability. After screening and analysis, the 6 most promising PAD4 inhibitors are suggested, with strong interactions (pi-stacking, hydrogen bonds, hydrophobic contacts) and suitable pharmacotherapeutic profile as well.
Receptor-interacting protein kinase 2 (RIPK2) plays an essential role in autoimmune response and is suggested as a target for inflammatory diseases. A pharmacophore model was built from a dataset ...with ponatinib (template) and 18 RIPK2 inhibitors selected from BindingDB database. The pharmacophore model validation was performed by multiple linear regression (MLR). The statistical quality of the model was evaluated by the correlation coefficient (
R
), squared correlation coefficient (
R
2
), explanatory variance (adjusted
R
2
), standard error of estimate (SEE), and variance ratio (
F
). The best pharmacophore model has one aromatic group (LEU24 residue interaction) and two hydrogen bonding acceptor groups (MET98 and TYR97 residues interaction), having a score of 24.739 with 14 aligned inhibitors, which were used in virtual screening via ZincPharmer server and the ZINC database (selected in function of the RMSD value). We determined theoretical values of biological activity (logRA) by MLR, pharmacokinetic and toxicology properties, and made molecular docking studies comparing binding affinity (kcal/mol) results with the most active compound of the study (ponatinib) and WEHI-345. Nine compounds from the ZINC database show satisfactory results, yielding among those selected, the compound ZINC01540228, as the most promising RIPK2 inhibitor. After binding free energy calculations, the following molecular dynamics simulations showed that the receptor protein’s backbone remained stable after the introduction of ligands.
New graduate clinical nurse specialists (CNSs) face many challenges when starting their new role. To address this, a CNS fellowship program was developed to mentor new CNSs during their first year of ...practice. This CNS fellowship program would provide opportunities to increase skills related to each of the CNS spheres of influence, including nursing practice, patient care, and systems and organization. Experienced CNSs mentored CNS fellows and identified learning opportunities. The fellows completed an online self-assessment based on the National Association of Clinical Nurse Specialists CNS Competency Checklist during week one of orientation and again at months 3, 6, 9, and 12. The CNS fellows completed and presented three projects designed to explore the spheres of the CNS role, along with a formal onboarding. The results of the fellowship depicted significant competency development within all three CNS spheres at program completion. The CNS fellowship program provided structure and guidance to the newly graduated CNSs and clearly transitioned staff nurses to advanced practice nurses. The fellowship has demonstrated a positive effect on both the new CNSs and the organization in which it was developed.
Extremely compact resistive-feedback CMOS low-noise amplifiers (LNAs) are presented as a cost-effective alternative to multiple narrowband LNAs using high- Q inductors for multiband wireless ...applications. Limited linearity and high power consumption of the inductorless resistive-feedback LNAs are analyzed and circuit techniques are proposed to solve these issues. A 12-mW resistive-feedback LNA, based on current-reuse transconductance boosting is presented with a gain of 21 dB and a noise figure (NF) of 2.6 dB at 5 GHz. The LNA achieves an output third-order intercept point (IP3) of 12.3 dBm at 5 GHz by reducing loop-gain rolloff and by improving linearity of individual stages. The active die area of the LNA is only 0.012 mm 2 . A 9.2-mW tuned resistive-feedback LNA utilizing a single compact low- Q on-chip inductor is presented, showing an improved tradeoff between performance, power consumption, and die area. At 5.5 GHz, the fully integrated LNA achieves a measured gain of 24 dB, an NF of 2 dB, and an output IP3 of 21.5 dBm. The LNA draws 7.7 mA from the 1.2-V supply and has a 3-dB bandwidth of 3.94 GHz (4.04-7.98 GHz). The LNA occupies a die area of 0.022 mm 2 . Both LNAs are implemented in a 90-nm CMOS process and do not require any costly RF enhancement options.
Measurements of serum thyrotropin (TSH) and free thyroxine (T4) concentrations were conducted in infants, children, and adults to assess maturation of the hypothalamic-pituitary-thyroid (HPT) ...feedback control axis. Serum free T4 and TSH concentration data were collated for cord blood of the midgestation fetus, for premature and term infants, and for peripheral blood from newborn infants, children, and adults. Mean values were plotted on a nomogram developed to characterize the reference ranges of the normal axis quantitatively based on data from 522 healthy subjects, 2 weeks to 54 years of age; 83 untreated hypothyroid patients; and 116 untreated hyperthyroid patients. Samples for 75 patients with thyroid hormone resistance were also plotted. The characterized pattern of HPT maturation included a progressive decrease in the TSH/free T4 ratio with age, from 15 in the midterm fetus, to 4.7 in term infants, and 0.97 in adults. Maturation plotted on the nomogram was complex, suggesting increasing hypothalamic-pituitary T4 resistance during fetal development, probably secondary to increasing thyrotropin-releasing hormone (TRH) secretion, the marked, cold-stimulated TRH-TSH surge at birth with reequilibration by 2-20 weeks, and a final maturation phase characterized by a decreasing serum TSH with minimal change in free T4 concentration during childhood and adolescence. The postnatal maturative phase during childhood and adolescence correlates with the progressive decrease in thyroxine secretion rate (on a microg/kg per day basis) and metabolic rate and probably reflects decreasing TRH secretion.
Osteoporosis and fractures are increasingly recognized in children and adults with cystic fibrosis. To investigate the prevalence and pathogenesis of osteoporosis and low bone mass in adults with ...advanced pulmonary disease due to cystic fibrosis, we examined the relationships between bone mineral density (BMD), anthropomorphic variables, pulmonary status, glucocorticoid therapy, and vitamin D concentrations. BMD of the lumbar spine, hip, and proximal radius was measured by dual energy X-ray absorptiometry in 30 white adults (16 women), age 30 +/- 2 yr (mean +/- SEM). Compared with a normal control population, the patients had significantly reduced BMD at the lumbar spine (17 +/- 3%), total hip and femoral neck (24 +/- 3% and 20 +/- 4%, respectively). The radius was significantly less demineralized (4 +/- 2%; p <= 0.003) than the other sites. Moreover, only 21% of patients with cystic fibrosis had normal BMD (T score > -1.0) at the lumbar spine, 23% at the hip sites, and 39% at the radius. Age, weight, and body mass index (BMI) were most strongly correlated with bone mass, whereas glucocorticoid therapy and pulmonary function were not predictive. Despite oral vitamin D (400 to 800 IU daily), the mean serum 25-hydroxyvitamin D (25-OHD) concentration was at the low end of the normal range (16 +/- 2 ng/ml; normal 10 to 52 ng/ml); 8 of 20 patients (40%) had frankly low (<= 10 ng/ml) levels. BMD was significantly lower in patients with low 25-OHD concentrations at the lumbar spine (0.774 +/- 0.02 versus 0.913 +/- 0.04 g/cm2; p = 0.01) and total hip (0.648 +/- 0.04 versus 0.811 +/- 0.04 g/cm2; p = 0.01). Vertebral fractures were present in 19% of subjects and 41% had a confirmed history of previous fracture. In summary, osteoporosis, low bone mass, and fractures are common in adults with advanced cystic fibrosis lung disease. Despite oral supplements, vitamin D deficiency is also common and is associated with more severe demineralization at the lumbar spine and hip. We conclude that the widespread practice of oral supplementation with 400 to 800 units of vitamin D is ineffective in maintaining normal vitamin D stores in many patients with cystic fibrosis. To ensure adequacy of vitamin D stores, measurement of serum 25-OHD should be included in the routine management of patients with cystic fibrosis.
Fractures, a common complication of cardiac and liver transplantation, have not been reported in association with lung transplantation. However, many patients with end-stage pulmonary disease have ...multiple risk factors for osteoporosis, and several studies have suggested that osteoporosis before transplantation may increase the risk of fracture after transplantation. Therefore, we evaluated a group of patients with end-stage pulmonary disease who were awaiting lung transplantation to determine the prevalence of osteoporosis.
Seventy patients (aged 18–70 years) were evaluated consecutively with bone densitometry by dual-energy x-ray absorptiometry. The patients were predominantly Caucasian (96%). Bone mass was expressed as bone mineral density (BMD; g/cm
2), as the number of standard deviations (SD) below peak bone mass (T score), and as bone mineral apparent density (BMAD; g/cm
3), a measurement that minimizes the effects of bone size on BMD. Spine radiographs were obtained in a subset of 50 consecutive patients to detect vertebral compression fractures. Vitamin D status was assessed with serum concentrations of 25-hydroxyvitamin D. The patients were sorted into groups by pulmonary diagnosis: chronic obstructive pulmonary disease (COPD; n = 28); cystic fibrosis (n = 11); idiopathic pulmonary fibrosis; and other lung diseases (Other; n = 31).
results: In the group as a whole, osteoporosis (T score below −2.5) was present in 30% of the patients at the lumbar spine and 49% at the femoral neck. Osteopenia (T score between −1 and −2.5) was present in an additional 35% at the lumbar spine and 31% at the femoral neck. The average femoral neck T score of patients with COPD and cystic fibrosis fell into the osteoporotic range (−2.7 ± 0.3 and −2.6 ± 0.3, respectively), significantly (
P < 0.01) below that of the patients in the Other category (−1.5 ± 0.3). The average lumbar spine T score fell into the osteopenic range in all three groups. Low BMAD in patients with cystic fibrosis confirmed that their low BMD was not due to their smaller body size. The prevalence rate of vertebral fractures was 29% in patients with COPD and 25% in those with cystic fibrosis. Vitamin D deficiency (25-hydroxyvitamin D levels ≤10 ng/ml) was present in 36% of patients with cystic fibrosis and 20% with COPD and Other lung diseases. Lumbar spine BMD tended to be lower in cystic fibrosis patients with vitamin D deficiency. Patients with exposure to glucocorticoids (n = 46) had significantly more vertebral fractures (
P < 0.05) and duration of exposure correlated negatively with lumbar spine BMD (r = −0.398;
P = 0.008). COPD and Other patients not on glucocorticoids had mild lumbar spine osteopenia (0.972 ± 0.06 g/cm
2; T = −1.2 ± 0.6). Very few of the patients on glucocorticoids were on any regimen to prevent osteoporosis.
Osteoporosis and vitamin D deficiency are extremely common in patients with end-stage pulmonary disease. Only 34% of patients had normal lumbar spine BMD and only 22% had normal BMD at the hip. Patients with cystic fibrosis and glucocorticoid-treated patients with COPD were most severely affected. Therapies to prevent bone loss and treat established osteoporosis are uncommonly utilized in glucocorticoid-treated patients with end-stage pulmonary disease. Candidates for lung transplantation should be evaluated for osteoporosis and vitamin D deficiency at the time of acceptance to the transplant waiting list.
Spectacular trilobite Lagerstätten occur in distinctive offshore calcareous mudstone facies through the Late Ordovician to Devonian, and reflect a combination of mass mortality or molting and burial, ...coupled with early diagenetic enhancement. Evidence indicates two distinct modes of burial, Type I and II assemblages, which show evidence for burial without or with seafloor disturbance, respectively. Type I assemblages suggest rapid (hours to days), but not instantaneous burial, without bottom disruption, enabling preservation of in situ behavior, including mass aggregations and molt ensembles. Most occurrences contain bedding planes in which trilobites exhibit incipient disarticulation. These assemblages were buried by cascades of flocculated sediment from hypopycnal, detached flows. Type II assemblages show well-articulated, enrolled, semi-enrolled, and outstretched trilobites in varied orientations relative to bedding. In such cases, bottom flows and seafloor disruption by storm or seismic disturbances in shallow waters suspended large amounts of flocculated muds as viscous slurries, which developed into hyperpycnal flows that entrained carcasses of trilobites and other organisms. In many cases, both Type I and II obrution was followed by additional sedimentation, geochemical zones moved upward through the sediment column, and there was little tendency to form diagenetic overprints. Alternatively, if burial was followed by an interval of sediment starvation, the sediments were bioturbated and very early diagenetic mineralization was superimposed, first, in rare cases, as mineralized soft parts in entombed carcasses, and later as pyritization of burrow linings. Development of the concretionary layers required more prolonged periods of stability of the sulfate reduction zone. Cementation of sediment shielded organism bodies from most or all effects of compaction. Thus, ironically, the best preservation of delicate remains required rapid burial, associated with mass mortality, and very low rates of background sedimentation following the event.
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