Chemical probes are urgently needed to functionally annotate hitherto-untargeted kinases and stimulate new drug discovery efforts to address unmet medical needs. The size of the human kinome combined ...with the high cost associated with probe generation severely limits access to new probes. We propose a large-scale public-private partnership as a new approach that offers economies of scale, minimized redundancy and sharing of risk and cost.
Background. Non‐adherence to human immunodeficiency virus (HIV) medications often results in irreparable drug resistance and poor outcomes. Hence, care providers generally think that treatment of ...HIV disease should be delayed until a person is ‘ready’ to adhere. However, little research has focused on understanding the process that results in readiness for successful adherence.
Aim. The aim of this phenomenological study was to describe and understand the experience and decision‐making processes of people who became adherent to their HIV medication regimens after previously failing treatment because of non‐adherence.
Method. A Husserlian phenomenological approach was taken, and in‐depth interviews were analysed using Giorgi's method of phenomenological description and analysis.
Findings. Thirteen HIV‐positive men and women who had previously failed two or more treatment regimens because of non‐adherence were purposefully selected from two infectious diseases clinics in the Midwest region of the United States. They had achieved and sustained adherence to their HIV medications for 1 year or longer without formal intervention. All participants experienced a ‘trigger’ event preceding the process that led to the ability to incorporate lifestyle and health behaviour changes necessary for successful adherence. Factors associated with the process leading to adherence were: changing attitudes towards HIV medication, finding the right health care provider, creating the right support system, getting control of life and having goals.
Conclusions. This study demonstrated that HIV‐positive individuals who had been non‐adherent and had been viewed as ‘difficult to treat’ nonetheless successfully adhered to treatment once they became ‘ready’. Findings from this study implicate that readiness may be a necessary component for successful adherence, particularly in HIV‐positive individuals who have previously failed treatment. Understanding the relationship between the phenomenon of readiness and subsequent HIV treatment adherence has implications for clinical decision‐making and for development of interventions that enhance adherence and prevent HIV drug resistance.
We present device and circuit characterization resulting from technology/design co-development to improve the design and manufacture of analog/mixed-signal (AMS) circuits in processors. We introduce ...I D -based MOSFET transconductance measurements and a new measurement of drain saturation margin at realistic analog biasing. We also describe routinely monitored scribe lane replicas of key AMS passives and circuits. Such measurements enable construction and validation of compact models better suited to AMS needs than those historically tailored for logic design.
GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor (EGFR, ErbB-1) and ErbB-2. We determined the ...crystal structure of EGFR bound to GW572016. The compound is bound to an inactive-like conformation of EGFR that is very different from the active-like structure bound by the selective EGFR inhibitor OSI-774 (Tarceva) described previously. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). Treatment of tumor cells with these inhibitors results in down-regulation of receptor tyrosine phosphorylation. We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off-rate from the purified intracellular domain. The slow off-rate of GW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells. The differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB-2 can be explained by the enzyme-inhibitor structures.
To assess factors that may predict failure to improve at 12 and 24 months after unilateral laminotomy with bilateral decompression (ULBD) for the management of lumbar spinal stenosis.
A database of ...255 patients who underwent microdecompression surgery by a single orthopedic spine surgeon between 2014 and 2018 was queried. Patients who underwent primary single-level ULBD of the lumbar spine were included. Visual analog scale (VAS) for back pain and leg pain and Oswestry Disability Index (ODI) results were collected preoperatively and at 12 and 24 months postoperatively. Demographic, radiographic, and operative factors were assessed for associations with failure to improve. Clinically important improvement was defined as reaching or surpassing the previously established minimum clinically important difference for ODI (12.8) and not requiring revision.
A total of 68 patients were included. Compared with preoperative values for back pain, leg pain, and ODI (7.32, 7.53, and 51.22, respectively), there were significant improvements on follow-up at 12 months (2.89, 2.23, and 22.40, respectively; P < 0.001) and 24 months (2.80, 2.11, 20.32, respectively; P < 0.001). Based on the defined criteria, 50 patients showed clinically important improvement after ULBD. Of the 18 patients who failed to improve, 12 required revision. Independent predictors of failure to improve included female sex (adjusted odds ratio, 5.06; 95% confidence interval, 1.49-21.12; P = 0.014) and current smoker status (adjusted odds ratio, 5.39; 95% confidence interval, 1.39-23.97; P = 0.018).
ULBD for the management of lumbar spinal stenosis leads to clinically important improvement that is maintained over a 24-month follow-up period. Female sex and tobacco smoking are associated with poorer outcomes.
Poly(propylacrylic acid) (PPAAc) is a synthetic pH-responsive polymer that has been shown to disrupt cell membranes at low pH values typical of the endosome, but not at physiological pH, suggesting ...its use as an endosomal-releasing agent Murthy et al. J. Controlled Release 61, 137−43. We have constructed an antibody-targeted biotherapeutic model to investigate whether PPAAc can enhance intracellular trafficking of proteins to the cytoplasm. A ternary complex composed of a biotinylated anti-CD3 antibody, streptavidin, and biotinylated PPAAc was fluorescently labeled, and its intracellular fate was analyzed by confocal microscopy, flow cytometry, and quantitative western blotting of cell fractionates. The 64.1 anti-CD3 antibody was previously shown to direct receptor-mediated endocytosis in the Jurkat T-cell lymphoma cell line and was rapidly trafficked from the endosome to the lysosomal compartment. The antibody−streptavidin complex was also rapidly internalized to the endosomal/lysosomal compartment and retained there, as evidenced by punctate regions of fluorescence observed by confocal fluorescence microscopy. In samples containing the ternary complex of antibody, streptavidin, and PPAAc−biotin, diffuse fluorescence in the cytoplasm was observed, indicating that PPAAc enhanced translocation to the cytoplasm. This was confirmed by western blotting analysis of the isolated cytoplasm. Flow cytometry results demonstrated that neither streptavidin nor PPAAc caused nonspecific uptake of the complex, nor did they inhibit antibody-mediated endocytosis. The striking enhancement of protein delivery to the cytoplasm by complexed PPAAc suggests that this polymer could provide a new delivery agent for theapeutic, vaccine, and diagnostics development.
The cross section of neutrino-induced neutral-current coherent π0 production on a carbon-dominated target is measured in the NOvA near detector. This measurement uses a narrow-band neutrino beam with ...an average neutrino energy of 2.7 GeV, which is of interest to ongoing and future long-baseline neutrino oscillation experiments. The measured, flux-averaged cross section is σ = 13.8 ± 0.9 ( stat ) ± 2.3 ( syst ) × 10−40 cm2 / nucleus , consistent with model prediction. This result is the most precise measurement of neutral-current coherent π 0 production in the few-GeV neutrino energy region.
Drug delivery systems that increase the rate and/or quantity of drug release to the cytoplasm are needed to enhance cytosolic delivery and to circumvent nonproductive cell trafficking routes. We have ...previously demonstrated that poly(2-ethylacrylic acid) (PEAAc) has pH-dependent hemolytic properties, and more recently, we have found that poly(2-propylacrylic acid) (PPAAc) displays even greater pH-responsive hemolytic activity than PEAAc at the acidic pHs of the early endosome. Thus, these polymers could potentially serve as endosomal releasing agents in immunotoxin therapies. In this paper, we have investigated whether the pH-dependent membrane disruptive activity of PPAAc is retained after binding to a protein. We did this by measuring the hemolytic activity of PPAAc−streptavidin model complexes with different protein to polymer stoichiometries. Biotin was conjugated to amine-terminated PPAAc, which was subsequently bound to streptavidin by biotin complexation. The ability of these samples to disrupt red blood cell membranes was investigated for a range of polymer concentrations, a range of pH values, and two polymer-to-streptavidin ratios of 3:1 and 1:1. The results demonstrate that (a) the PPAAc−streptavidin complex retains the ability to lyse the RBC lipid bilayers at low pHs, such as those existing in endosomes, and (b) the hemolytic ability of the PPAAc−streptavidin complex is similar to that of the free PPAAc.
To determine the pharmacokinetics of gentamicin sulfate in healthy llamas after i.v. administration of a single bolus and after repeated parenteral administration.
Prospective clinical trial.
19 ...clinically normal, adult male llamas for the single-dose trial and 10 of the 19 llamas for the multiple-dose trial.
In the first trial, llamas were given gentamicin (5 mg/kg of body weight, i.v.) as a single bolus, and serum gentamicin concentration was monitored over the next 48 hours. 2 months later, llamas were given gentamicin (2.5 mg/kg) i.v. for the first day, then IM every 8 hours for 7 days. Serum gentamicin concentration and indices of renal function and damage were monitored during the 7 days.
There were no significant dose- or time-related differences in clearance of the drug; volume of distribution; apparent coefficients of the distribution and elimination phases, alpha and beta, respectively; mean residence time; or distribution (t1/2 alpha) and elimination phase (t1/2 beta) half-lives. The 5 mg/kg i.v. kinetic study revealed t1/2 alpha of 14.5 +/- 5.06 minutes and t1/2 beta of 166 +/- 20.5 minutes. The 2.5 mg/kg i.v. kinetic study revealed t1/2 alpha of 17.7 +/- 6.59 minutes and t1/2 beta of 165 +/- 40.3 minutes. Peak serum gentamicin concentration averaged 10.10 micrograms/ml in the multiple-dose trial, and trough concentration averaged 1.50 micrograms/ml.
Dose effects were not observed for gentamicin clearance, volume of distribution, or half-lives. Multiple dosing at 2.5 mg/kg every 8 hours does not appear to cause renal impairment in healthy llamas.
Gentamicin pharmacokinetic variables in llamas appear to resemble those in other ruminant species.
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