Poly ADP-ribose polymerase (PARP) inhibitors, including talazoparib, potentiate temozolomide efficacy in multiple tumor types; however, talazoparib-mediated sensitization has not been evaluated in ...orthotopic glioblastoma (GBM) models. This study evaluates talazoparib ± temozolomide in clinically relevant GBM models. Talazoparib at 1-3 nmol/L sensitized T98G, U251, and GBM12 cells to temozolomide, and enhanced DNA damage signaling and G
-M arrest
cyclical therapy with talazoparib (0.15 mg/kg twice daily) combined with low-dose temozolomide (5 mg/kg daily) was well tolerated. This talazoparib/temozolomide regimen prolonged tumor stasis more than temozolomide alone in heterotopic GBM12 xenografts median time to endpoint: 76 days versus 50 days temozolomide (
= 0.005), 11 days placebo (
< 0.001). However, talazoparib/temozolomide did not accentuate survival beyond that of temozolomide alone in corresponding orthotopic xenografts median survival 37 vs. 30 days with temozolomide (
= 0.93), 14 days with placebo,
< 0.001. Average brain and plasma talazoparib concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49 ± 0.07 ng/g and 25.5±4.1 ng/mL, respectively. The brain/plasma distribution of talazoparib in Bcrp
versus wild-type (WT) mice did not differ, whereas the brain/plasma ratio in Mdr1a/b
mice was higher than WT mice (0.23 vs. 0.02,
< 0.001). Consistent with the
brain distribution, overexpression of MDR1 decreased talazoparib accumulation in MDCKII cells. These results indicate that talazoparib has significant MDR1 efflux liability that may restrict delivery across the blood-brain barrier, and this may explain the loss of talazoparib-mediated temozolomide sensitization in orthotopic versus heterotopic GBM xenografts.
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Effective sensitizing strategies potentially can extend the benefit of temozolomide (TMZ) therapy in patients with glioblastoma (GBM). We previously demonstrated that robust TMZ-sensitizing effects ...of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888) are restricted to TMZ-sensitive GBM xenografts. The focus of this study is to provide an understanding for the differential sensitization in paired TMZ-sensitive and -resistant GBM models.
The impact of veliparib on TMZ-induced cytotoxicity and DNA damage was evaluated in vitro and in vivo in models of acquired TMZ resistance (GBM12TMZ-mgmt(High), GBM12TMZ-mgmt(Low), and U251TMZ), inherent TMZ resistance (T98G), and TMZ-sensitive (U251 and GBM12). In vivo drug efficacy, pharmacokinetics, and pharmacodynamics were analyzed using clinically relevant dosing regimens.
Veliparib enhanced TMZ cytotoxicity and DNA-damage signaling in all GBM models in vitro with more pronounced effects in TMZ-resistant lines at 3 to 10 μmol/L veliparib. In vivo, combined TMZ/veliparib, compared with TMZ alone, significantly delayed tumor growth and enhanced DNA-damage signaling and γH2AX levels in the sensitive GBM12 xenograft line but not in the resistant GBM12TMZ lines. The pharmacokinetic profile of veliparib was similar for GBM12 and GBM12TMZ tumors with Cmax (∼1.5 μmol/L) in tissue significantly lower than concentrations associated with optimal in vitro sensitizing effects for resistant tumors. In contrast, robust suppression of PARP-1 expression by shRNA significantly increased TMZ sensitivity of U251TMZ in vitro and in vivo.
In vitro cytotoxicity assays do not adequately model the therapeutic index of PARP inhibitors, as concentrations of veliparib and TMZ required to sensitize TMZ-resistant cancer cells in vivo cannot be achieved using a tolerable dosing regimen.
Ferroelectric BaTiO3 is widely used in capacitors, but the low Curie temperature limits a further use of BaTiO3. In this work we present an aqueous chemical solution deposition (CSD) route for BaTiO3 ...thin films, demonstrating that organic solvents are not required for CSD. Textured BaTiO3 thin films were deposited on SrTiO3 substrates. The in-plane dielectric properties were investigated using interdigitated electrodes and ferroelectric switching was observed up to 160±5 °C. The increased Curie temperature is proposed to result from thermal strain due to a mismatch in thermal expansion coefficient between the film and the substrate, and is in good agreement with the theory of strain engineering in BaTiO3. Finally, the decomposition and crystallization of BaTiO3 during thermal treatment were determined by the combination of thermal analysis, IR spectroscopy and X-ray diffraction of powder prepared from the solution.
In epidemiological studies, Helicobacter pylori infection is usually detected by enzyme-linked immunosorbent assay (ELISA). However, infection can spontaneously clear from the mucosa during the ...progression of atrophy and could lead to substantial under-detection of infection and underestimation of its effect on gastric cancer (GC) risk. Antibodies detected by western blot are known to persist longer after the loss of the infection.
In a nested case–control study from the Eurogast-EPIC cohort, including 88 noncardia GC cases and 338 controls, we assessed the association between noncardia GC and H. pylori infection comparing antibodies detected by western blot (HELICOBLOT2.1) to those detected by ELISA (Pyloriset EIA-GIII®).
By immunoblot, 82 cases (93.2%) were H. pylori positive, 10 of these cases (11.4%) were negative by ELISA and only 6 cases (6.8%) were negative by both ELISA and immunoblot. Multivariable odds ratio (OR) for noncardia GC comparing immunoglobulin G positive versus negative by ELISA was 6.8 95% confidence interval (CI) 3.0–15.1, and by immunoblot, the OR was 21.4 (95% CI 7.1–64.4).
Using a western blot assay, nearly all noncardia GC were classified as H. pylori positive and the OR was more than threefold higher than the OR assessed by ELISA, supporting the hypothesis that H. pylori infection is a necessary condition for noncardia GC.
National Pharmacist Workforce Studies (NPWS) have been conducted in the U.S. every five years since 2000. This article describes the online survey methods used for the latest NPWS conducted in 2019 ...and provides an assessment for nonresponse bias. Three waves of emails containing a link to the online survey were sent to a random sample of about 96,000 pharmacists licensed in the United States. The survey asked about pharmacist employment, work activities, work-life balance, practice characteristics, pharmacist demographics and training. A total of 5467 usable responses were received, for a usable response rate of 5.8%. To assess for nonresponse bias, respondent characteristics were compared to the population of U.S. pharmacists and a benchmark, while a wave analysis compared early and late respondents. The pharmacist sample-population comparison and the benchmark comparison showed that the NPWS respondents had a higher percentage of female pharmacists and a lower proportion of young pharmacists compared to the population of U.S. pharmacists and the benchmark sample. In some contrast, the wave analysis showed that the early respondents had a higher percentage of males and older pharmacists compared to the late respondents. Both the wave analysis and the benchmark comparison showed that the NPWS respondents (and early respondents) had a lower percent of pharmacists with a PharmD degree than did the late respondents and the benchmark group. These differences should be considered when interpreting the findings from the 2019 NPWS.
Aurora A kinase (AURKA), a member of the serine/threonine kinase family, plays a critical role in cell division, and it is widely overexpressed in a variety of tumors including glioblastoma (GBM). ...Alisertib (MLN8237) is an orally administered selective AURKA inhibitor with potent antiproliferative activity, currently undergoing clinical testing in different tumor types. In vitro evaluation of alisertib against the primary GBM lines, GBM6, GBM10, GBM12 and GBM39 showed significant antitumor activity with IC
50s
ranging between 30 and 95 nM. Orthotopic xenografts of GBM10 and the bevacizumab resistant lines GBM6 and GBM39 were established by implantating 3 × 10
5
cells in the caudate nucleus of nude mice; animals were randomized to treatment with either alisertib 30 mg/kg/day or vehicle. In all three models, treatment with alisertib resulted in a statistically significant prolongation of survival (p < 0.0001). In addition, alisertib administration in these mice decreased phosphorylated aurora-A, induced mitotic arrest and significantly decreased histone H3 phosphorylation in tumors. In conclusion, alisertib displays significant antitumor activity against primary GBM lines and xenografts, including patient derived GBM lines resistant to bevacizumab; these data support clinical translation in GBM.
An abstract of the study by Kim et al examining the brain distributional kinetics of SAR405838, and correlate the observed changes in delivery with efficacy in glioblastoma (GBM) models is presented. ...In this study, a GBM PDX-model overexpressing MDM2 (G108) was modified with lentiviral transduction with either empty vector (G108-EV) or vector containing VEGFA transcript (G108-VEGF). Results, the tumor distribution of SAR405838 was greater and more homogeneous in G108-VEGFA tumors, based on the results of MALDI-Mass Spectrometry Imaging. Furthermore, brain delivery of SAR405838 is limited due to p-glyco-protein-mediated active efflux at the BBB.
Abstract
Purpose
The purpose of this study was to describe the demographics, training, clinical specialties, and practice activities of ambulatory care pharmacists using data from the 2019 National ...Pharmacist Workforce Study (NPWS).
Summary
The 2019 NPWS was conducted using a 3-contact electronic survey sent to a random sample of 94,803 pharmacists using the National Association of Boards of Pharmacy Foundation e-Profile system. The 2019 NPWS had a response rate of 67.3% (5,705/8,466), based on the number of prospective respondents who clicked the survey link. A subset of pharmacists’ responses (n = 4,557) was used for this analysis, which included those who selected an employment status of “practicing as a pharmacist.” Of the 4,557 actively practicing pharmacists responding, 338 (8.0%) reported working in the ambulatory care setting. Ambulatory care pharmacists were predominately White (71.6%), women (67.5%), and/or between the ages of 31 and 40 years (36.9%). A total of 41.3% had completed PGY1 residency training, 14% had completed PGY2 residency training, and 29.3% had completed one or more board certifications. Their most common clinical specialty areas were anticoagulation (21.7%), endocrinology (19.7%), hematology/oncology (16.2%), and primary care (16.2%). A total of 49.6% reported using a collaborative practice agreement.
Conclusion
Ambulatory care pharmacists reported more training and certifications than the overall sample of pharmacists. These pharmacists practiced in a variety of clinical specialty areas and engaged in a range of in-person and telecommunication medication management activities. This study provides a baseline assessment of the ambulatory care pharmacist workforce that can be used to assess changes over time.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
An abstract of the study by Sarkaria et al evaluating the statistical designs for PDX pre-clinical trials such as a recently reported 1x1x1 trial design is presented. In this study, using orthotopic ...tumor survival data collected for radiation (RT), temozolomide (TMZ) and combined RT/TMZ treatments for 39 models, they empirically evaluated trial designs by varying the number of PDX models per treatment group as well as the number of mice per model per treatment. Results, in comparison to placebo survival, TMZ alone was associated with two-fold improvement in survival and RT/TMZ with nearly three-fold improvement. Furthermore, the results reiterate that the design of PDX pre-clinical trials is dependent on the expected effect sizes (improvement in survival across treatment groups) and demonstrate how existing data can be used to guide design of PDX trials.
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