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Inhibition of AKT with the Orally Active Allosteric AKT Inhibitor, MK-2206, Sensitizes Endometrial Cancer Cells to Progestin
Progestin resistance is a major obstacle to treating early stage, well-differentiated endometrial cancer as well as recurrent endometrial cancer. The mechanism behind the suboptimal response to progestin is not well understood. The PTEN tumor suppressor gene is frequently mutated in type I endometrial cancers and this mutation results in hyperactivation of the PI3K/AKT pathway. We hypothesized that increased activation of AKT promotes an inadequate response to progestins in endometrial cancer cells. Ishikawa cells stably transfected with progesterone receptor B (PRB23 cells) were treated with the AKT inhibitor, MK-2206, which effectively decreased levels of p(Ser473)-AKT in a dose-dependent (10 nM to 1 uM) and time-dependent manner (0.5 h to 24 h). MK-2206 inhibited levels of p(Thr308)-AKT and a downstream target, p(Thr246)-PRAS40, but did not change levels of p(Thr202/Tyr204)ERK or p(Thr13/Tyr185)SAPK/JNK, demonstrating specificity of MK-2206 for AKT. Additionally, MK-2206 treatment of PRB23 cells resulted in a significant increase in levels of progesterone receptor B (PRB) protein. Microarray analysis of PRB23 cells identified PDK4 as the most highly upregulated gene among 70 upregulated genes in response to R5020. Inhibition of AKT further upregulated progestin-mediated expression of PDK4 but did not affect another progestin-responsive gene, SGK1. Treatment of PRB23 cells with R5020 and MK-2206 independently decreased viability of cells while the combination of R5020 and MK-2206 caused the greatest decrease in cell viability. Furthermore, mice with xenografted tumors treated with MK-2206 alone or with progesterone alone exhibited modest reductions in their tumor volume. The largest decrease in tumor size was observed in the mice treated with both MK-2206 and progesterone; these tumors exhibited the least proliferation (Ki67) and the most apoptosis (cleaved caspase-3) of all the treatment groups. In summary, inhibition of AKT stabilizes the Progesterone Receptor B and augments progesterone response in endometrial cancer cells that have hyperactivated AKT
Efficacy and safety of bevacizumab in recurrent sex cord-stromal ovarian tumors: Results of a phase 2 trial of the Gynecologic Oncology Group: Bevacizumab for Stromal Ovarian Tumors
The Gynecologic Oncology Group conducted this phase II trial to estimate the anti-tumor activity of bevacizumab and to determine the nature and degree of toxicity in patients with recurrent sex cord-stromal tumors of the ovary
'Use of antipsychotics in children and adolescents: a picture from the ARITMO population-based European cohort study'
Aims. Prevalence of the use of antipsychotics (APs) in the paediatric population is globally
increasing. The aim of this study was to describe multinational trends and patterns in AP
use in children and adolescents in Europe.
Methods. This was a dynamic retrospective cohort study comprising all children and adolescents
(⩽18 years of age). Data were extracted from five population-based electronic healthcare databases in Europe (Denmark, Germany, Italy, the Netherlands and United Kingdom) from 2000
to 2010. Yearly prevalence and incidence of AP use was expressed per 1000 person-years (PYs).
Results. Prevalence increased from 1.44 to 3.41/1000 PYs (2008) in Denmark and from 2.07
to 4.35/1000 PYs in the NL (2009), moderately increased from 2.8 to 3.24/1000 in UK (2009)
and from 1.53 to 1.74/1000 PYs in Germany (2008) and remained low from 0.61 to 0.34/1000
PYs in Italy (2010). Similarly, incidence rates increased from 0.69 to 1.52/1000 PYs in
Denmark and from 0.86 to 1.49/1000 PYs in the NL, stabilised from 2.29 to 2.37/1000 PYs
in the UK and from 0.79 to 0.80/1000 PYs in Germany and remained low from 0.32 to
0.2/1000 PYs in Italy. AP use was highest in 15–18 year olds and in boys compared to
girls. Yet, the use observed in the 5–9 year olds was found to be comparatively high in the
NL. Prescriptions of second generation APs, especially risperidone, were privileged but the
first generation APs were still prescribed in the youngest.
Conclusions. A steady increase in AP use in children and adolescents was observed essentially
in the NL and Denmark. The use in Germany and Italy was lowest among countries. The use
of APs under 9 years of age underlines their off-label use and should be carefully monitored as
the risk/benefit ratio of these medications remains unclear in young children. AP use was
altogether lower in Europe as compared to that reported in North America
Systemic antibiotic prescribing to paediatric outpatients in 5 European countries: A population-based cohort study
Background: To describe the utilisation of antibiotics in children and adolescents across 5 European countries based on the same drug utilisation measures and age groups. Special attention was given to age-group-specific distributions of antibiotic subgroups, since comparison in this regard between countries is lacking so far.Methods: Outpatient paediatric prescriptions of systemic antibiotics during the years 2005-2008 were analysed using health care databases from the UK, the Netherlands, Denmark, Italy and Germany. Annual antibiotic prescription rates per 1,000 person years were estimated for each database and stratified by age (≤4, 5-9, 10-14, 15-18 years). Age-group-specific distributions of antibiotic subgroups were calculated for 2008.Results: With 957 prescriptions per 1000 person years, the highest annual prescription rate in the year 2008 was found in the Italian region Emilia Romagna followed by Germany (561), the UK (555), Denmark (481) and the Netherlands (294). Seasonal peaks during winter months were most pronounced in countries with high utilisation. Age-group-specific use varied substantially between countries with regard to total prescribing and distributions of antibiotic subgroups. However, prescription rates were highest among children in the age group ≤4 years in all countries, predominantly due to high use of broad s
Antipsychotic drug use in pregnancy: A multinational study from ten countries
Aim: To compare the prevalence and trends of antipsychotic drug use during pregnancy between countries across
four continents.
Methods: Individually linked health data in Denmark (2000−2012), Finland (2005–2014), Iceland (2004–2017),
Norway (2005–2015), Sweden (2006–2015), Germany (2006–2015), Australia (New South Wales, 2004–2012),
Hong Kong (2001–2015), UK (2006–2016), and the US (Medicaid, 2000–2013, and IBM MarketScan, 2012–2015)
were used. Using a uniformed approach, we estimated the prevalence of antipsychotic use as the proportion of
pregnancies where a woman filled at least one antipsychotic prescription within three months before pregnancy
until birth. For the Nordic countries, data were meta-analyzed to investigate maternal characteristics associated
with the use of antipsychotics.
Results: We included 8,394,343 pregnancies. Typical antipsychotic use was highest in the UK (4.4%) whereas
atypical antipsychotic use was highest in the US Medicaid (1.5%). Atypical antipsychotic use increased over
time in most populations, reaching 2% in Australia (2012) and US Medicaid (2013). In most countries,
prochlorperazine was the most commonly used typical antipsychotic and quetiapine the most commonly used
atypical antipsychotic. Use of antipsychotics decreased across the trimesters of pregnancy in all populations except Finland. Antipsychotic use was elevated among smokers and those with parity ≥4 in the Nordic countries.
Conclusion: Antipsychotic use during pregnancy varied considerably between populations, partly explained by
varying use of the typical antipsychotic prochlorperazine, which is often used for nausea and vomiting in early
pregnancy. Increasing usage of atypical antipsychotics among pregnant women reflects the pattern that was previously reported for the general population
Antipsychotic drug use in pregnancy: A multinational study from ten countries
Aim: To compare the prevalence and trends of antipsychotic drug use during pregnancy between countries across four continents
Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: What size of data platforms and which study designs do we need to assess safety issues?
Background: Data on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project.Methods: We used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0-18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children.Results: The source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest).Conclusions: Patterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children
Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project
OBJECTIVES: To estimate the risk of AMI for individual NSAIDs.METHODS: A nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999-2011) match