Evaluation of the pharmacokinetics of prednisolone in paediatric patients with acute lymphoblastic leukaemia treated according to Dutch Childhood Oncology Group protocols and its relation to treatment response

Glucocorticoids form the backbone of paediatric acute lymphoblastic leukaemia (ALL) treatment. Many studies have been performed on steroid resistance; however, few studies have addressed the relationship between dose, concentration and clinical response. The aim of the present study was to evaluate the pharmacokinetics of prednisolone in the treatment of paediatric ALL and the correlation with clinical parameters. A total of 1028 bound and unbound prednisolone plasma concentrations were available from 124 children (aged 0–18 years) with newly diagnosed ALL enrolled in the Dutch Childhood Oncology Group studies. A population pharmacokinetic model was developed and post hoc area under the curve (AUC) was tested against treatment outcome parameters. The pharmacokinetics of unbound prednisolone in plasma was best described with allometric scaling and saturable binding to proteins. Plasma protein binding decreased with age. The AUC of unbound prednisolone was not associated with any of the disease parameters or treatment outcomes. Unbound prednisolone plasma concentrations correlated with age. No effect of exposure on clinical treatment outcome parameters was observed and does not substantiate individualised dosing. Poor responders, high-risk and relapsed patients showed a trend towards lower exposure compared to good responders. However, the group of poor responders was small and requires further research.</p

Peat humification records from Restionaceae bogs in northern New Zealand as potential indicators of Holocene precipitation, seasonality, and ENSO

In comparison with temperature reconstructions, New Zealand proxy records for paleo-precipitation are rare, despite the importance of precipitation in contemporary climate variability and for projected climate impacts. In this study, records of mid-late Holocene palaeomoisture variation were derived for two hydrologically separate ombrotrophic Restionaceae bogs in northern New Zealand, based on peat humification analysis. At each site, three cores were analysed for peat humification, facilitating both intra- and inter-site comparisons. Age models for the six sequences were developed using radiocarbon dating and tephrochronology. Twelve tephras (including six cryptotephras) were recognised, four of which were used to precisely link the two sites and to define start and end points for the records at 7027 ± 170 (Tuhua tephra) and 1718 ± 10 cal yr BP (Taupo tephra) (2σ-age ranges), respectively. We find individual differences between the six peat humification records at short-term timescales that are presumably due to local site factors, in particular changing vegetation and microtopography, or to changes in the composition of the material analysed. Stronger longer-term coherence is observed between all six records but is attributed to slow anaerobic decay over time because the implied trend towards wetter summers in the late Holocene cannot be corroborated by independent climate proxies. Despite these confounding factors, centennial scale shifts in bog surface wetness are a pervasive feature of all six records with varying degrees of overlap in time that show strong correspondence with El Niño-Southern Oscillation reconstructions from the eastern equatorial Pacific. These results indicate the potential for peat humification records from New Zealand's ombrotrophic bogs to elucidate past climate variability and also demonstrate the importance of developing multiple well-dated profiles from more than one site

Population Pharmacokinetics and Pharmacodynamics of Ciprofloxacin Prophylaxis in Pediatric Acute Lymphoblastic Leukemia Patients

Background. Ciprofloxacin is used as antimicrobial prophylaxis in pediatric acute lymphoblastic leukemia (ALL) to decrease infections with gram-negative bacteria. However, there are no clear guideline

Synchronous vegetation response to the last glacial-interglacial transition in northwest Europe

The North Atlantic region experienced abrupt high-amplitude cooling at the onset of the Younger Dryas stadial. However, due to chronological uncertainties in the available terrestrial records it is unclear whether terrestrial ecosystem response to this event was instantaneous and spatially synchronous, or whether regional or time-transgressive lags existed. Here we use new palynological results from a robustly dated lake sediment sequence retrieved from lake Hämelsee (north Germany) to show that vegetation change started at 12,820 cal. yr BP, concurrent with the onset of changes in local climate. A comparison of the Hämelsee results to a compilation of precisely dated palynological records shows instant and, within decadal-scale dating uncertainty, synchronous response of the terrestrial plant community to Late-Glacial climate change across northwest Europe. The results indicate that the environmental impact of climate cooling was more severe than previously thought and illustrates the sensitivity of natural terrestrial ecosystems to external forcing. © 2022, The Author(s)

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk