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Purpose Data regarding the presence of a prolactin (PRL) threshold above which a pituitary magnetic resonance imaging (MRI) is mandatory in patients with hyperprolactinemia (hyperPRL) are controversial and derived primarily from studies focused on female populations. Aim of our study was to evaluate in a cohort of patients of both sexes with confirmed hyperPRL, the possible correlation between PRL values and the presence of pituitary abnormalities. Methods We retrospectively analyzed data from patients who underwent serial PRL sampling at our Division between January 2015 and December 2022. Patients diagnosed with monomeric hyperPRL at serial sampling and with subsequent contrast-enhanced MRI results available for the pituitary region were included in the study. Exclusion criteria were prior pituitary disease, severe renal insufficiency, liver cirrhosis, uncompensated primary hypothyroidism and ongoing therapy with hyperprolactinemic drugs. Physiological causes of hyperPRL were also ruled out. Results Out of the 1253 patients who underwent serial PRL sampling, 139 patients (101 women and 38 men) met the inclusion criteria: 106 (76.3%) patients had some form of pituitary disease, with microlesions observed in 69.8%, macrolesions in 25.5% and other findings in 4.7% of subjects. PRL values showed a modest accuracy in predicting the presence of a pituitary abnormality and the best cut-offs identified were >25 µg/L (AUC 0.767, p  = 0.003) and >44.2 µg/L (AUC 0.697, p  < 0.001) in men and women, respectively; however, if only patients with PRL values > 500 µg/L were excluded from the analysis, as they were already supposed to harbor a macroprolactinoma, PRL levels were not able to predict the presence of a macrolesion neither in men nor women. Conclusion Given the high prevalence of pituitary abnormalities in patients of both sexes with hyperPRL at serial sampling, performing a pituitary imaging in all cases of hyperPRL, even if mild, appears to be a cautious choice.

Ashfall Fossil Beds in Nebraska, USA, was a mid-Miocene (11.86 ± 0.13 Ma) watering-hole that preserved hundreds of herbivores in volcanic ash. The short-legged, barrel-bodied rhinoceros, Teleoceras major (Mammalia; Rhinocerotidae), is abundant at Ashfall (> 100 individuals), leading some researchers to suggest individuals formed large groups, while others have argued they congregated at Ashfall seeking refuge from the ash that ultimately caused their death. Here, we evaluated three types of mobility—natal dispersal of subadults, seasonal migration, and response to natural disaster—using carbon, oxygen, and strontium isotope ratios in tooth enamel from thirteen T. major adult individuals. We bulk and serially sampled enamel from mandibular second and third molars, which should respectively record behaviour after weaning but before and after possible natal dispersal. Results indicate that all sampled individuals had limited mobility and were local to Ashfall. Semi-aquatic adaptations likely restricted T. major to wet habitats and prohibited long-distance movement. Social (rather than spatial) dispersal, seasonal dietary flexibility, and elevated Miocene primary productivity could have allowed individuals to maintain genetic diversity and avoid depleting local resources. Reconstructing how extinct ungulates utilized ancient landscapes provides important context for understanding their paleoecology and sociality as well as the environments they inhabited.

The rapid advance of sequencing technology, coupled with improvements in molecular methods for obtaining genetic data from ancient sources, holds the promise of producing a wealth of genomic data from time-separated individuals. However, the population-genetic properties of time-structured samples have not been extensively explored. Here, we consider the implications of temporal sampling for analyses of genetic differentiation and use a temporal coalescent framework to show that complex historical events such as size reductions, population replacements, and transient genetic barriers between populations leave a footprint of genetic differentiation that can be traced through history using temporal samples. Our results emphasize explicit consideration of the temporal structure when making inferences and indicate that genomic data from ancient individuals will greatly increase our ability to reconstruct population history.

PurposeThe purpose of this study was to validate a ligand binding assay for the quantitation of a monoclonal antibody-based biotherapeutics (PF-57781346) in samples collected via capillary microsampling to support a regulated mouse toxicity study.MethodA quantitative ligand binding assay on the Gyrolab platform was developed to quantify PF-57781346 in blood samples derived from capillary mouse serial sampling. The method validation evaluated assay characteristics including accuracy and precision, influence of sample processing on drug quantitation, whole blood matrix selectivity, dilution linearity and the stability of the drug in the study sample matrix.ResultsThe method validation demonstrated acceptable analytical characteristics. The whole blood selectivity testing demonstrated accuracy between −4.8% and 13.9% in 10 out of 10 individual whole blood samples, suggesting that drug quantitation from whole blood is not impacted by the serial sampling procedure. Short-term and long-term drug stability in study sample matrix were established to cover required stability for sample storage and analysis (accuracy between −7.3% and 6.1%).ConclusionWe reported a successful validation of a bioanalytical method that quantifies PF-55781346 in samples collected via capillary microsampling. The experience shared in this study could serve as a model process for bioanalytical method validation when capillary microsampling is used.

Abstract At the ancient Shona centre of Great Zimbabwe (1200-1700 CE), cattle (Bos taurus) were centrally important for economic, social, and symbolic purposes. 87Sr/86Sr for modern plants collected in southern Zimbabwe vary from 0.7054 to 0.8780 and ranges differ between some geological substrates. 87Sr/86Sr in serial samples of Bos taurus tooth enamel provides information on where animals consumed at Great Zimbabwe were raised and how herds were managed. The majority of animals sampled were born and remained for their first year of life in a region some 40-120 km south of Great Zimbabwe. Few animals came from geological substrates like that of Great Zimbabwe itself, and none from areas underlain by basalts (> 120 km south of Great Zimbabwe). Earlier hypotheses of transhumance are not supported. These findings will help to build a fuller picture of the role of local commodities (in this case, cattle) in the economic networks that supported the rise and florescence of Great Zimbabwe as a major centre of power.

Purpose The standard-of-care for locally advanced rectal cancer is radiotherapy-based neoadjuvant therapy followed by surgical resection. This article reviews the evidence of molecular changes at the transcriptome level induced through radiotherapy in rectal cancer. Methods The PubMed search “(radiation OR radiotherapy) cancer (transcriptome OR “gene expression”) rectal” was used. The studies taken forward utilised gene-expression data on both pre-treatment and post-treatment rectal adenocarcinoma biospecimens from patients treated with RT-based neoadjuvant strategies. Results Twelve publications met the review criteria. There was variation in approaches in terms of design, patient population, cohort size, timing of the post-radiotherapy sampling and method of measuring gene expression. Most of the post-treatment biospecimen retrievals were at resection. The literature indicates a broad upregulation of immune activity through radiotherapy using gene-expression data. Conclusion Future studies would benefit from standardised prospective approaches to sampling to enable the inclusion of timepoints relevant to the tumour and immune response.

Purpose The purpose of this study was to validate the approach of serial sampling from one mouse through ligand binding assay (LBA) quantification of dosed biotherapeutic in diluted whole blood to derive a pharmacokinetic (PK) profile. Methods This investigation compared PK parameters obtained using serial and composite sampling methods following administration of human IgG monoclonal antibody. The serial sampling technique was established by collecting 10 μL of blood via tail vein at each time point following drug administration. Blood was immediately diluted into buffer followed by analyte quantitation using Gyrolab to derive plasma concentrations. Additional studies were conducted to understand matrix and sampling site effects on drug concentrations. Results The drug concentration profiles, irrespective of biological matrix, and PK parameters using both sampling methods were not significantly different. There were no sampling site effects on drug concentration measurements except that concentrations were slightly lower in sodium citrated plasma than other matrices. Conclusions We recommend the application of mouse serial sampling, particularly with limiting drug supply or specialized animal models. Overall the efficiencies gained by serial sampling were 40–80% savings in study cost, animal usage, study length and drug conservation while inter-subject variability across PK parameters was less than 30%.

Dynamics of mRNA from circulating tumor cells (CTCs), mRNA from extracellular vesicles (EVs), and cell-free DNA (cfDNA) were assessed to examine the relevance of a longitudinal multi-parametric liquid biopsy strategy. Eighteen milliliters of blood was drawn from 27 hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) patients at disease progression and at two subsequent radiologic staging time points. CTC mRNA and EV mRNA were analyzed using multi-marker qPCR, and cfDNA was analyzed using targeted next-generation sequencing (NGS). The presence of ERBB2 or ERBB3 overexpression signals in CTCs significantly correlated with disease progression (87% specificity, 36% sensitivity, p-value = 0.023), and the presence of either ERBB3 signals in CTCs or EVs or cfDNA variants in ERBB3 also showed a significant association with progressive MBC. Fluctuations during treatment were detected in the EV fraction with the appearance of hitherto undetected ERCC1 signals correlating with progressive disease (97% specificity, 18% sensitivity, p-value = 0.030). Allele frequency development of ESR1 and PIK3CA variants detected at subsequent staging time points could be used as a predictor for therapy success and, importantly, might help guide therapy decisions. The three analytes, each with their own unique features for disease monitoring, were shown to be complementary, underlining the usefulness of the longitudinal multi-parametric liquid biopsy approach.

Background: Stress hyperprolactinemia is a common cause of elevated prolactin (PRL) and often leads to additional investigation and radiation exposure. The results of PRL serial sampling in healthy adult volunteers to determine the utility of delayed collection are reported. Methods: Cannulated serial PRL samples were collected from 30 healthy adult volunteers between April and May 2018 at 20-minute intervals from arrival to 60 minutes (T0, T20, T40 and T60). Exclusion criteria were known risk factors for hyperprolactinemia, and patients fasted for six hours. Cortisol (CORT) was collected as a surrogate marker for stress. Results: Thirty (30) adult volunteers (n = 15 female) had a mean age of 34.7 (+/- 9.5), and mean baseline PRL of 9.7 μg/l in males and 15.8 μg/l females. Elevated PRL-T0 was observed in four volunteers (n = 3 male), all of which normalised at different intervals by T60 with serial sampling. The highest PRL was 33.7 μg/ml, normalised at T20, and had concomitant elevated cortisol levels, which remained elevated at T60. The delta decrease (Δ) for PRL was negative for all intervals (p < 0.05) and mirrored the delta decrease of cortisol (p < 0.05). Conclusion: In 30 healthy adult volunteers presenting for cannulated serial PRL sampling, four had elevated baseline levels that normalised at different intervals up to T60. The delta decrease (Δ) for PRL was negative for all intervals.

Pharmacokinetic studies are commonly analyzed using a two-stage approach where the first stage involves estimation of pharmacokinetic parameters for each subject separately and the second stage uses the individual parameter estimates for statistical inference. This two-stage approach is not applicable in sparse sampling situations where only one sample is available per subject. Nonlinear models are often applied to analyze pharmacokinetic data assessed in such serial sampling designs. Modelling approaches are suitable provided that the form of the true model is known, which is rarely the case in early stages of drug development. This paper presents an alternative approach to estimate pharmacokinetic parameters based on non-compartmental and asymptotic theories in the case of serial sampling when a drug is given as an intravenous bolus. The statistical properties of estimators of the pharmacokinetic parameters are investigated and evaluated using Monte Carlo simulations.