Development of a pig mammary epithelial cell culture model as a non‐clinical tool for studying epithelial barrier— a contribution from the imi‐conception project

The ConcePTION project aims at generating further knowledge about the risks related to the use of medication during breastfeeding, as this information is lacking for most commonly used drugs. Taking into consideration multiple aspects, the pig model has been considered by the consortium as the most appropriate choice. The present research was planned to develop an efficient method for the isolation and culture of porcine Mammary Epithelial Cells (pMECs) to study the mammary epithelial barrier in vitro. Mammary gland tissues were collected at a local slaughterhouse, dissociated and the selected cellular population was cultured, expanded and characterized by morphology, cell cycle analysis and immunophenotyping. Their ability to create a barrier was tested by TEER measurement and sodium fluorescein transport activity. Expression of 84 genes related to drug transporters was evaluated by a PCR array. Our results show that primary cells express epithelial cell markers: CKs, CK18, E‐Cad and tight junctions molecules ZO‐1 and OCL. All the three pMEC cellular lines were able to create a tight barrier, although with different strengths and kinetics, and express the main ABC and SLC drug transporters. In conclusion, in the present paper we have reported an efficient method to obtain primary pMEC lines to study epithelial barrier function in the pig model

A comprehensive review on non-clinical methods to study transfer of medication into breast milk – A contribution from the ConcePTION project

Breastfeeding plays a major role in the health and wellbeing of mother and infant. However, information on the safety of maternal medication during breastfeeding is lacking for most medications. This leads to discontinuation of either breastfeeding or maternal therapy, although many medications are likely to be safe. Since human lactation studies are costly and challenging, validated non-clinical methods would offer an attractive alternative. This review gives an extensive overview of the non-clinical methods (in vitro, in vivo and in silico) to study the transfer of maternal medication into the human breast milk, and subsequent neonatal systemic exposure. Several in vitro models are available, but model characterization, including quantitative medication transport data across the in vitro blood-milk barrier, remains rather limited. Furthermore, animal in vivo models have been used successfully in the past. However, these models don't always mimic human physiology due to species-specific differences. Several efforts have been made to predict medication transfer into the milk based on physicochemical characteristics. However, the role of transporter proteins and several physiological factors (e.g., variable milk lipid content) are not accounted for by these methods. Physiologically-based pharmacokinetic (PBPK) modelling offers a mechanism-oriented strategy with bio-relevance. Recently, lactation PBPK models have been reported for some medications, showing at least the feasibility and value of PBP

Glomerular Filtration Rate in Asphyxiated Neonates Under Therapeutic Whole-Body Hypothermia, Quantified by Mannitol Clearance

BACKGROUND Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate. OBJECTIVES The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate. METHODS The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO (ALlopurinol in addition to TH for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4. RESULTS Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease). CONCLUSIONS Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT03162653

Review on analog RF performance of advanced MOSFET

Aggressive gate-length downscaling of the metal-oxide-semiconductor field-effect transistor (MOSFET) has been the main stimulus for the growth of the integrated circuit industry. This downscaling, which has proved beneficial to digital circuits, is primarily the result of the need for improved circuit performance and cost reduction and has resulted in tremendous reduction of the carrier transit time across the channel, thereby resulting in very high cut-off frequencies. It is only in recent decades that complementary metal-oxide-semiconductor (CMOS) field-effect transistor (FET) has been considered as the radio frequency (RF) technology of choice. In this review, the status of the digital, analog and RF figures of merit (FoM) of silicon-based FETs is presented. State-of-the-art devices with very good performance showing low values of drain-induced barrier lowering, sub-threshold swing, high values of gate transconductance, Early voltage, cut-off frequencies, and low minimum noise figure, and good low-frequency noise characteristic values are reported. The dependence of these FoM on the device gate length is also shown, helping the readers to understand the trends and challenges faced by shorter CMOS nodes. Device performance boosters including silicon-on-insulator substrates, multiple-gate architectures, strain engineering, ultra-thin body and buried-oxide and also III-V and 2D materials are discussed, highlighting the transistor characteristics that are influenced by these boosters. A brief comparison of the two main contenders in continuing Moore's law, ultra-thin body buried-oxide and fin field-effect transistors are also presented. The authors would like to mention that despite extensive research carried out in the semiconductor industry, silicon-based MOSFET will continue to be the driving force in the foreseeable future