High-Throughput and Cost-Effective Characterization of Induced Pluripotent Stem Cells.

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) offers the possibility of studying the molecular mechanisms underlying human diseases in cell types difficult to extract from living patients, such as neurons and cardiomyocytes. To date, studies have been published that use small panels of iPSC-derived cell lines to study monogenic diseases. However, to study complex diseases, where the genetic variation underlying the disorder is unknown, a sizable number of patient-specific iPSC lines and controls need to be generated. Currently the methods for deriving and characterizing iPSCs are time consuming, expensive, and, in some cases, descriptive but not quantitative. Here we set out to develop a set of simple methods that reduce cost and increase throughput in the characterization of iPSC lines. Specifically, we outline methods for high-throughput quantification of surface markers, gene expression analysis of in vitro differentiation potential, and evaluation of karyotype with markedly reduced cost

Privacy-Preserving Credit Scoring via Functional Encryption

The majority of financial organizations managing confidential data are aware of security threats and leverage widely accepted solutions (e.g., storage encryption, transport-level encryption, intrusion detection systems) to prevent or detect attacks. Yet these hardening measures do little to face even worse threats posed on data-in-use. Solutions such as Homomorphic Encryption (HE) and hardware-assisted Trusted Execution Environment (TEE) are nowadays among the preferred approaches for mitigating this type of threats. However, given the high-performance overhead of HE, financial institutions —whose processing rate requirements are stringent— are more oriented towards TEE-based solutions. The X-Margin Inc. company, for example, offers secure financial computations by combining the Intel SGX TEE technology and HE-based Zero-Knowledge Proofs, which shield customers’ data-in-use even against malicious insiders, i.e., users having privileged access to the system. Despite such a solution offers strong security guarantees, it is constrained by having to trust Intel and by the SGX hardware extension availability. In this paper, we evaluate a new frontier for X-Margin, i.e., performing privacy-preserving credit risk scoring via an emerging cryptographic scheme: Functional Encryption (FE), which allows a user to only learn a function of the encrypted data. We describe how the X-Margin application can benefit from this innovative approach and —most importantly— evaluate its performance impact

Weight discordance and perinatal mortality in twin pregnancy: systematic review and meta‐analysis

Objectives The primary aim of this systematic review was to explore the strength of association between birth‐weight (BW) discordance and perinatal mortality in twin pregnancy. The secondary aim was to ascertain the contribution of gestational age and growth restriction in predicting mortality in growth‐discordant twins. Methods MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched. Only studies reporting on the risk of mortality in twin pregnancies affected compared with those not affected by BW discordance were included. The primary outcomes explored were incidence of intrauterine death (IUD), neonatal death (NND) and perinatal death. Outcome was assessed separately for monochorionic (MC) and dichorionic (DC) twin pregnancies. Analyses were stratified according to BW discordance cut‐off (≥ 15%, ≥ 20%, ≥ 25% and ≥ 30%) and selected gestational characteristics, including incidence of IUD or NND before and after 34 weeks' gestation, presence of at least one small‐for‐gestational age (SGA) fetus in the twin pair and both twins being appropriate‐for‐gestational age. Risk of mortality in the larger vs smaller twin was also assessed. Meta‐analyses using individual data random‐effects logistic regression and meta‐analyses of proportion were used to analyze the data. Results Twenty‐two studies (10 877 twin pregnancies) were included in the analysis. In DC pregnancies, a higher risk of IUD, but not of NND, was observed in twins with BW discordance ≥ 15% (odds ratio (OR) 9.8, 95% CI, 3.9–29.4), ≥ 20% (OR 7.0, 95% CI, 4.15–11.8), ≥ 25% (OR 17.4, 95% CI, 8.3–36.7) and ≥ 30% (OR 22.9, 95% CI, 10.2–51.6) compared with those without weight discordance. For each cut‐off of BW discordance explored in DC pregnancies, the smaller twin was at higher risk of mortality compared with the larger one. In MC twin pregnancies, excluding cases affected by twin–twin transfusion syndrome, twins with BW discordance ≥ 20% (OR 2.8, 95% CI, 1.3–5.8) or ≥ 25% (OR 3.2, 95% CI, 1.5–6.7) were at higher risk of IUD, compared with controls. MC pregnancies with ≥ 25% weight discordance were also at increased risk of NND (OR 4.66, 95% CI, 1.8–12.4) compared with those with concordant weight. The risk of IUD was higher when considering discordant pregnancies involving at least one SGA fetus. The overall risk of mortality in MC pregnancies was similar between the smaller and larger twin, except in those with BW discordance ≥ 20%. Conclusion DC and MC twin pregnancies discordant for fetal growth are at higher risk of IUD but not of NND compared with pregnancies with concordant BW. The risk of IUD in BW‐discordant DC and MC twins is higher when at least one fetus is SGA

Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation: implications for the pathogenesis and treatment of bone metastasis.

Significant relief of bone pain in patients with bone metastases was observed in a clinical trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in breast cancer. Osteoclast activation and differentiation are regulated by bone marrow stromal cells (BMSC), a heterogeneous cell compartment that comprehends undifferentiated mesenchymal stem cells (MSC) and their specialized progeny. In this regard, we found that human primary BMSCs express immunoreactive EGFR. Expression of EGFR mRNA and protein was also demonstrated in two human, continuous MSC-like cell lines, HDS-1 and HDS-2 cells. Treatment of HDS cells with EGF produced a significant increase in the levels of activated EGFR which was not observed in the presence of gefitinib. A significant reduction in the basal levels of activation of the EGFR and of Akt was observed in HDS cells following treatment with gefitinib. Treatment of HDS cells with gefitinib produced a significant reduction in the levels of secreted macrophage colony-stimulating factor (M-CSF) and cell-associated receptor activator of NF-kappaB ligand (RANKL) in both cell lines, as assessed by using specific ELISA and Western blotting techniques. Finally, the ability to sustain the differentiation of pre-osteoclasts of conditioned medium from gefitinib-treated HDS cells was reduced by approximately 45% as compared with untreated HDS cells. These data have demonstrated for the first time that the EGFR regulates the ability of BMSCs to induce osteoclast differentiation and strongly support clinical trials of gefitinib in breast cancer patients with bone disease

Author Correction: Longitudinal assessment of tumor development using cancer avatars derived from genetically engineered pluripotent stem cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

A population approach to characterise amisulpride pharmacokinetics in older people and Alzheimer's disease

Introduction Current prescribing guidelines for the antipsychotic amisulpride are based largely on pharmacokinetic (PK) studies in young adults, and there is a relative absence of data on older patients, who are at greatest risk of developing adverse events. Methods This study aimed to develop a population PK model for amisulpride specifically in older people, by combining data from a richly sampled phase 1, single (50 mg) dose study in healthy older people (n = 20, 65–79 years), with a clinical dataset obtained during off label, low-dose (25–75 mg daily) amisulpride prescribing in older people with Alzheimer’s disease (AD) (n = 25, 69–92 years), as part of an observational study. Results After introducing a scaling factor based on body weight, age accounted for 20 % of the inter-individual variability in drug clearance (CL), resulting in a 54 % difference in CL between those aged 65 and those aged 85 years, and higher blood concentrations in older patients. Discussion These findings argue for the consideration of age and weight-based dose stratification to optimise amisulpride prescribing in older people, particularly in those aged 85 years and above

The Holocene volcanism at El Hierro: insights from petrology and geochemistry

The Holocene volcanism at El Hierro consists of basaltic monogenetic volcanic fields associated with o the three rift systems present in this island. In this work we report preliminary petrological and geochemical data of Holocene lava flows belonging to the WNW-striking rift. Sampling was focused in three zones: Orchilla, Verodal-Sabinosa, and Tanganasoga. Petrography of the studied lavas shows that they are homogeneous. All samples are porphyritic with macrocrysts of clinopyroxene and olivine immersed in a groundmass formed by microcrysts of plagioclase, Fe-Ti oxides and clinopyroxene. Clinopyroxenes are diopsides, olivines have forsterite contents ranging from 74 to 84 % and anorthite in plagioclase varies from 66 to 76% (labradorite). Whole-rock geochemical results evidence that all magmas are basic in composition, ranging from picrobasalts to phonotephrites. Major, trace elements and isotope suppor fractional crystallization as the main process of magma evolution. However, petrography and chemistry of clinopyroxene cores agree with a xenocrystic nature of some of them. We suggest that these clinopyroxene cores crystallized from a genetically related magma and subsequently were entrapped o cannibalized by the basic rising magmas

SARMA: a web resource for species assignment of high-throughput sequencing reads from metagenomics analysis

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