Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an ...'interrogator' that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood-brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling.
Analyses of drug pharmacokinetics (PKs) and pharmacodynamics (PDs) performed in animals are often not predictive of drug PKs and PDs in humans, and in vitro PK and PD modelling does not provide ...quantitative PK parameters. Here, we show that physiological PK modelling of first-pass drug absorption, metabolism and excretion in humans-using computationally scaled data from multiple fluidically linked two-channel organ chips-predicts PK parameters for orally administered nicotine (using gut, liver and kidney chips) and for intravenously injected cisplatin (using coupled bone marrow, liver and kidney chips). The chips are linked through sequential robotic liquid transfers of a common blood substitute by their endothelium-lined channels (as reported by Novak et al. in an associated Article) and share an arteriovenous fluid-mixing reservoir. We also show that predictions of cisplatin PDs match previously reported patient data. The quantitative in-vitro-to-in-vivo translation of PK and PD parameters and the prediction of drug absorption, distribution, metabolism, excretion and toxicity through fluidically coupled organ chips may improve the design of drug-administration regimens for phase-I clinical trials.
Abstract
The main objective of this study was to evaluate the effects of increasing greenhouse gases (GHGs) and total deforestation of the Amazon on extreme rainfall events in the Amazon basin. In ...order to quantify these impacts, numerical experiments were performed with the Eta regional climate model forced from initial and boundary conditions from the BESM, HadGEM2‐ES, and MIROC5 earth system models. In the experiment related to the increase in GHGs, numerical simulations were performed according to the IPCC RCP8.5 scenario. The effect of deforestation was quantified via an experiment in which the forest in the Amazon basin was replaced by areas of degraded pasture in the Eta model. For the analyses of the changes in extreme rainfall events, the multi‐model ensemble technique was used. The results were evaluated in terms of anomalies relative to the sensitivity and control experiments. In the results, it was observed that in an RCP8.5‐type GHG emission scenario there is a statistically significant increase in the maximum number of consecutive days without rain, a reduction in the maximum number of consecutive rainy days, reduction in total annual precipitation, and reduction in maximum annual precipitation accumulated over one and 5 days, respectively. The results for the scenario with increased GHGs and large‐scale deforestation in the Amazon basin are similar to the RCP8.5 scenario, but the intensity of changes in climate indices is significantly greater. It was also verified that the changes in the climatic indices are strongly associated with alterations in the energy balances at the surface and, consequently, in the large‐scale circulation. In general, it can be highlighted that the climate in the Amazon region is strongly dependent on the presence of the forest.
Summary
This study was designed to assess the clinical usefulness of imaging for predicting the prognosis of patients with combined hepatocellular cholangiocarcinoma (cHCC‐CC). Between 1999 and 2004, ...30 patients with histopathologically proven cHCC‐CC underwent computed tomography (CT) or magnetic resonance imaging (MRI). The imaging data and survival were analysed. Univariate log‐rank analysis of imaging findings revealed that tumour necrosis, bile duct invasion, major vascular branch invasion, multiplicity, bilobar distribution, regional lymph node involvement, regional organ invasion, distant metastasis and ascites had adverse influences on overall survival. Multivariate Cox proportional hazard analysis demonstrated that major vascular branch invasion, regional organ invasion, nodal and distant metastases were independent prognostic factors that adversely affected overall survival rates. Overall cumulative survival rates at 1, 3 and 5 years were 53%, 26% and 12%, respectively. Analysing the survival of our patients by using clinical stages of the newly updated American Joint Committee on Cancer (AJCC) classification for liver neoplasm based on the imaging findings, we found significant differences between stages I/II and III (p < 0.001) and between stages III and IV (p = 0.040). We conclude CT or MRI can be used to identify the prognostic factors and to estimate the outcomes of patients with cHCC‐CC.
The oversolubility of the non-polar methane (CH4) gas in nano-confined liquid in nanoporous silica materials is investigated. A series of mesoporous silica materials with different pore sizes, pore ...volumes, and different amounts of nano-confined water (H2O) are prepared using a pore-expanding reagent and surfactants of different chain-lengths, and the CH4 absorption by the silica nano-materials is studied at 298 K under low CH4 gas pressures. Analysis of the CH4 absorption data reveals unequivocal evidence for oversolubility of CH4 in the nano-confined H2O of all the hydrated nano-materials. The solubility enhancements are several hundred fold relative to the CH4 solubility in bulk H2O. Interestingly, the enhancements are 25–30% higher when a tricopper cluster complex capable of efficient selective CH4 oxidation under ambient conditions is immobilized into the nano-channels of the silica materials. This dramatic enhancement of the CH4 solubility is attributed to specific CH4 binding to the tricopper cluster complexes embedded within the mesopores of the nanoporous materials.
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•CH4 oversolubility in nano-confined H2O in nanoporous silica materials is measured.•The nanomaterials studied include MSN and MCM-41 of varying pore sizes and volumes.•CH4 solubility enhancements in MSN are ~500 fold relative to bulk H2O.•Immobilization of a tricopper catalyst in MSN enhances CH4 oversolubility by 30%.•CH4 oxidation activity of catalyst is significantly higher for MSN than for MCM-41.
Infectious diseases are closely related to cancer. Human cytomegalovirus (HCMV) has been implicated in the promotion of tumour growth, and is present in the tumour specimens of colorectal cancer ...(CRC). This study aimed to investigate whether tumoral presence of HCMV is associated with a different clinical outcome in elderly patients with CRC. We analysed archived tumour specimens from 95 CRC patients aged ≥65 years. HCMV was detected by PCR. Clinical, pathological, disease-free and overall survival data were compared between patients with HCMV-positive and HCMV-negative tumours. A quantitative RT-PCR array was used to evaluate the expression levels of cytokines genes of T-helper subpopulations in tumours. In the Kaplan–Meier analysis of the 81 patients who underwent curative surgery, 39 patients with HCMV-positive tumours had a lower disease-free survival rate (p 0.024). For patients with stage II or stage III tumours, tumoral HCMV status correlated with disease-free survival more closely than the traditional histopathological staging methods. In a multivariate Cox proportional hazard model, tumoral presence of HCMV independently predicted tumour recurrence in 5 years (hazard ratio 4.42; 95% CI 1.54–12.69, p 0.006). The qRT-PCR analysis of ten stage II tumours showed that the gene expression levels of interleukin-17—the signature cytokine of T-helper 17 cells—and its receptor, interleukin-17 receptor C, were higher in the five HCMV-positive tumours. Our results suggest that the presence of HCMV in CRC is associated with poorer outcome in elderly patients. How the virus interacts with the tumour microenvironment should be further investigated.
The oxidation behavior of SiAlON materials has been investigated. The kinetic studies reported in literatures were also discussed. Based on the kinetic curves of the oxidation of SiAlON, a new model ...for predicting the oxidation weight gain as a function of temperature and other variables was established. The application of this new model to both experiment data of β-SiAlON (
z
=
3.0) powder and that of O′-SiAlON (
x
=
0.18) powder as well as that of β-SiAlON-Al
2O
3 pellet demonstrated that this new model could be used to predict the oxidation behavior and the calculated results agreed well with the experimental data, moreover, these formulae can not only be used to treat the oxidation for SiAlON materials but also can be applied to treat the problems of other non-metallic oxide materials due to similar mechanism.
This study examines the effects of perceived discrimination on quality of life (QOL). We used a random sample of 380 Chinese immigrants from a 1-year longitudinal secondary dataset and conducted ...bivariate and multivariate multiple regressions to examine the associations of QOL with perceived discrimination, sense of control, optimism, perceived social support, pre-migration planning, collective efficacy and perceived neighborhood disorder. Our results showed that perceived discrimination was significantly associated with QOL, even after a year spent in Hong Kong. Collective efficacy, perceived social support and preparation for immigration are also important factors contributing the QOL among new immigrants in Hong Kong. The findings suggest that interventions to reduce discrimination should be designed and implemented in order to improve the QOL among new immigrants in Hong Kong.
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