This paper reports a multi-throughput multi-organ-on-a-chip system formed on a pneumatic pressure-driven medium circulation platform with a microplate-sized format as a novel type of ...microphysiological system. The pneumatic pressure-driven platform enabled parallelized multi-organ experiments (i.e. simultaneous operation of multiple multi-organ culture units) and pipette-friendly liquid handling for various conventional cell culture experiments, including cell seeding, medium change, live/dead staining, cell growth analysis, gene expression analysis of collected cells, and liquid chromatography-mass spectrometry analysis of chemical compounds in the culture medium. An eight-throughput two-organ system and a four-throughput four-organ system were constructed on a common platform, with different microfluidic plates. The two-organ system, composed of liver and cancer models, was used to demonstrate the effect of an anticancer prodrug, capecitabine (CAP), whose metabolite 5-fluorouracil (5-FU) after metabolism by HepaRG hepatic cells inhibited the proliferation of HCT-116 cancer cells. The four-organ system, composed of intestine, liver, cancer, and connective tissue models, was used to demonstrate evaluation of the effects of 5-FU and two prodrugs of 5-FU (CAP and tegafur) on multiple organ models, including cancer and connective tissue.
The Asian Society of Toxicology (ASIATOX), which consists of the seven national toxicology member societies of Japan, Korea, China, Taiwan, Thailand, Singapore, and Iran, now boasts of more than ...3,000 members from a variety of industries, academia, and regulatory organizations. ASIATOX congresses are spaced three years apart and rotated among the member societies. In 1995, ASIATOX joined the International Union of Toxicology (IUTOX) as a regional society, and now serves as the scientific voice of toxicology in Asia under the IUTOX umbrella. Since its inauguration, the society has worked diligently to handle matters deemed essential to promoting the vision set fourth by its founders. Future perspectives of ASIATOX include the establishment of education and training programs, and the certification and accreditation of toxicologists. As the leading voice of toxicology in Asia, the society seeks to extend knowledge of toxicological issues to developing nations in Asia based on the following missions and goals: (1) to provide leadership as a worldwide scientific organization that objectively addresses global issues involving the toxicological sciences, (2) to broaden the geographical base of toxicology as a discipline and profession to all countries of the world, and (3) to pursue capacity building in toxicology, particularly in developing countries, while utilizing its global perspective and network to contribute to the enhancement of toxicology education and the career development of young toxicologists.
We investigate the role of domain walls in the ultrafast magnon dynamics of an antiferromagnetic NiO single crystal in a pump-probe experiment with variable pump photon energy. Analyzing the ...amplitude of the energy-dependent photoinduced ultrafast spin dynamics, we detect a yet unreported coupling between the material's characteristic terahertz- and gigahertz-magnon modes. We explain this unexpected coupling between two orthogonal eigenstates of the corresponding Hamiltonian by modeling the magnetoelastic interaction between spins in different domains. We find that such interaction, in the nonlinear regime, couples the two different magnon modes via the domain walls and it can be optically exploited via the exciton-magnon resonance.
Summary
Background
With the development of direct‐acting anti‐virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR).
Aim
To ...evaluate the short‐term risk of HCC among patients with SVR by DAAs, including those with cirrhosis or previous HCC.
Methods
This large‐scale, multicentre cohort study included 1,675 consecutive patients who achieved SVR by treatment with interferon‐free sofosbuvir‐based regimens, divided into groups with (n = 152) or without previous HCC (n = 1,523). The Kaplan‐Meier method and Cox proportional hazard analysis were used to calculate the cumulative HCC incidence and related factors of HCC.
Results
During the follow‐up period (median: 17 months), 46 (2.7%) patients developed HCC. The 1‐year cumulative rates of de novo HCC were 0.4% and 4.9% for the noncirrhosis and cirrhosis groups respectively (log‐rank test: P < 0.001). For cirrhotic patients, serum α‐fetoprotein level at the end of treatment (EOT‐AFP) was the strongest predictor of de novo HCC. The 1‐year cumulative de novo HCC rates were 1.4% and 13.1% in the EOT‐AFP < 9.0 ng/mL and ≥ 9.0 ng/mL groups (cut‐off value) respectively (log‐rank test: P < 0.001). The 1‐year cumulative rates of HCC recurrence were 6.5% and 23.1% for the noncirrhosis and cirrhosis groups respectively (log‐rank test: P = 0.023). For cirrhotic patients, previous HCC characteristics were significantly associated with HCC recurrence. In contrast, sex, age and metabolic features did not influence de novo HCC or recurrence.
Conclusions
For cirrhotic patients after elimination of HCV, serum EOT‐AFP level and previous HCC characteristics would be useful markers for predicting de novo HCC or recurrence.
Linked ContentThis article is linked to Tan and Lim paper. To view this article visit https://doi.org/10.1111/apt.14437.
Summary
Neutrophils constitute essential players in inflammatory responses and are the first line of defence against harmful stimuli. However, dysregulation of neutrophil homeostasis can result in ...excessive inflammation and subsequent tissue damage. Neutrophilic dermatoses are a spectrum of inflammatory disorders characterized by skin lesions resulting from a neutrophil‐rich inflammatory infiltrate in the absence of infection. The exact molecular pathophysiology of neutrophilic dermatoses has long been poorly understood. Interestingly, neutrophil‐rich cutaneous inflammation is also a cardinal feature of several autoinflammatory diseases with skin involvement, the latter being caused by aberrant innate immune responses. Overactivation of the innate immune system leading to increased production of interleukin‐1 family members and ‘sterile’ neutrophil‐rich cutaneous inflammation are features of both inherited autoinflammatory syndromes with skin involvement and an increasing number of neutrophilic dermatoses. Therefore, we propose that autoinflammation may be a cause of neutrophilic dermatoses.
What's already known about this topic?
Many inherited autoinflammatory diseases have characteristic skin manifestations composed of a neutrophil‐rich cutaneous inflammatory infiltrate.
Neutrophilic dermatoses have similar clinical skin manifestations to inherited autoinflammatory diseases caused by overproduction of certain cytokines of the interleukin‐1 family.
What does this study add?
Certain unifying features of these disorders suggest that they are a cutaneous consequence of autoinflammation and may be considered as autoinflammatory diseases.
Some of these neutrophilic dermatoses may lack IL‐1 as a triggering cytokine, but can still benefit from IL‐1‐targeted therapy.
Terrestrial exoplanets orbiting within or near their host stars' habitable zone are potentially apt for life. It has been proposed that time-series measurements of reflected starlight from such ...planets will reveal their rotational period, main surface features and some atmospheric information. From imagery obtained with the Akatsuki spacecraft, here we show that Venus' brightness at 283, 365, and 2020 nm is modulated by one or both of two periods of 3.7 and 4.6 days, and typical amplitudes <10% but occasional events of 20-40%. The modulations are unrelated to the solid-body rotation; they are caused by planetary-scale waves superimposed on the super-rotating winds. Here we propose that two modulation periods whose ratio of large-to-small values is not an integer number imply the existence of an atmosphere if detected at an exoplanet, but it remains ambiguous whether the atmosphere is optically thin or thick, as for Earth or Venus respectively. Multi-wavelength and long temporal baseline observations may be required to decide between these scenarios. Ultimately, Venus represents a false positive for interpretations of brightness modulations of terrestrial exoplanets in terms of surface features.
This phase II trial evaluated the efficacy of cisplatin and fluorouracil (CF)-based combination neoadjuvant chemotherapy on the outcome of patients with resectable locally advanced esophageal ...squamous cell carcinoma (ESCC). We compared the recurrence-free survival (RFS) associated with CF plus Adriamycin (ACF) with that associated with CF plus docetaxel (DCF) to select an alternative regimen in a new phase III trial investigating the optimal neoadjuvant treatment of patients with ESCC.
Patients with resectable advanced ESCC were randomly assigned to either ACF (Adriamycin 35mg/m2, cisplatin 70mg/m2 i.v. on day 1, fluorouracil 700mg/m2 continuous infusion for 7 days) every 4 weeks or DCF (docetaxel 70mg/m2, cisplatin 70mg/m2 i.v. on day 1, fluorouracil 700mg/m2 continuous infusion for 5 days) every 3 weeks. Surgery was scheduled after completion of two cycles of chemotherapy. The primary end point was RFS, analyzed by the intention-to-treat.
Between October 2011 and October 2013, 162 patients at 10 institutions were enrolled in the study, all of whom were eligible and randomly assigned to the two groups (81 to the ACF group and 81 to the DCF group). The R0 resection rates for the ACF and DCF groups were equivalent (95.9% versus 96.2%, P=0.93). The 2-year RFS and overall survival rates for DCF versus ACF were 64.1% versus 42.9% (hazard ratio 0.53, 95% confidence interval 0.33–0.83, P=0.0057) and 78.6% versus 65.4% (P=0.08), respectively.
Compared with ACF, DCF chemotherapy was associated with prolonged RFS for patients with resectable advanced ESCC. Thus, DCF chemotherapy has potential as a standard neoadjuvant therapy for resectable ESCC.
University Hospital Medical Information Network Clinical Trials Registry of Japan (identification number UMIN000004555/000004616).
NLR family pyrin domain containing 3 (NLRP3) is a cytoplasmic pattern recognition receptor that regulates innate immune responses by forming a protein complex, the inflammasome. It leads to ...production of proinflammatory cytokine productions such as interleukin 1β (IL-1β). We and others demonstrated that an induction of activated NLRP3 also induced cell death. However, little is known about the characteristics and mechanisms of the cell death and its involvement in the pathogenesis of inflammatory conditions. In this study, we established cell lines in which NLRP3 was induced by doxycycline using a tetracycline-inducible expression (Tet-on) system. Using this system, the expression of NLRP3 mutants in cryopyrin-associated periodic syndrome (CAPS) patients was sufficient for the induction of necrotic cell death without lipopolysaccharide stimulation or generation of mature IL-1β. We also found that CA074-Me, a cathepsin B inhibitor, blocked cell death before oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC), whereas Z-VAD-fmk, a pan-caspase inhibitor, blocked the cell death after the oligomerization. Silencing of the ASC gene (Pycard) by small hairpin RNA treatment inhibited the NLRP3 mutant-induced cell death, but silencing of the caspase-1 gene (Casp1) did not. Taken together, these results indicated that ASC was indispensable for NLRP3-mediated programmed necrotic cell death, and that this type of cell death was distinct from 'pyroptosis', which requires caspase-1. Finally, we demonstrated in an in vivo model that the programmed necrotic cell death induced by activated NLRP3 could cause neutrophil infiltration, indicating a possible role of cell death in neutrophil infiltration of skin lesions in CAPS patients.
The existence of large stationary gravity waves was discovered during Akatsuki's first observation sequence in 2015. In this study, the further detection of large stationary gravity waves in ...brightness temperature images over a 1.5 year period is reported. The waves periodically appeared mostly above four specific highland regions in the low latitudes when these regions were in the local afternoon. The wave amplitudes attenuated after the wave locations passed beyond the evening terminator, and the locations of the waves tended to slowly drift eastward over their lifetimes. The appearances of stationary waves depend not only on surface topography but also on latitude and local time, suggesting that solar heating during the daytime and atmospheric structure affected by solar heating may control the excitation and propagation of stationary waves.
Plain Language Summary
The Japanese Venus satellite “Akatsuki” has repeatedly found large atmospheric waves with north‐south lengths, which sometimes reach more than 10,000 km at the cloud top level on Venus (altitude ~70 km). These waves have repeatedly appeared above the Venusian highlands in low latitudes, such as Aphrodite Terra. Interestingly, the waves appeared and became clearer each time the highlands passed from noon to evening; therefore, they can be regarded as “daily” Venusian phenomena. Despite westward wind speeds reaching 100 m s−1 at the cloud top level (known as atmospheric superrotation), the east‐west propagation speeds of the large waves were nearly zero, and the waves stayed above their initial locations (stationary). This means that the origin of the waves could be the highland terrains below. Because waves can transport energy via propagation, stationary waves may transport atmospheric energy from the lower atmosphere to the cloud top level and may affect the speed of the superrotation. The existence and regular appearance of the large stationary waves indicate a continuous interaction between the lower and upper atmospheres on Venus via wave propagation, which provides a novel perspective of the Venusian atmosphere.
Key Points
Stationary gravity waves with large horizontal extent at the cloud top level of Venus have been repeatedly identified
The locations of these waves show a clear connection to Venusian highlands, and wave amplitude depends on the local time at the highlands
Monitoring of the stationary waves would bring information of the Venusian atmosphere along the wave propagation paths
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