Summary The cause of elevated level of amyloid β-peptide (Aβ42) in common late-onset sporadic (AD) has not been established. Here we show that the membrane lipid peroxidation product 4-hydroxynonenal (HNE) is associated with amyloid and neurodegenerative pathologies in AD, and that it enhances γ-secretase activity and Aβ42 production in neurons. The γ-secretase substrate receptor, nicastrin was found to be modified by HNE in cultured neurons and in brain specimens from AD patients, in which HNE-nicastrin levels were found to be correlated with increased γ-secretase activity and Aβ plaque burden. Furthermore, HNE modification of nicastrin enhanced its binding to the γ-secretase substrate, amyloid precursor protein (APP) C99. In addition, the stimulation of γ-secretase activity and Aβ42 production by HNE were blocked by an HNE-scavenging histidine analog in a 3xTgAD mouse model of AD. These findings suggest a specific molecular mechanism by which oxidative stress increases Aβ42 production in AD, and identify HNE as a novel therapeutic target upstream of the γ-secretase cleavage of APP.

Our study suggested that dexamethasone has inhibitory effects on cell migration and invasion by suppressing EMT of colon cancer cell lines in hypoxic condition.

Adoptive cell transfer of ex vivo-activated natural killer (NK) cells is a promising therapy for cancer treatment. Because of inhibitory signaling through killer immunoglobulin-like receptor (KIR)-KIR ligands, KIR-mismatched allogeneic NK cell transfer is considered to be a more effective strategy than is autologous transfer. However, purified NK cells do not expand well enough in vitro with good manufacturing practice-compliant components for clinical use. Some investigators have developed selective expansion of NK cells from peripheral blood mononuclear cells, but these cells have the risk of graft-versus-host disease in allogeneic settings because of T cells contamination. In this study, we developed a novel method for NK cell activation and expansion. Using only good manufacturing practice-compliant components and autologous feeder cells, once purified NK cells were effectively expanded (2500-fold at day 17). The expanded cells were highly purified NK cells, and the use of these cells is suitable for allogeneic transfer without the risk of graft-versus-host disease induction. Importantly, the expanded NK cells also showed enhanced cytotoxicity compared with NK cells conventionally expanded by recombinant human interleukin 2. Finally, induction of NKG2D ligand expression on feeder cells implies that the NKG2D-NKG2DL interaction may play a role in NK cell expansion. In conclusion, this method can be used to obtain NK cells for more successful allogeneic NK cell adoptive transfer for use in antitumor immune therapy.

No abstract

In vivo cells express their characteristics in three-dimensional (3D) microenvironments via cell-cell interactions through autocrine, contact-dependent, paracrine, and synaptic signaling, often between heterologous cell types. Various in vitro 3D microwell-based culture methods have been proposed to further identify cellular characteristics by recreating cellular environments, typically in the form of spheroids and organoids, thereby realizing contact-based cell-cell interactions. However, in vivo cells generally exhibit multiple cellular interaction modes that have not been completely evaluated using existing microwell-based methods. This has led to a demand for more advanced and comprehensive methods. This study introduces a novel apparatus, the membrane-bottomed microwell (MBM) for non-contact co-cultures and 3D cell cultures. The MBM is a combination of a Transwell and a microwell array; these have previously been utilized to facilitate heterologous cell co-culturing and spheroid 3D cell culturing, respectively. In the Transwell insert, the lower part of the MBM is immersed in the culture media in which the cells are being two-dimensionally (2D) cultured, and the spheroids of the MBM are affected by the 2D cultured cells via the membrane at the bottom of the microwell. Here, we describe the methods for manufacturing the MBM in detail and elucidate the results of simulations of diffusion through the bottom of the membrane. We validate the proposed MBM for the spheroid culture of spermatogonial stem cells (SSCs), which had previously been 2D co-cultured with Sandos inbred mouse (SIM)-derived 6-thioguanine-and ouabain-resistant (STO; a mouse embryonic feeder cell line) feeder cells. The proposed system is shown to facilitate successful SSC spheroid culturing with paracrine signaling of STOs through an apparatus that simplifies both the loading and the evaluation processes; therefore, we believe that our findings will enable a more comprehensive understanding of SSCs and associated phenomena and that our system can be applied to various in vitro cell and tissue experiments.

There is a known high disparity in access to perinatal care services between urban and rural areas in Tanzania. This study analysed repeated cross-sectional (RCS) data from Tanzania to explore the relationship between antenatal care (ANC) visits, facility-based delivery and the reasons for home births in women who had made ANC visits. We used data from RCS Demographic and Health Surveys spanning 20 years and a cluster sample of 30 830 women from ∼52 districts of Tanzania. The relationship between the number of ANC visits (up to four) and facility delivery in the latest pregnancy was explored. Regional changes in facility delivery and related variables over time in urban and rural areas were analysed using linear mixed models. To explore the disconnect between ANC visits and facility deliveries, reasons for home delivery were analysed. In the analytic model with other regional-level covariates, a higher proportion of ANC (>2–4 visits) and exposure to media related to an increased facility delivery rate in urban areas. For rural women, there was no significant relationship between the number of visits and facility delivery rate. According to the fifth wave result (2009–10), the most frequent reason for home delivery was ‘physical distance to facility’, and a significantly higher proportion of rural women reported that they were ‘not allowed to deliver in facility’. The disconnect between ANC visits and facility delivery in rural areas may be attributable to physical, cultural or familial barriers, and quality of care in health facilities. This suggests that improving access to ANC may not be enough to motivate facility-based delivery, especially in rural areas.

This study aims to analyze South Korea’s experience during the COVID-19 outbreak through a gendered lens. We briefly introduce the COVID-19 outbreak in Korea, scrutinize gendered vulnerability in contracting the virus, and then analyze the gendered aspects of the pandemic response in two phases: quarantine policy and mitigation policy. The authors elicit four lessons from the analysis. First, gender needs to be mainstreamed at all stages of a public health emergency response. Second, in addition to medical care, all formal and informal care work should be considered as an essential component of health care systems. Third, a people-centered approach in health governance should be prioritized to make women’s voices heard at every level. Fourth, medical technology and resources to cope with pandemic should be produced and distributed in an equitable manner, acknowledging differential vulnerability and susceptibility.

Objectives The purpose of this study was to estimate the mediating effect of subjective unmet healthcare needs on poor health. The mediating effect of unmet needs on health outcomes was estimated. Methods Cross-sectional research method was used to analyze Korea Health Panel data from 2011 to 2015, investigating the mediating effect for each annual dataset and lagged dependent variables. Results The magnitude of the effect of low income on poor health and the mediating effect of unmet needs were estimated using age, sex, education level, employment status, healthcare insurance status, disability, and chronic disease as control variables and self-rated health as the dependent variable. The mediating effect of unmet needs due to financial reasons was between 14.7% to 32.9% of the total marginal effect, and 7.2% to 18.7% in lagged model. Conclusions The fixed-effect logit model demonstrated that the existence of unmet needs raised the likelihood of poor self-rated health. However, only a small proportion of the effects of low income on health was mediated by unmet needs, and the results varied annually. Further studies are necessary to search for ways to explain the varying results in the Korea Health Panel data, as well as to consider a time series analysis of the mediating effect. The results of this study present the clear implication that even though it is crucial to address the unmet needs, but it is not enough to tackle the income related health inequalities.