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Dendritic cells (DCs) are attractive antigen-presenting cells to be targeted for vaccinations. However, the systemic delivery of mRNA to DCs is hampered by technical challenges. We recently reported that it is possible to regulate the size of RNA-loaded lipid nanoparticles (LNPs) to over 200 nm with the addition of salt during their formation when a microfluidic device is used and that larger LNPs delivered RNA more efficiently and in greater numbers to splenic DCs compared to the smaller counterparts. In this study, we report on the in vivo optimization of mRNA-loaded LNPs for use in vaccines. The screening included a wide range of methods for controlling particle size in addition to the selection of an appropriate lipid type and its composition. The results showed a clear correlation between particle size, uptake and gene expression activity in splenic DCs and indicated that a size range from 200 to 500 nm is appropriate for use in targeting splenic DCs. It was also found that it was difficult to predict the transgene expression activity and the potency of mRNA vaccines in splenic DCs using the whole spleen. A-11-LNP, which was found to be the optimal formulation, induced better transgene expression activity and maturation in DCs and induced clear therapeutic antitumor effects in an E.G7-OVA tumor model compared to two clinically relevant LNP formulations.

Distance learning has been expanding. Learner engagement is particularly important in project-based learning (PBL), but the interaction between teacher and learner and the understanding of learner status, including engagement, is not easy. This study aims to support teacher-learner communication based on learner engagement for remote PBL. In this paper, we propose the use of video activity reports by learners to estimate and understand learner engagement and to demonstrate its feasibility on the basis of the relationship between verbal and nonverbal information that can be obtained from video activity reports and learner engagement. Analysis of 232 video activity reports submitted by eight graduate students while working on remote research-based PBLs reveals that learner engagement decreases (1) when the report contained negative words, (2) when filled pauses were frequent or long, and (3) when silent pauses were infrequent or short. Furthermore, the feasibility of an AI-based support system is demonstrated through the design and implementation of a prototype.

Dysphagia in patients with heart failure leads to poorer outcomes during hospitalization and after discharge. Therefore, addressing dysphagia is critical for improving patient prognosis. This retrospective observational study aimed to evaluate associations between improvements in swallowing dysfunction at the time of hospital discharge and the physical function, cognitive function, nutritional status, and maximum tongue pressure (MTP). Overall, 111 patients who underwent cardiac rehabilitation and were deemed to have oral intake impairment were included. The exclusion criteria comprised the following: pre-admission diagnosis of dysphagia, in-hospital death, and missing data. Patients were categorized based on whether they did (n = 65) or did not (n = 46) exhibit improvements in oral intake impairment, which were determined from the functional oral intake scale (FOIS) score at discharge. Associations between potential explanatory variables and the FOIS score at discharge were assessed using a linear regression model. After adjusting for covariates, such as age, sex, heart failure severity, short physical performance battery score, Mini-Mental State Examination score, transthyretin level, and provision of swallowing therapy, the FOIS score at discharge was significantly associated with the MTP ( P  = 0.024, confidence interval: 0.006–0.046). In conclusion, the MTP was independently associated with improvements in FOIS in patients with heart failure.

Background: Lung cancer is a major cause of death. Japan has a higher rate of early detection of lung cancer, which is attributed to the impact of chest X-ray examinations implemented as mass screening. This study describes the characteristics and outcomes of patients with lung cancer in Japan, where chest X-ray screening is recommended for everyone aged >40 years old. Methods: This observational study linked the Kyoto City Integrated Database with data from a nationwide cancer registry in Japan. This study assessed individuals aged ≥65 years diagnosed with primary lung cancer between 2014 and 2018. Patients were categorized into the screened or unscreened groups based on their screening history within 1 year before diagnosis. Results: Of 4473 patients with lung cancer, 231 were included in the screened group. The screened group had a mortality rate of 25% at 1.7 years and 50% at 5.6 years, versus 25% at 0.5 years and 50% at 1.8 years for the unscreened group. Conclusions: Patients with primary lung cancer who underwent lung cancer screening had longer survival and better overall health at diagnosis than those who did not undergo screening. Further study is required to estimate the effectiveness of chest X-ray lung cancer screening.

Background The interplay between cancer cells and stromal components, including soluble mediators released from cancer cells, contributes to the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we set out to identify key secreted proteins involved in PDAC progression. Methods We performed secretome analyses of culture media of mouse pancreatic intraepithelial neoplasia (PanIN) and PDAC cells using Stable Isotope Labeling by Amino acid in Cell culture (SILAC) with click chemistry and liquid chromatography-mass spectrometry (LC-MS/MS). The results obtained were verified in primary PDAC tissue samples and cell line models. Results Complement factor B (CFB) was identified as one of the robustly upregulated proteins, and found to exhibit elevated expression in PDAC cells compared to PanIN cells. Endogenous CFB knockdown by a specific siRNA dramatically decreased the proliferation of PDAC cells, PANC-1 and MIA PaCa-II. CFB knockdown induced increases in the number of senescence-associated-β-galactosidase (SA-β-gal) positive cells exhibiting p21 expression upregulation, which promotes cellular senescence with cyclinD1 accumulation. Furthermore, CFB knockdown facilitated downregulation of proliferating cell nuclear antigen and led to cell cycle arrest in the G1 phase in PDAC cells. Using immunohistochemistry, we found that high stromal CFB expression was associated with unfavorable clinical outcomes with hematogenous dissemination after surgery in human PDAC patients. Despite the presence of enriched CD8 + tumor infiltrating lymphocytes in the PDAC tumor microenvironments, patients with a high stromal CFB expression exhibited a significantly poorer prognosis compared to those with a low stromal CFB expression. Immunofluorescence staining revealed a correlation between stromal CFB expression in the tumor microenvironment and an enrichment of immunosuppressive regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We also found that high stromal CFB expression showed a positive correlation with high CD8 + /Foxp3 + Tregs populations in PDAC tissues. Conclusions Our data indicate that CFB, a key secreted protein, promotes proliferation by preventing cellular senescence and is associated with immunological tumor promotion in PDAC. These findings suggest that CFB may be a potential target for the treatment of PDAC.

Background Recent studies indicate that complement plays pivotal roles in promoting or suppressing cancer progression. We have previously identified C4b-binding protein α-chain (C4BPA) as a serum biomarker for the early detection of pancreatic ductal adenocarcinoma (PDAC). However, its mechanism of action remains unclear. Here, we elucidated the functional roles of C4BPA in PDAC cells and the tumor microenvironment. Methods We assessed stromal C4BPA, the C4BPA binding partner CD40, and the number of CD8 + tumor-infiltrating lymphocytes in resected human PDAC tissues via immunohistochemical staining. The biological functions of C4BPA were investigated in peripheral blood mononuclear cells (PBMCs) and human PDAC cell lines. Mouse C4BPA (mC4BPA) peptide, which is composed of 30 amino acids from the C-terminus and binds to CD40, was designed for further in vitro and in vivo experiments. In a preclinical experiment, we assessed the efficacy of gemcitabine plus nab-paclitaxel (GnP), dual immune checkpoint blockades (ICBs), and mC4BPA peptide in a mouse orthotopic transplantation model. Results Immunohistochemical analysis revealed that high stromal C4BPA and CD40 was associated with favorable PDAC prognosis ( P =0.0005). Stromal C4BPA strongly correlated with the number of CD8 + tumor-infiltrating lymphocytes ( P =0.001). In in vitro experiments, flow cytometry revealed that recombinant human C4BPA (rhC4BPA) stimulation increased CD4 + and CD8 + T cell numbers in PBMCs. rhC4BPA also promoted the proliferation of CD40-expressing PDAC cells. By contrast, combined treatment with gemcitabine and rhC4BPA increased PDAC cell apoptosis rate. mC4BPA peptide increased the number of murine T lymphocytes in vitro and the number of CD8 + tumor-infiltrating lymphocytes surrounding PDAC tumors in vivo . In a preclinical study, GnP/ICBs/mC4BPA peptide treatment, but not GnP treatment, led to the accumulation of a greater number of CD8 + T cells in the periphery of PDAC tumors and to greater tumor regression than did control treatment. Conclusions These findings demonstrate that the combination of GnP therapy with C4BPA inhibits PDAC progression by promoting antitumor T cell accumulation in the tumor microenvironment.

This study aims to identify the relationship between dysphagia and developing hospital-acquired disability (HAD) in older patients with heart failure (HF). This single-center retrospective cohort study included 360 patients (median age, 84 years: 58.1% female, 41.9% male) who had undergone rehabilitation and were aged 65 years and older. Patients were divided into dysphagia and non-dysphagia groups and compared based on the Functional Oral Intake Scale score. HAD was defined as a decline in the Barthel Index score (indication of daily activity levels) at discharge relative to that before admission. The relationship between dysphagia and HAD was analyzed using bivariate analysis after adjusting for age, sex, body mass index, medical history, clinical and laboratory data, short physical performance battery (SPPB), and cognitive function at the start of rehabilitation, using propensity score matching. HAD was observed in 38.1% of the patients. Patients with dysphagia were significantly older, and had lower body mass index and physical and cognitive function than those without. After propensity score matching, the prevalence of HAD was significantly higher in the dysphagia group than in the non-dysphagia group (61.9% vs. 42.9%, P = 0.032). Dysphagia at the start of rehabilitation was an independent predictor of HAD. The results of this study may contribute to risk stratification of HAD.

Intracranial artery dissection is a recognized cause of cerebral infarction and subarachnoid hemorrhage. In Japan, anterior cerebral artery dissection (ACD) represents one of the causes leading to ischemia. This study compares our clinical experience with existing literature to characterize the distinctive features of ischemia-onset anterior cerebral artery dissection (infarction-anterior cerebral artery dissection (iACD)). We conducted a retrospective analysis of 16 iACD cases identified among 2,776 cerebral infarction patients hospitalized between 2010 and 2019. Comprehensive imaging evaluations were performed at onset and systematically followed at two weeks, four weeks, one month, three months, six months, and 12 months post-onset. The patient cohort had a mean age of 59.1 ± 11.2 years, with six patients (37.5%) being female. Clinical presentation included aphasia in four patients (25.0%), while headache, typically considered characteristic of dissection, was reported in only one patient. Magnetic resonance imaging demonstrated intramural hematoma in 10 patients (62.5%), all confirmed during the second week following onset. Therapeutic management consisted of blood pressure control in all cases, with adjunctive antithrombotic therapy using cilostazol administered to five patients (31.3%). No patients developed progression to dissecting aneurysms or subarachnoid hemorrhage. While radiological deterioration occurred in the form of worsening stenosis (11 patients, 68.8%) and enlargement of cerebral infarcts (15 patients, 93.8%), and clinical deterioration manifested as worsening neurological symptoms in four patients (25.0%), none of these adverse events correlated with long-term prognosis. Our findings diverge from previous reports in two significant aspects: iACD affects elderly populations more commonly than previously recognized, and the classic presenting symptom of headache is notably infrequent. Clinicians should maintain a high index of suspicion for ACD when evaluating cerebral infarction in the anterior cerebral artery territory, even in the absence of typical findings such as headache or age.

Dual-energy computed tomography (DECT) is an imaging technique based on data acquisition at two different energy settings. Recent advances in CT have allowed data acquisitions and simultaneous analyses of X-rays at two energy levels, and have resulted in novel developments in the field of abdominal imaging. The use of low and high X-ray tube voltages in DECT provide fused images that improve the detection of liver tumors owing to the higher contrast-to-noise ratio (CNR) of the tumor compared with the liver. The use of contrast agents in CT scanning improves image quality by enhancing the CNR and signal-to-noise ratio while reducing beam-hardening artifacts. DECT can improve detection and characterization of hepatic abnormalities, including mass lesions. The technique can also be used for the diagnosis of steatosis and iron overload. This article reviews and illustrates the different applications of DECT in liver imaging.

We studied the comprehensive DNA methylation status in the naturally derived gastric adenocarcinoma cell line SNU‐719, which was infected with the Epstein–Barr virus (EBV) by methylated CpG island recovery on chip assay. To identify genes specifically methylated in EBV‐associated gastric carcinomas (EBVaGC), we focused on seven genes, TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1, based on the results of methylated CpG island recovery on chip assay. We confirmed DNA methylation of the genes by methylation‐specific PCR and bisulfite sequencing in SNU‐719. The expression of the genes, except for BCL7A, was upregulated by a combination of 5‐Aza‐2′‐deoxycytidine and trichostatin A treatment in SNU‐719. After the treatment, unmethylated DNA became detectable in all seven genes by methylation‐specific PCR. We verified DNA methylation of the genes in 75 primary gastric cancer tissues from 25 patients with EBVaGC and 50 EBV‐negative patients who were controls. The methylation frequencies of TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1 were significantly higher in EBVaGC than in EBV‐negative gastric carcinoma. We identified seven genes with promoter regions that were specifically methylated in EBVaGC. Inactivation of these genes may suppress their function as tumor suppressor genes or tumor‐associated antigens and help to develop and maintain EBVaGC.