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The repertoire of tumor-infiltrating T cells is an emerging method for characterizing effective antitumor T-cell responses. Oligoclonal expansion of the tumor T-cell repertoire has been evaluated; however, their association with antitumor effects is unclear. We demonstrate here that the polyclonal fraction of the tumor-reactive T-cell repertoire, consisting of relatively minor clones, increased in tumor-bearing mice treated with monoclonal anti–programmed death-ligand 1 (PD-L1) or anti-CD4, which correlated with antitumor effects. Meanwhile, the size of the oligoclonal fraction consisting of major clones remained unchanged. Moreover, the polyclonal fraction was enriched in progenitor exhausted T cells, which are essential for a durable antitumor response, and was more dependent on CCR7+ migratory dendritic cells, which are responsible for priming tumor-reactive T cells in the tumor-draining lymph nodes. These results suggest that the expansion of diverse tumor-reactive clones (“clonal spreading”) represents characteristics of antitumor T-cell responses induced by anti-CD4 and anti–PD-L1 treatment.

Colonic metastasis from ovarian cancer is extremely rare, with only seven reported cases. A 77-year-old woman who had previously undergone surgery for ovarian cancer was admitted to a local hospital with anal bleeding. Histopathological analysis confirmed the presence of adenocarcinoma. Colonoscopy revealed a descending colon tumor. The patient was diagnosed with Union for International Cancer Control T3N0M0 descending colon cancer or colon metastasis of the ovarian cancer. Laparoscopic left colectomy was performed; intraoperative frozen section diagnosis confirmed metastasis from ovarian cancer, and the absence of invasion to the serosal surface suggested hematogenous metastasis. This is the first case of colonic metastasis from ovarian cancer that was diagnosed using an intraoperative frozen section and laparoscopically treated.

mRNA vaccines have attracted considerable attention as a result of the 2019 coronavirus pandemic; however, challenges remain regarding use of mRNA vaccines, including insufficient delivery owing to the high molecular weights and high negative charges associated with mRNA. These characteristics of mRNA vaccines impair intracellular uptake and subsequent protein translation. In the current study, we prepared a minimal mRNA vaccine encoding a tumor associated antigen human gp10025–33 peptide (KVPRNQDWL), as a potential treatment for melanoma. Minimal mRNA vaccines have recently shown promise at improving the translational process, and can be prepared via a simple production method. Moreover, we previously reported the successful use of iontophoresis (IP) technology in the delivery of hydrophilic macromolecules into skin layers, as well as intracellular delivery of small interfering RNA (siRNA). We hypothesized that combining IP technology with a newly synthesized minimal mRNA vaccine can improve both transdermal and intracellular delivery of mRNA. Following IP-induced delivery of a mRNA vaccine, an immune response is elicited resulting in activation of skin resident immune cells. As expected, combining both technologies led to potent stimulation of the immune system, which was observed via potent tumor inhibition in mice bearing melanoma. Additionally, there was an elevation in mRNA expression levels of various cytokines, mainly interferon (IFN)-γ, as well as infiltration of cytotoxic CD8+ T cells in the tumor tissue, which are responsible for tumor clearance. This is the first report demonstrating the application of IP for delivery of a minimal mRNA vaccine as a potential melanoma therapeutic.

The Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system aggregates information related to antimicrobial resistance (AMR) measures in participating medical institutions nationwide and is intended to be used for promotion of AMR measures in participating facilities and their communities. This multicenter study aimed to determine the usefulness of the J-SIPHE system for evaluating the correlation between antibiotic use and antibiotic resistance in Hokkaido, Japan.Data on antibiotic use and detection rate of major resistant Gram-negative bacteria at 19 hospitals in 2020 were collected from the J-SIPHE system, and data correlations were analyzed using JMP Pro.The detection rate of carbapenem-resistant Pseudomonas aeruginosa was significantly positively correlated with carbapenem use (Spearman's ρ = 0.551; P = .015). There were significant positive correlations between the detection rate of fluoroquinolone-resistant Escherichia coli and the use of piperacillin/tazobactam, carbapenems, and quinolones [ρ = 0.518 (P = .023), ρ = 0.76 (P.001), and ρ = 0.502 (P = .029), respectively].This is the first multicenter study to investigate the correlation between antibiotic use and antibiotic resistance using the J-SIPHE system. The results suggest that using this system may be beneficial for promoting AMR measures.

Background: Long-term outcomes are unknown in patients with asymptomatic moyamoya disease. In this report, we aimed to clarify their 5-year risk of stroke and its predictors. Methods: We are conducting a multicenter, prospective cohort study (Asymptomatic Moyamoya Registry) in Japan. Participants were eligible if they were 20 to 70 years, had bilateral or unilateral moyamoya disease, experienced no episodes suggestive of TIA and stroke; and were functionally independent (modified Rankin Scale score 0–1). Demographic and radiological information was collected at enrollment. In this study, they are still followed up for 10 years. In this interim analysis, we defined the primary end point as a stroke occurring during a 5-year follow-up period. Independent predictors for stroke were also determined, using a stratification analysis method. Results: Between 2012 and 2015, we enrolled 109 patients, of whom 103 patients with 182 involved hemispheres completed the 5-year follow-up. According to the findings on DSA and MRA, 143 hemispheres were judged as moyamoya disease and 39 hemispheres as questionable manifestations (isolated middle cerebral artery stenosis). The patients with questionable hemispheres were significantly older, more often male, and more frequently had hypertension than those with moyamoya hemisphere. Moyamoya hemispheres developed 7 strokes, including 6 hemorrhagic and 1 ischemic stroke, during the first 5 years. The annual risk of stroke was 1.4% per person, 0.8% per hemisphere, and 1.0% per moyamoya hemisphere. Independent predictor for stroke was Grade-2 choroidal anastomosis (hazard ratio, 5.05 [95% CI, 1.24–20.6]; P =0.023). Furthermore, microbleeds (hazard ratio, 4.89 [95% CI, 1.13-21.3]; P =0.0342) and Grade-2 choroidal anastomosis (hazard ratio, 7.05 [95% CI, 1.62–30.7]; P =0.0093) significantly predicted hemorrhagic stroke. No questionable hemispheres developed any stroke. Conclusions: The hemispheres with asymptomatic moyamoya disease may carry a 1.0% annual risk of stroke during the first 5 years, the majority of which are hemorrhagic stroke. Grade-2 choroidal anastomosis may predict stroke, and the microbleeds and Grade-2 choroidal anastomosis may carry the risk for hemorrhagic stroke. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: UMIN000006640.

A catalyst based on lanthanum chromite with exsolved metallic ruthenium nanoparticles (LaCrO3-Ru) was applied as a catalytic layer for internal ethanol steam reforming of anode-supported and metal-supported solid oxide fuel cells. The metal support exhibits limited catalytic properties for the ethanol steam reforming reaction. Thus, the LaCrO3-Ru catalysts were optimized for operating temperatures in the 600-700 °C range to promote stable ethanol reforming. The catalytic layer had no significant impact on the electrochemical properties of the fuel cell, and samples with and without the catalytic layer exhibited similar performance in hydrogen. Initial durability tests with LaCrO3-Ru layer have shown that the catalytic layer plays a crucial role in the stability of the metal-supported fuel cell under ethanol.

Esse artigo procura analisar um dos tantos pseudônimos de Kierkegaard, Johannes de Silentio, autor apenas de uma obra: Temor e Tremor. Discutiremos sua apresentação no livro como um poeta e admirador, além de como essas categorias também são analisadas em A Prática do Cristianismo e em A Doença para a Morte, escrito sob o pseudônimo Anti-Climacus, o cristão por excelência. A partir daí, colocaremos o poeta e o admirador à contraluz da discussão da massa ou multidão. Por fim, observaremos para o seu papel de poeta importante em direção ao religioso.

Bone organoids offer a novel path for the reconstruction and repair of bone defects. We previously fabricated scaffold-free bone organoids using cell constructs comprising only bone marrow-derived mesenchymal stem cells (BMSCs). However, the cells in the millimetre-scale constructs were likely to undergo necrosis because of difficult oxygen diffusion and nutrient delivery. Dental pulp stem cells (DPSCs) are capable of differentiating into vascular endothelial lineages and have great vasculogenic potential under endothelial induction. Therefore, we hypothesized that DPSCs can serve as a vascular source to improve the survival of the BMSCs within the bone organoid. In this study, the DPSCs had greater sprouting ability, and the proangiogenic marker expressions were significantly greater than those of BMSCs. DPSCs were incorporated into the BMSC constructs at various ratios (5%–20%), and their internal structures and vasculogenic and osteogenic characteristics were investigated after endothelial differentiation. As a result, the DPSCs are differentiated into the CD31-positive endothelial lineage in the cell constructs. The incorporation of DPSCs significantly suppressed cell necrosis and improved the viability of the cell constructs. In addition, lumen-like structures were visualized by fluorescently labelled nanoparticles in the DPSC-incorporated cell constructs. The vascularized BMSC constructs were successfully fabricated using the vasculogenic ability of the DPSCs. Next, osteogenic induction was initiated in the vascularized BMSC/DPSC constructs. Compared with only BMSCs, constructs with DPSCs had increased mineralized deposition and a hollow structure. Overall, this study demonstrated that vascularized scaffold-free bone organoids were successfully fabricated by incorporating DPSCs into BMSC constructs, and the biomimetic biomaterial is promising for bone regenerative medicine and drug development.

Objective: The consumption of various foods is internationally recommended in healthy diet although the association between dietary variety and incident dementia is unknown. We aimed to examine the association between dietary variety and the incidence of disabling dementia in older Japanese adults. Design: We conducted a prospective cohort study. Dietary variety was assessed based on the Dietary Variety Score (DVS). DVS was assessed by counting the number of ten food components (meat, fish/shellfish, eggs, milk, soyabean products, green/yellow vegetables, potatoes, fruit, seaweed and fats/oils) that were consumed almost daily using a FFQ. Participants were categorised into low (0–2 points), middle (3–4 points) and high (5–10 points) groups based on the DVS. Data on newly diagnosed disabling dementia were retrieved from the public long-term care insurance database. Cox proportional hazards regression was used to estimate hazard ratios (HR) with 95 % CI. Setting: Yabu cohort study, Japan. Participants: A total of 4972 community-dwelling adults aged 65 years or older. Results: During the median follow-up of 6·8 years, 884 participants were newly diagnosed with disabling dementia. After adjusting for confounders, the multivariable-adjusted HR for incident disabling dementia was 0·82 (95 % CI, 0·69, 0·97) for participants in the highest DVS category compared with those in the lowest DVS category (Pfor trend = 0·019). Conclusions: A higher dietary variety is associated with a reduced risk of disabling dementia in older Japanese adults. These results have potential implications for the development of effective public nutritional approaches to prevent dementia in older adults.

In recent years, advances in pharmacotherapy for rheumatoid arthritis (RA) have dramatically improved the control of disease activity. However, a significant number of patients still develop forefoot deformity. The purpose of this study was to investigate the results of more than 20 years' follow-up of metatarsal neck shortening oblique osteotomy (SOO) for forefoot deformity in patients with RA.The metatarsal neck SOO was performed on 163 feet in 108 patients between January 1985 and December 1996 in the authors' hospital. For the patients, who met the survey criteria, an observational study was performed clinically and radiologically at the baseline and at more than 20 years after surgery.A retrospective cohort study was conducted on 36 feet in 22 patients, all of whom were female, and the mean age at surgery was 45.6 (35.0-63.0) years old. The follow-up period was 25.1 (21.0-31.0) years. The presence of painful callosities in the surgically treated feet without revised surgeries decreased from 32 feet (100%) to 4 feet (12.5%) at the last follow-up with mild pain that did not cause any footwear problems. Re-osteotomy at the metatarsal of the lessor toe was performed on four feet in two patients. Radiologically, among 128 toes without revised surgeries, 85% were able to have the joint space preserved, and 89% maintained a pain-free condition without any recurrence of deformity. The mean total Japanese Society for Surgery for the Foot (JSSF) RA foot and ankle score was 64.0/100, and the visual analogue scale (VAS) of overall satisfaction was 62 (0: dissatisfied, 100: highly satisfied). The overall satisfaction had a positive correlation with calcaneal pitch and negative correlation with joint space narrowing at the talocrural joint.Metatarsal neck SOO appeared to be effective for patients with RA. The deformity was corrected and retained for a long time.