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Kohei Kubota,1,2 Kohei Onishi,3 Kazuaki Sawaki,3 Tianshu Li,4 Kaoru Mitsuoka,5 Takaaki Sato,6 Shinji Takeoka1,3,4 1Cooperative Major in Advanced Biomedical Sciences, Graduate School of Advanced Sciences and Engineering, Waseda University (TWIns), Tokyo, Japan; 2Formulation Research and Phramaceutical Process Group, CMC R&D Center, Kyowa Hakko Kirin Co., Ltd, Shizuoka, Japan; 3Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering,Waseda University (TWIns), Tokyo, Japan; 4Research Organization for Nano and Life Innovation, Waseda University (TWIns), Tokyo, Japan; 5Research Center for Ultra-High Voltage Electron Microscopy, Osaka University, Osaka, Japan; 6Department of Chemistry and Materials, Faculty of Textile Science and Technology, Shinshu University, Nagano, Japan Abstract: Two lipid-based nanoformulations have been used to date in clinical studies: lipoplexes and lipid nanoparticles (LNPs). In this study, we prepared small interfering RNA (siRNA)-loaded carriers using lipid components of the same composition to form molecular assemblies of differing structures, and evaluated the impact of structure on cellular uptake and immune stimulation. Lipoplexes are electrostatic complexes formed by mixing preformed cationic lipid liposomes with anionic siRNA in an aqueous environment, whereas LNPs are nanoparticles embedding siRNA prepared by mixing an alcoholic lipid solution with an aqueous siRNA solution in one step. Although the physicochemical properties of lipoplexes and LNPs were similar except for small increases in apparent size of lipoplexes and zeta potential of LNPs, siRNA uptake efficiency of LNPs was significantly higher than that of lipoplexes. Furthermore, in the case of LNPs, both siRNA and lipid were effectively incorporated into cells in a co-assembled state; however, in the case of lipoplexes, the amount of siRNA internalized into cells was small in comparison with lipid. siRNAs in lipoplexes were thought to be more likely to localize on the particle surface and thereby undergo dissociation into the medium. Inflammatory cytokine responses also appeared to differ between lipoplexes and LNPs. For tumor necrosis factor-α, release was mainly caused by siRNA. On the other hand, the release of interleukin-1β was mainly due to the cationic nature of particles. LNPs released lower amounts of tumor necrosis factor-α and interleukin-1β than lipoplexes and were thus considered to be better tolerated with respect to cytokine release. In conclusion, siRNA-loaded nanoformulations effect their cellular uptake and immune stimulation in a manner that depends on the structure of the molecular assembly; therefore, nanoformulations should be optimized before extending studies into the in vivo environment. Keywords: nanoformulation, siRNA, cryo-TEM, confocal microscopy, endocytosis, immune stimulation

Athletes become increasingly susceptible to infection with intense exercise, which has an immunosuppressive effect. Sixteen long-distance runners participated in the present study. The clinical indexes, mainly related to the immune state, of 8 subjects in the amino acid intake group and 8 subjects in the placebo intake group were measured before and after a 7-day training camp. Significant increases in levels of myoglobin (Mb) and growth hormone (GH), and significant decreases in natural killer cell activity (NK) and Fisher's ratio were observed after as compared to before the training camp in the placebo group. However, these changes were not observed in the amino acid supplementation group. These findings suggest that amino acid supplementation during a training camp may have a stress-reducing effect by inhibition of muscle protein degradation, as well as by inhibiting the reduction of immunological functions, and may also contribute to protection against infectious diseases. [ABSTRACT FROM AUTHOR]

< MRI for stress fracture > Early diagnosis and treatment for stress fractures are important to enable a return to full athletic activities as soon as possible. We investigated the early diagnostic efficacy of MRI for stress fractures. Subjects were 38 patients (39 limbs)whose ages ranged from 12 to 27 years(mean, 20 years). Each patient was examined by MRI, plain radiography, and bone scintigraphy during the same period. The signal change was more evident in the femur and lateral malleolus and tarsal navicular bone, but, signal changes of tibia stress fractures were varied. The subjects examined by MRI within 2 weeks from onset showed obvious signal change, but their plain radiograms at the same time revealed no abnormalities. These subjects diagnosed in the early stage by MRI could return to sports earlier than those diagnosed 4 or more weeks after onset. < Bone metabolism markers(BMM)and bone mineral density(BMD)for stress fracture > We investigated the bone metabolism markers(BMM)and bone mineral density(BMD)in female long-distance runners of a university. Subjects were 14 female runners. As BMM, we investigated PICP, osteocalcin, AL-P(bone), DPD, and NTx. As BMD, femoral neck, knee and lumber vertebrae were investigated at the stage between rest and hard training. In runners with amenorrhea or with stress fracture, NTx was markedly higher and BMD was lower than in female runners with normal menstruation. These factors are good markers for studying the condition of female runners. [ABSTRACT FROM AUTHOR]

1. This study examined the effect of diazepam (DZP) on phosphoinositide turnover, which plays an important role in the regulation of salivary secretion, in rat parotid acinar cells. 2. DZP (10(-9) M to 10(-5) M), a potent agonist of both central- and peripheral-type benzodiazepine receptors, dose-dependently decreased inositol 1,4,5-trisphosphate IP3 production stimulated by carbachol, a muscarinic receptor agonist, in the cells. 3. DZP produced a maximum inhibitory response at a concentration of 10(-5) M, with IP3 production decreased to 63% of maximal levels. The concentration inducing half maximal inhibition of IP3 production was approximately 3.5 x 10 (-8) M. 4. An inhibitory response to DZP was produced by a short-term pretreatment (<3 min) of the cells and prevented by antagonist and competing ligand for the central- and peripheral-type benzodiazepine receptors, flumazenil and PK 11195, respectively. 5. DZP showed a non-competitive inhibition of carbachol-stimulated IP3 production. It did not directly inhibit the activities of GTP-binding regulatory proteins and phosphatidylinositol 4,5-bisphosphate-specific phospholipase C (PLC) in the parotid gland membranes, though choline chloride inhibited PLC activity. 6. DZP (10(-5) M) attenuated the increase in the intracellular Ca2+ concentration ([Ca(2+)](i)) in the cells following stimulation of the muscarinic and alpha(1)-adrenoceptors. 7. These results suggest that in the parotid acinar cells, DZP inhibits muscarinic receptor-stimulated IP3 production through benzodiazepine receptors and that PLC activity which produces IP3 is inhibited by chloride. The decreases in IP3 and [Ca(2+)](i) in the cells may be connected with the suppression of salivary secretion induced by DZP. [ABSTRACT FROM AUTHOR]

Genetic screens in Drosophila melanogaster have long been used to identify genes found in a variety of developmental, cellular, and behavioral processes. Here we describe the characterization and mapping of a mutation identified in a conditional screen for genetic regulators of cell growth and cell division. Within a Flp/FRT system, mutant G.3.2 results in a reduction of mutant tissue and a rough eye phenotype. We find that G.3.2 maps to the gene cnk , providing further support that cnk is a critical gene in Drosophila eye development. This mutant was characterized, mapped and sequenced by undergraduate students within the Fly-CURE consortium., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2024 by the authors.)

Sturge-Weber syndrome (SWS) is a neurocutaneous syndrome with vascular lesions of the cerebral meninges, port wine spots on the face, and glaucoma of the eyes; it is a congenital, non-genetic disease whose etiology and mechanisms are unknown. In this report, we describe a rare case of SWS with unilateral large odontogenic tumors in the maxilla and mandible. The histopathological diagnosis of the maxillary bone lesion on biopsy was juvenile psammomatoid ossifying fibroma, which is considered a type of ossifying fibroma of craniofacial bone origin. However, the final pathological diagnosis of the excision was cemento-ossifying fibroma derived from periodontal ligament cells, and we discuss the histopathology in detail. In addition, the mandibular lesion was one of the largest odontomas reported to date. Furthermore, in this case, we suggest the possibility that the maxillary and mandibular bone lesions are not separate lesions, but a series of lesions related to SWS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Purpose: The present multicenter randomized controlled trial explored the effectiveness of a person-centered care program (intervention group) and a dementia-type-specific program (control group) for nurses in acute-care hospitals., Methods: Seven hospitals in Prefecture A were randomly allocated to two groups (an intervention group and a control group), and a study of these groups was conducted from July 2021 to January 2022., Results: A total of 158 participants were included in the study: 58 in the control group and 100 in the intervention group. In a comparison of assessment values immediately after the course, three months later, and six months later for both the intervention and control groups, "expertise in dementia nursing," "medical expertise in dementia, " and "confidence in nursing older people with dementia" were all significantly higher than before the course. Significant improvements in the intervention group's "knowledge of dementia" and "sense of dignity" on the ethical sensitivity scale were found immediately after the course compared to baseline, three months later, and six months later and were also significantly greater than the control group in terms of the amount of change. In the control group's "unique care tailored to cognitive function and the person," there were significant improvements in the ratings immediately after the course and three and six months after the course compared to baseline, with significantly greater amounts of change than in the intervention group., Conclusion: The person-centered care program for nurses led to improvements in the knowledge about dementia and awareness of the dignity of ethical sensitivity. In addition, the type of dementia program had a significant influence on medical knowledge and unique care tailored to the cognitive function and the individual patient. Further outcome evaluations of physical restraint rates as a quality of care in nursing practice are needed.

Objective: This study aimed to identify factors associated with the response to the SARS-CoV-2 vaccine in people living with HIV (PLWH)., Methods: This study was conducted at the Jikei University School of Medicine, Tokyo, Japan. IgG antibodies against spike and nucleocapsid proteins were detected using Abbott SARS-CoV-2 IgG II Quant assays., Results: During the investigation period, 371 PLWH were enrolled in this study. PLWH with previous COVID-19 infection, untreated or poorly controlled HIV infection, and those whose blood samples were obtained within less than seven days after the second vaccination were excluded. A total of 310 PLWH controlled with anti-retroviral therapy were included in the final analysis. Multivariate analysis demonstrated that chronic kidney disease (CKD) (β = -0.353, p = 0.049) and the duration between the second vaccination and blood sampling (β = -0.005, p < 0.001) were associated with low spike protein IgG titers., Conclusion: Even without hemodialysis or kidney transplant, CKD was associated with vaccine response in PLWH., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Purpose: We aimed to develop a simulation program for physicians and nurses involved in virtual reality (VR) and augmented reality (AR) treatment and care from the perspective of these professionals and older adults with dementia who developed delirium, and to test the effectiveness of the program., Methods: effectiveness of the program was analyzed through free-response statements from 67 nurses (84.8%) and 12 doctors (15.2%) who participated in the program between February 16 and April 18, 2023., Results: Regarding the experience of delirium from the perspective of older adults with dementia (personal experience), the following statements were extracted "1. I do not understand where I am, the situation, and the treatment/care that is about to be given"; "2. I want the situation to be explained to me so that I can understand the reasons for my hospitalization and the treatment/care I am receiving"; "3. The eerie environment of the hospital and the high pressure of the staff made me feel anxious and fearful"; "4. Please respect my existence as I endure pain, anxiety, and loneliness"; "5. I feel relieved when doctors and nurses deal with me from my point of view"; and "6. I feel relieved when there is a familiar presence, such as a family member or the name I am calling on a daily basis"., Conclusion: Specific categories of self-oriented empathy were extracted from the experience of physical restraint at night using VR and the experience of delirium using AR. This suggests the possibility of objective effects on treatment and care in future practice.

Pancreatic tumors grow in an "austerity" tumor microenvironment characterized by nutrient deprivation and hypoxia. This leads to the activation of adaptive pathways in pancreatic cancer cells, promoting tolerance to nutrition starvation and aggressive malignancy. Conventional anticancer drugs are often ineffective against tumors that grow in such austerity condition. Plumbagin, a plant-derived naphthoquinone, has shown potent preferential cytotoxicity against pancreatic cancer cells under nutrient-deprived conditions. Therefore, we synthesized a series of plumbagin derivatives and found that 2-(cyclohexylmethyl)-plumbagin ( 3f ) was the most promising compound with a PC 50 value of 0.11 μM. Mechanistically, 3f was found to inhibit the PI3K/Akt/mTOR signaling pathways, leading to cancer cell death under nutrient-deprived conditions. In vivo studies using pancreatic cancer xenograft mouse models confirmed the efficacy of 3f , demonstrating significant inhibition of tumor growth in a dose-dependent manner. Compound 3f represents a highly promising lead for anticancer drug development based on an antiausterity strategy.

Seasonal influenza is a major upper respiratory tract infection occurring in winter. Vaccination is the best method for preventing this infection. We conducted two randomized, double-blind, placebo-controlled trials to examine whether consumption of yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1, which has been reported to reduce the risk of catching the common cold, augments serum antibody titers against seasonal influenza vaccines. In the first trial, which included university students, serum antibody titers against influenza A (H3N2) and B viruses were significantly higher in the yogurt group than in the placebo group. According to the guidelines established by the European Medicines Agency (EMA) for the assessment of vaccines, the seroconversion rate and mean geometric increase of influenza A (H3N2) and seroprotection of influenza B met the criteria only in the yogurt group. In the second trial, which included healthy adults, serum antibody titers against influenza A (H1N1) and B viruses were significantly higher in the yogurt group than in the placebo group. The seroconversion rate and mean geometric increase of influenza B met the EMA criteria only in the yogurt group. Furthermore, the cumulative days of ill health, such as throat complaints, upper respiratory inflammation, and cold, were significantly lower in the yogurt group than in the placebo group. Therefore, daily intake of yogurt fermented with L. bulgaricus OLL1073R-1 could reduce the duration of symptoms caused by respiratory infections and act as a mucosal adjuvant enhancing acquired immune responses against vaccines, leading to the improvement of public health., (©2023 BMFH Press.)

Background: Novel therapeutic targets are needed to improve the poor prognosis of patients with advanced gastric cancer. The aim of this study was to identify a novel therapeutic target for the treatment of GC and to investigate the potential therapeutic value of an antibody raised against the target., Methods: We identified gamma-aminobutyric acid type A receptor subunit delta as a candidate therapeutic target by differential transcriptome analysis of metastatic GC tissue and adjacent nontumor tissues. GABRD mRNA levels were analyzed in 230 pairs of gastric tissue by quantitative reverse-transcription polymerase chain reaction. GABRD function was assessed in proliferation, invasion, and apoptosis assays in human GC cell lines expressing control or GABRD-targeting small interfering RNA (siRNA). Mouse anti-human polyclonal GABRD antibodies were generated and assessed for inhibition of GC cell growth in vitro and in a mouse xenograft model of peritoneal GC dissemination., Results: High GABRD mRNA expression level in primary human GC tissue was associated with poor prognosis. Expression of siGABRD in GC cell lines significantly decreased cell proliferation and invasion and increased apoptosis compared with control siRNA expression. Anti-GABRD polyclonal antibodies inhibited GC cell proliferation in vitro and decreased peritoneal tumor nodule size in the mouse xenograft model., Conclusion: We identified GABRD as novel regulator of GC cell growth and function. GABRD is upregulated in GC tissue and is associated with poor prognosis, suggesting that it may be a potential therapeutic target for GC., (© 2022. Society of Surgical Oncology.)

Introduction: In Japan, patients with coronavirus disease 2019 (COVID-19) who do not require medical intervention are provided care in recovery accommodation facilities (RAFs). However, some patients may require hospitalization if their symptoms become more severe during their stay. We conducted an observational study using epidemiological data of patients with COVID-19 admitted to RAFs in Tokyo., Methods: This was an observational cohort study using data from COVID-19 patients admitted to one of the RAFs in Tokyo from December 2020 to November 2021. Admissions to the facilities were limited to patients with asymptomatic or mild COVID-19 with no underlying disease or at least stable underlying disease at the time of admission. Patients were hospitalized when they required oxygen administration or when they had, or persistent fever, or severe respiratory symptoms. We evaluated the association between hospitalization and the risk factors for hospitalization using a Cox regression model., Results: The number of patients with COVID-19 admitted to the RAF was 6176. The number of hospitalized patients was 393 (6.4%), and the median length of stay was 5.50 days (IQR: 4.50, 6.50). In the Cox regression analysis, the hazard ratio increased with age and was significantly higher among patients aged >60 years (HR = 10.23, 95% CI: 6.72-15.57) than those in other age groups. This trend is similar to that observed in the sensitivity analysis., Conclusion: Patients with diabetes, the elderly, obesity, and medications for gout and psychiatric diseases may be at a high risk of hospitalization. In particular, an age over 60 years was strongly associated with hospitalization., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Kinetic vision acuity (KVA) is an index developed in Japan that refers to the capacity to recognize a moving object that moves back and forth against the observer. This review outlines the history of KVA and studies on KVA conducted at the Faculty of Health and Sports Science of Juntendo University, i.e. characteristics of KVA in athletes, factors associated with KVA, sports and age-dependent decline of KVA, and effects of docosahexaenoic acid (DHA) and astaxanthin on KVA. KVA was defined in the early 1960s, and the measurement device was invented in 1968. Studies at the Faculty of Health and Sports Science began in the 1990s. In track-and-field athletics and skeleton, a winter downhill event, higher-ranked athletes had higher KVA than lower-ranked athletes. Although KVA cannot be predicted from static visual acuity or reaction time, a significant correlation was found between KVA and the peak latency of visual-evoked potentials. KVA could not be improved by training and did not change between age of 8 and 17 years. In contrast, habitual practice in kendo may inhibit the age-dependent decline in KVA. DHA may also improve KVA in subjects with low KVA; however, astaxanthin did not improve KVA., Competing Interests: The authors declare that there are no conflicts of interest., (© 2022 The Juntendo Medical Society.)

Background: Metastatic gastric cancer (GC) has a poor prognosis, and elucidating the molecular mechanisms involved in metastasis may lead to the development of novel therapeutic modalities., Methods: Transcriptome analysis of surgically resected metastatic tissue from GC patients and noncancerous tissue was performed to identify novel metastasis-related genes. Analyses of in vitro cell function, apoptosis, the cell cycle and cancer stemness were performed using GC cell lines with a stable knockout of a candidate gene. In vivo percutaneous, peritoneal dissemination and liver metastasis xenograft models were also generated. PCR array and proteome analyses were performed. Expression of the candidate gene was analyzed in GC tissues from 300 patients., Results: Lysosomal Associated Membrane Protein Family Member 5 (LAMP5) was upregulated in the metastatic tissues. LAMP5 knockout significantly suppressed proliferation, invasion, and migration of GC cells and increased apoptosis, cell cycle arrest and cancer stemness. LAMP5 knockout virtually suppressed tumor growth in in vivo percutaneous, peritoneal dissemination and liver metastasis models. EMT- and autophagy-related genes were associated with LAMP5. High LAMP5 mRNA levels were significantly associated with a worse prognosis., Conclusion: LAMP5 plays a vital role in metastasis formation and may be a promising novel target of drug development for metastatic GC in the future., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: The expression of solute carrier (SLC) 7 family genes is reportedly associated with several malignancies. Here, we focused on SLC7A9 and investigated its expression, function, and clinical significance in esophageal squamous cell carcinoma (ESCC)., Methods: SLC7A9 transcription levels were evaluated in 13 ESCC cell lines, and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with SLC7A9. SLC7A9 contributions to proliferation, invasion, and migration were evaluated in ESCC cells subjected to siRNA-mediated gene knockdown and pCMV6-entry plasmid-mediated overexpression. SLC7A9 expression was detected in 189 ESCC tissues by quantitative reverse-transcription (qRT)-PCR and correlated with clinicopathological parameters., Results: The expression levels of SLC7A9 varied widely in ESCC cell lines and correlated with FGFBP1 expression. Knockdown of SLC7A9 significantly suppressed the proliferation, invasion, and migration of the ESCC cell lines. Moreover, overexpression of SLC7A9 enhanced cell proliferation and migration. In analyses of clinical specimens, SLC7A9 mRNA was overexpressed in the ESCC tissues compared with the adjacent normal esophageal tissues. High mRNA expression was significantly associated with high levels of squamous cell carcinoma-related antigen and carcinoembryonic antigen, advanced disease stage, and lymph node metastasis. High SLC7A9 expression was also significantly associated with poor disease-specific and disease-free survival, and lymph node recurrence after radical surgery, but not with the other recurrence patterns. On multivariate analysis, high SLC7A9 expression was an independent predictor of lymph node recurrence., Conclusions: SLC7A9 influences the malignant behavior of ESCC cells. Tumor SLC7A9 expression may serve as a novel biomarker for predicting lymph node metastasis and recurrence in ESCC patients., (© 2021. Society of Surgical Oncology.)

Purpose: The number of hospitalizations of older patients with dementia who require medical treatment has increased and delirium or physical restriction have become problems in the acute care setting. Dementia nursing intervention ability developing program by e-learning assumed the quality improvement of dementia medical care and the nursing of older patients with dementia based on person-centered aimed at reduction of body restriction. The purpose of this study was to validate the effectiveness of the developed e-learning programs for nurses in the acute care setting of seven to one nursing standards., Method: This study was conducted between April and December 2020. This study was introduced to the floor nurse of the hospital for suitable application. Interested nurses were asked to attend "Developing programs for Dementia nursing intervention ability (4 weeks)" at four different time points (1) before attendance (baseline), post-attendance (1 month later), (3) practiced 3 months post-attendance, and (4) practiced 6 months post-attendance. A questionnaire to evaluate program effectiveness asked about consciousness of the dementia nursing with four items on "Interest in nursing of people with dementia and so on (four items)".In the evaluation on the person-centered dementia care, using the Self-assessment Scale of Nursing Practice for Elderly Patients with Cognitive Impairment, the Approach to Dementia Questionnaire - Japanese Edition (19 items). In the evaluation of ethics, ethical sensitivity scale for clinical nurses (19 items), self-efficacy on reduction of the physical restriction (six items). A statistical analysis was conducted using the Bonferroni test as the multiple test method to compare baseline values with the values obtained 1, 3, and 6 months later., Results: A total of 70 subjects were analyzed in this study. They belonged to different wards including the surgical and internal wards from where 60 subjects (85.7%) were recruited. The average clinical experience of the nurses was 13.5±9.5 years. The degree of self-efficacy was assessed in terms of attaching mitten type gloves as a physical restraint to avoid the pulling of tubes used for intravenous feeding, central veins, normal feeding, etc. by the patients and so on. Most patients had cognitive functional disorder, including dementia [n = 30 (42.9%)]. The self-assessed scale of nursing practice for elderly people with cognitive impairment, which aimed to promote person-centered care in an acute care hospital, revealed that the total score of each of the Approaches to Dementia Questionnaire - Japanese Edition significantly increased just after intervention (1 month) in comparison to baseline, and 3 months and 6 months after intervention., Conclusion: This study indicated that the program developed to improve dementia nursing intervention ability significantly increased the above-mentioned evolution and consciousness of nurses after the intervention program (1 month), followed by 3 months and 6 months later. Along with ethical sensitivity, practice aimed at person-centered care was also found to improve. It was suggested that the intervention program of this study was effective and that nurses could easily learn using their respective free time and practice.

Here, we evaluated the therapeutic potential of antibodies (Abs) targeting cholinergic receptor nicotinic beta 2 subunit (CHRNB2) in gastric cancer. To investigate the effects of these Abs on malignant phenotypes in vitro and in mouse xenograft models, we generated gene knockouts through genome editing, performed RNA interference-mediated knockdown of gene expression, and ectopically expressed CHRNB2 in gastric cancer cells. The effects of anti-CHRNB2 Abs on the proliferation of cancer cells were evaluated both in vitro and in vivo. We determined the effects of Chrnb2 deficiency on mice and the clinical significance of CHRNB2 expression in gastric cancer clinical specimens. Knockdown of CHRNB2 attenuated gastric cancer cell proliferation, whereas forced overexpression of CHRNB2 increased cell proliferation. Knockout of CHRNB2 significantly influenced cell survival and functions associated with metastasis. The effects of polyclonal Abs targeting the C- and N-termini of CHRNB2 guided the development of anti-CHRNB2 monoclonal Abs that inhibited the growth of gastric cancer cells in vitro and in vivo. Pathway analysis revealed that CHRNB2 interfered with signaling through the PI3K-AKT and JAK-STAT pathways. Chrnb2-deficient mice exhibited normal reproduction, organ functions, and motor functions. CHRNB2 regulates multiple oncological phenotypes associated with metastasis, and blockade of CHRNB2 expression using specific Abs shows promise for controlling metastasis in gastric cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The liver is the most common site for haematogenous metastasis of gastric cancer, and liver metastasis is fatal., Methods: We conducted a transcriptomic analysis between metastatic foci in the liver, primary tumour and adjacent tissues from gastric cancer patients with metastasis limited to the liver. We determined mRNA expression levels in tumour tissues of 300 patients with gastric cancer via quantitative RT-PCR. The oncogenic phenotypes of GNG4 were determined with knockdown, knockout and forced expression experiments. We established and compared subcutaneous and liver metastatic mouse xenograft models of gastric cancer to reveal the roles of GNG4 in tumorigenesis in the liver., Results: GNG4 was upregulated substantially in primary gastric cancer tissues as well as liver metastatic lesions. High levels of GNG4 in primary cancer tissues were associated with short overall survival and the likelihood of liver recurrence. Functional assays revealed that GNG4 promoted cancer cell proliferation, the cell cycle and adhesiveness. Tumour formation by GNG4-knockout cells was moderately reduced in the subcutaneous mouse model and strikingly attenuated in the liver metastasis mouse model., Conclusions: GNG4 expression may provide better disease monitoring for liver metastasis, and GNG4 may be a novel candidate therapeutic target for liver metastasis., (© 2021. The Author(s), under exclusive licence to Cancer Research UK.)

The clinical manifestations of COVID-19 vary broadly, ranging from asymptomatic infection to acute respiratory failure and death. But the predictive biomarkers for characterizing the variability are still lacking. Since emerging evidence indicates that extracellular vesicles (EVs) and extracellular RNAs (exRNAs) are functionally involved in a number of pathological processes, we hypothesize that these extracellular components may be key determinants and/or predictors of COVID-19 severity. To test our hypothesis, we collected serum samples from 31 patients with mild COVID-19 symptoms at the time of their admission for discovery cohort. After symptomatic treatment without corticosteroids, 9 of the 31 patients developed severe/critical COVID-19 symptoms. We analyzed EV protein and exRNA profiles to look for correlations between these profiles and COVID-19 severity. Strikingly, we identified three distinct groups of markers (antiviral response-related EV proteins, coagulation-related markers, and liver damage-related exRNAs) with the potential to serve as early predictive biomarkers for COVID-19 severity. As the best predictive marker, EV COPB2 protein, a subunit of the Golgi coatomer complex, exhibited significantly higher abundance in patients remained mild than developed severe/critical COVID-19 and healthy controls in discovery cohort (AUC 1.00 (95% CI: 1.00-1.00)). The validation set included 40 COVID-19 patients and 39 healthy controls, and showed exactly the same trend between the three groups with excellent predictive value (AUC 0.85 (95% CI: 0.73-0.97)). These findings highlight the potential of EV COPB2 expression for patient stratification and for making early clinical decisions about strategies for COVID-19 therapy., Competing Interests: Yu Fujita is a chief science advisor, Mitsuru Miyato is a chief executive officer, and Takahiro Ochiya is a technical executive officer of International Space Medical Co., Ltd. The other authors have declared that no conflict of interest exists., (© 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)