Coil embolization of a celiac artery pseudoaneurysm under balloon-assisted flow control: A case report.

Coil migration can occur when coil embolization is used for treating pseudoaneurysms associated with large arteries. The double microcatheter technique is useful for preventing coil migration; the balloon catheter can reduce blood flow and active bleeding upon balloon inflation, and can also compress the bleeding point and arrest bleeding temporarily. We report a case describing the management of a pseudoaneurysm with coil embolization using double microcatheters and a balloon catheter to control blood flow and prevent coil migration. A 73-year-old male patient presented with a pseudoaneurysm of the celiac artery arising from the splenic artery stump following surgery. Coil embolization of the pseudoaneurysm using a double microcatheter embolization technique with a balloon catheter was considered. A balloon catheter was inserted into the celiac artery and active bleeding was temporarily arrested with the inflated balloon. First, a microcatheter was inserted into the balloon catheter, and another microcatheter was placed in the celiac artery. An electrical detachable coil was inserted into the proximal common hepatic artery just distal to the pseudoaneurysm. The second electrically detachable coil was inserted while the first coil remained attached. After detachment of the second coil, additional electrically detachable coils were inserted for similar embolization. The balloon was gradually deflated. Finally, the first coil was detached and we confirmed absence of the bleeding. Our case report demonstrated that a balloon catheter can control the flow vessels, and the double microcatheter embolization technique with a balloon catheter is useful for coil embolization in high-flow or large vessels.

Corrigendum: Use of the index of pulmonary vascular disease for predicting longterm outcome of pulmonary arterial hypertension associated with congenital heart disease.

[This corrects the article DOI: 10.3389/fcvm.2023.1212882.].

Indoleamine 2,3-dioxygenase 2 deficiency associates with autism-like behavior via dopaminergic neuronal dysfunction.

Indoleamine 2,3-dioxygenase 2 (IDO2) is an enzyme of the tryptophan-kynurenine pathway that is constitutively expressed in the brain. To provide insight into the physiological role of IDO2 in the brain, behavioral and neurochemical analyses in IDO2 knockout (KO) mice were performed. IDO2 KO mice showed stereotyped behavior, restricted interest and social deficits, traits that are associated with behavioral endophenotypes of autism spectrum disorder (ASD). IDO2 was colocalized immunohistochemically with tyrosine-hydroxylase-positive cells in dopaminergic neurons. In the striatum and amygdala of IDO2 KO mice, decreased dopamine turnover was associated with increased α-synuclein level. Correspondingly, levels of downstream dopamine D1 receptor signaling molecules such as brain-derived neurotrophic factor and c-Fos positive proteins were decreased. Furthermore, decreased abundance of ramified-type microglia resulted in increased dendritic spine density in the striatum of IDO2 KO mice. Both chemogenetic activation of dopaminergic neurons and treatment with methylphenidate, a dopamine reuptake inhibitor, ameliorated the ASD-like behavior of IDO2 KO mice. Sequencing analysis of exon regions in IDO2 from 309 ASD samples identified a rare canonical splice site variant in one ASD case. These results suggest that the IDO2 gene is, at least in part, a factor closely related to the development of psychiatric disorders.

Chromogenic in situ hybridization reveals specific expression pattern of long non-coding RNA DRAIC in formalin-fixed paraffin-embedded specimen.

Long non-coding RNA (lncRNA) plays an important role in the regulation of gene expression in normal and cancer cells. We previously discovered a novel tumor-suppressive lncRNA, DRAIC, in prostate cancer cells. Subsequent studies have demonstrated that DRAIC is dysregulated in various malignancies and exhibits a tumor-suppressive or pro-oncogenic function. However, details regarding its expression pattern in normal and cancerous tissues remain largely unknown. In this study, we performed chromogenic in situ hybridization (CISH) using RNAscope technology to assess DRAIC expression in formalin-fixed paraffin-embedded (FFPE) specimens. In the neuroendocrine-differentiated cancer cell line VMRC-LCD, CISH revealed a diffuse localization of DRAIC in the cytoplasm as well as specific accumulation in the nuclear compartment. DRAIC expression was comprehensively analyzed using tissue microarrays containing 89 normal and 155 tumor tissue samples. DRAIC was weakly expressed in normal epithelial cells of the colon, bronchiole, kidney, prostate, and testis. Conversely, DRAIC was moderately to highly expressed in some cancer tissues, including prostate adenocarcinoma, invasive ductal carcinoma of the breast, neuroendocrine carcinoma of the esophagus, lung adenocarcinoma, and small cell lung carcinoma. While DRAIC knockdown did not affect VMRC-LCD cellular viability and invasive ability, gene expression related to the neuroendocrine and cancer-related pathways was altered. Our expression analysis revealed the specific expression pattern of DRAIC in normal and cancerous FFPE tissues. The results presented here may lead to the elucidation of additional novel functions of DRAIC.

Storing electrons from H2 for transfer to CO2, all at room temperature.

We present an Ir complex that extracts electrons from H2 at room temperature and stores them as a H2-derived energy carrier (H2EC) at room temperature. Furthermore, we demonstrate that this complex reduces CO2 to a metal-CO22- species at room temperature, and present the first electrospray ionisation mass spectrum for this compound.

Use of the index of pulmonary vascular disease for predicting long-term outcome of pulmonary arterial hypertension associated with congenital heart disease.

Aims: Limited data exist on risk factors for the long-term outcome of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). We focused on the index of pulmonary vascular disease (IPVD), an assessment system for pulmonary artery pathology specimens. The IPVD classifies pulmonary vascular lesions into four categories based on severity: (1) no intimal thickening, (2) cellular thickening of the intima, (3) fibrous thickening of the intima, and (4) destruction of the tunica media, with the overall grade expressed as an additive mean of these scores. This study aimed to investigate the relationship between IPVD and the long-term outcome of CHD-PAH. Methods: This retrospective study examined lung pathology images of 764 patients with CHD-PAH aged <20 years whose lung specimens were submitted to the Japanese Research Institute of Pulmonary Vasculature for pulmonary pathological review between 2001 and 2020. Clinical information was collected retrospectively by each attending physician. The primary endpoint was cardiovascular death. Results: The 5-year, 10-year, 15-year, and 20-year cardiovascular death-free survival rates for all patients were 92.0%, 90.4%, 87.3%, and 86.1%, respectively. The group with an IPVD of ≥2.0 had significantly poorer survival than the group with an IPVD <2.0 (P = .037). The Cox proportional hazards model adjusted for the presence of congenital anomaly syndromes associated with pulmonary hypertension, and age at lung biopsy showed similar results (hazard ratio 4.46; 95% confidence interval: 1.45-13.73; P = .009). Conclusions: The IPVD scoring system is useful for predicting the long-term outcome of CHD-PAH. For patients with an IPVD of ≥2.0, treatment strategies, including choosing palliative procedures such as pulmonary artery banding to restrict pulmonary blood flow and postponement of intracardiac repair, should be more carefully considered.

H19 in Serum Extracellular Vesicles Reflects Resistance to AR Axis-targeted Therapy Among CRPC Patients.

BACKGROUND/AIM: We aimed to evaluate the changes of androgen receptor (AR) signaling-related long non-coding RNAs (lncRNAs) in serum extracellular vesicles (EVs) from prostate cancer (PC) patients, in order to identify novel biomarkers for AR axis-targeted therapy (ARAT)-resistance among castration-resistant PC (CRPC) patients. PATIENTS AND METHODS: EVs were isolated from 2 patients before and after acquiring ARAT-resistance. RNA profiling of EVs was performed by RNA-sequencing. The expression levels of selected lncRNAs in EVs were analyzed by digital droplet PCR (ddPCR) in 58 localized and 14 metastatic PC patients at diagnosis, 7 ARAT-naïve and 6 ARAT-resistant CRPC patients. LncRNA H19 expression in PC tissue was examined using published data. In order to analyze the role of H19, the prognosis was analyzed in PC patients and proteomic analysis was performed in 22Rv1 PC cells. RESULTS: RNA-sequencing revealed that AR-regulated RNAs were most enriched in EVs after acquiring ARAT-resistance. Among them, up-regulation of AR signaling-related lncRNAs (PCAT1, H19, HOXA-11AS, ZEB1-AS1, ARLNC1, PART1, CTBP1-AS and PCA3) was confirmed by ddPCR. H19 contained in EVs (EV-H19) was significantly increased among ARAT-resistant patients compared to ARAT-naïve CRPC or metastatic PC patients. In PC tissue, H19 was negatively correlated with AR protein and AR-activity score and up-regulated in neuroendocrine CRPC tissue with low AR expression. Furthermore, EV-H19 expression was significantly associated with worse outcome to androgen-deprivation therapy. Proteomic analysis demonstrated that H19 knockdown enhanced PC-related protein expression. CONCLUSION: EV-H19 may negatively correlate with AR-signaling activity and could be a marker to diagnose ARAT-resistance among CRPC patients.

Transcriptome of Oral Cancer Cells Adapted to Suspension Culture Is Potentially Related to Cancer Progressive Phenotypes.

BACKGROUND/AIM: Cervical lymph node metastasis worsens oral cancer prognosis. Cancer cells with high metastatic ability can delay or resist apoptosis and survive in the floating condition during circulation. The involved genes and pathways in this process remain largely unknown. This study aimed to establish an oral cancer cell line adapted to suspension culture by in vitro selection and perform gene expression analysis. MATERIALS AND METHODS: The oral cancer cell subline adapted to suspension culture was isolated by in vitro selection from the oral cancer cell line, HSC-3. The transcriptome profiles of HSC-3 and its subline were compared using gene expression microarrays. Gene Ontology (GO) enrichment analysis, Gene Set Enrichment Analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were performed to predict the involved pathways and molecules in cancer progression. RESULTS: The subline was designated as HSC-3S5 The cellular viability of HSC-3S5 cells at the suspension culture was higher than that of HSC-3 cells. A total of 961 genes were differentially expressed between HSC-3 and HSC-3S5 cells under the threshold cut-off (FDR-adjusted p-value of <0.05 and absolute fold change of >1.5). GO terms, such as growth regulation, were enriched in the DEGs. GSEA revealed the association between the DEGs and significant gene sets, including metastasis and stemness. IPA predicted that the proliferation-related pathways were enhanced while the apoptotic pathway was inhibited in HSC-3S5 cells compared to HSC-3 cells. CONCLUSION: Our transcriptome analysis revealed several potentially activated pathways and molecules in the floating-adapted oral cancer cells and indicated molecular implications for cancer progression.

Lumbar intradural space reduction during the Valsalva maneuver observed using cine MRI and MR myelography: a single-case experimental study.

BACKGROUND: Previous studies have shown that the Valsalva maneuver (VM) causes spinal canal object movements. We hypothesized that this occurs because of cerebrospinal fluid (CSF) flow generated from intradural space reduction. Previous studies using myelograms reported lumbar CSF space changes during inspiration. However, no similar studies have been conducted using modern MRI. Therefore, this study analyzed intradural space reduction during the VM using cine magnetic resonance imaging (MRI). METHODS: The participant was a 39-year-old, healthy, male volunteer. Cine MRI involved fast imaging employing steady-state acquisition cine sequence during three resting and VM sets for 60 s each. The axial plane was at the intervertebral disc and vertebral body levels between Th12 and S1 during cine MRI. This examination was performed on 3 separate days; hence, data from nine resting and VM sets were available. Additionally, two-dimensional myelography was performed during rest and the VM. RESULTS: Intradural space reduction was observed during the VM using cine MRI and myelography. The intradural space cross-sectional area during the VM (mean: 129.3 mm2; standard deviation [SD]: 27.4 mm2) was significantly lower than that during the resting period (mean: 169.8; SD: 24.8; Wilcoxon signed-rank test, P < 0.001). The reduction rate of the vertebral body level (mean: 26.7%; SD: 9.4%) was larger than that of the disc level (mean: 21.4%; SD: 9.5%; Wilcoxon rank sum test, P = 0.0014). Furthermore, the reduction was mainly observed on the ventral and bilateral intervertebral foramina sides at the vertebral body and intervertebral disc levels, respectively. CONCLUSION: The intradural space was reduced during the VM, possibly because of venous dilatation. This phenomenon may be associated with CSF flow, intradural object movement, and nerve compression, potentially leading to back pain.

Identification of 2',4',6'-Trihydroxyacetophenone as Promising Cysteine Conjugate Beta-Lyase Inhibitor for Preventing Cisplatin-Induced Nephrotoxicity.

Cisplatin is a chemotherapeutic agent used to treat many types of malignant tumors. However, irrespective of its potent anticancer properties and efficacy, nephrotoxicity is the dose-limiting factor of cisplatin treatment. Cisplatin infiltrates renal tubular cells in the kidneys and is metabolized by cysteine conjugate-beta lyase 1 (CCBL1) to form highly reactive thiol-cisplatin; this may mediate cisplatin's nephrotoxicity. Therefore, CCBL1 inhibition may prevent cisplatin-induced nephrotoxicity. Using a high-throughput screening assay, we identified 2',4',6'-trihydroxyacetophenone (THA) as an inhibitor of CCBL1. THA inhibited human CCBL1 ß-elimination activity in a concentration-dependent manner. We further investigated the preventive effect of THA on cisplatin-induced nephrotoxicity. THA attenuated the effect of cisplatin on the viability of confluent renal tubular cells (LLC-PK1 cells) but had no effect on cisplatin-induced reduction of proliferation in the tumor cell lines (LLC and MDA-MB-231). THA pretreatment significantly attenuated cisplatin-induced increases in blood urea nitrogen, creatinine, cell damage score, and apoptosis of renal tubular cells in mice in a dose-dependent manner. Furthermore, THA pretreatment attenuated cisplatin-induced nephrotoxicity without compromising its antitumor activities in mice bearing subcutaneous syngeneic LLC tumors. THA could help prevent cisplatin-induced nephrotoxicity and may provide a new strategy for cisplatin-inclusive cancer treatments.

Identification of 2',4',6'-trihydroxyacetophenone as promising cysteine conjugate beta-lyase inhibitor for preventing cisplatin-induced nephrotoxicity.

Cisplatin is a chemotherapeutic agent used to treat many types of malignant tumors. However, irrespective of its potent anticancer properties and efficacy, nephrotoxicity is the dose-limiting factor of cisplatin treatment. Cisplatin infiltrates renal tubular cells in the kidneys and is metabolized by cysteine conjugate-beta lyase 1 (CCBL1) to form highly reactive thiol-cisplatin; this may mediate cisplatin's nephrotoxicity. Therefore, CCBL1 inhibition may prevent cisplatin-induced nephrotoxicity. Using a high-throughput screening assay, we identified 2',4',6'-trihydroxyacetophenone (THA) as an inhibitor of CCBL1. THA inhibited human CCBL1 beta-elimination activity in a concentration-dependent manner. We further investigated the preventive effect of THA on cisplatin-induced nephrotoxicity. THA attenuated the effect of cisplatin on the viability of confluent renal tubular cells (LLC-PK1 cells) but had no effect on cisplatin-induced reduction of proliferation in the tumor cell lines (LLC and MDA-MB-231). THA pre-treatment significantly attenuated cisplatin-induced increases in blood urea nitrogen, creatinine, cell damage score, and apoptosis of renal tubular cells in mice in a dose-dependent manner. Furthermore, THA pre-treatment attenuated cisplatin-induced nephrotoxicity without compromising its anti-tumor activities in mice bearing subcutaneous syngeneic LLC tumors. THA could help prevent cisplatin-induced nephrotoxicity and may provide a new strategy for cisplatin-inclusive cancer treatments.

CD8+ Regulatory T Cells Induced by Lipopolysaccharide Improve Mouse Endotoxin Shock.

Sepsis is a systemic inflammatory disease caused by a bacterial infection that leads to severe mortality, especially in elderly patients, because of an excessive immune response and impaired regulatory functions. Antibiotic treatment is widely accepted as the first-line therapy for sepsis; however, its excessive use has led to the emergence of multidrug-resistant bacteria in patients with sepsis. Therefore, immunotherapy may be effective in treating sepsis. Although CD8+ regulatory T cells (Tregs) are known to have immunomodulatory effects in various inflammatory diseases, their role during sepsis remains unclear. In this study, we investigated the role of CD8+ Tregs in an LPS-induced endotoxic shock model in young (8-12 wk old) and aged (18-20 mo old) mice. The adoptive transfer of CD8+ Tregs into LPS-treated young mice improved the survival rate of LPS-induced endotoxic shock. Moreover, the number of CD8+ Tregs in LPS-treated young mice increased through the induction of IL-15 produced by CD11c+ cells. In contrast, LPS-treated aged mice showed a reduced induction of CD8+ Tregs owing to the limited production of IL-15. Furthermore, CD8+ Tregs induced by treatment with the rIL-15/IL-15Rα complex prevented LPS-induced body wight loss and tissue injury in aged mice. In this study, to our knowledge, the induction of CD8+ Tregs as novel immunotherapy or adjuvant therapy for endotoxic shock might reduce the uncontrolled immune response and ultimately improve the outcomes of endotoxic shock.

Spermidine enhances the efficacy of adjuvant in HBV vaccination in mice.

Background: Various vaccine adjuvants have been developed to eliminate HBV from patients with chronic HBV infection. In addition, spermidine (SPD), a type of polyamine, has been reported to enhance the activity of immune cells. In the present study, we investigated whether the combination of SPD and vaccine adjuvant enhances the HBV antigen-specific immune response to HBV vaccination. Methods: Wild-type and HBV-transgenic (HBV-Tg) mice were vaccinated 2 or 3 times. SPD was orally administered in drinking water. Cyclic guanosine monophosphate-AMP (cGAMP) and nanoparticulate CpG-ODN (K3-SPG) were used as the HBV vaccine adjuvants. The HBV antigen-specific immune response was evaluated by measuring the HBsAb titer in blood collected over time and the number of interferon-γ producing cells by enzyme-linked immunospot assay. Results: The administration of HBsAg + cGAMP + SPD or HBsAg + K3-SPG + SPD significantly enhanced HBsAg-specific interferon-γ production by CD8 T cells from wild-type and HBV-Tg mice. The administration of HBsAg, cGAMP, and SPD increased serum HBsAb levels in wild-type and HBV-Tg mice. In HBV-Tg mice, the administration of SPD + cGAMP or SPD + K3-SPG with HBV vaccination significantly reduced HBsAg levels in the liver and serum. CONCLUSIONS: These results indicate that the combination of HBV vaccine adjuvant and SPD induces a stronger humoral and cellular immune response through T-cell activation. These treatments may support the development of a strategy to completely eliminate HBV.

Absence of indoleamine 2,3­dioxygenase 2 promotes liver regeneration after partial hepatectomy in mice.

The partial loss of liver due to liver transplantation or acute liver failure induces rapid liver regeneration. Recently, we reported that the selective inhibition of indoleamine 2,3­dioxygenase (Ido) 1 promotes early liver regeneration. However, the role of Ido2 in liver regeneration remains unclear. Wild­type (WT) and Ido2­deficient (Ido2­KO) mice were subjected to 70% partial hepatectomy (PHx). Hepatocyte growth was measured using immunostaining. The mRNA expression of inflammatory cytokines and production of kynurenine in intrahepatic mononuclear cells (MNCs) were analyzed using reverse transcription­quantitative PCR and high­performance liquid chromatography. The activation of NF­κB was determined by both immunocytochemistry and western blotting analysis. The ratio of liver to body weight and the frequency of proliferation cells after PHx were significantly higher in Ido2­KO mice compared with in WT mice. The expression of IL­6 and TNF­α in MNCs were transiently increased in Ido2­KO mice. The nuclear transport of NF­κB was significantly higher in peritoneal macrophages of Ido2­KO mice compared with WT mice. These results suggested that Ido2 deficiency resulted in transiently increased production of inflammatory cytokines through the activation of NF­kB, thereby promoting liver regeneration. Therefore, the regulation of Ido2 expression in MNCs may play a therapeutic role in liver regeneration under injury and disease conditions.

Cytomorphology and Gene Expression Signatures of Anchorage-independent Aggregations of Oral Cancer Cells.

BACKGROUND/AIM: Cancer cells with high anchorage independence can survive and proliferate in the absence of adhesion to the extracellular matrix. Under anchorage-independent conditions, cancer cells adhere to each other and form aggregates to overcome various stresses. In this study, we investigated the cytomorphology and gene expression signatures of oral cancer cell aggregates. MATERIALS AND METHODS: Two oral cancer-derived cell lines, SAS and HSC-3 cells, were cultured in a low-attachment plate and their cytomorphologies were observed. The transcriptome between attached and detached SAS cells was examined using gene expression microarrays. Subsequently, gene enrichment analysis and Ingenuity Pathway Analysis were performed. Gene expression changes under attached, detached, and re-attached conditions were measured via RT-qPCR. RESULTS: While SAS cells formed multiple round-shaped aggregates, HSC-3 cells, which had lower anchorage independence, did not form aggregates efficiently. Each SAS cell in the aggregate was linked by desmosomes and tight junctions. Comparative transcriptomic analysis revealed 1,698 differentially expressed genes (DEGs) between attached and detached SAS cells. The DEGs were associated with various functions and processes, including cell adhesion. Moreover, under the detached condition, the expression of some epithelial genes (DSC3, DSP, CLDN1 and OCLN) were up-regulated. The changes in both cytomorphology and epithelial gene expression under the detached condition overall returned to their original ones when cells re-attached. CONCLUSION: The results suggest specific cytomorphological and gene expression changes in oral cancer cell aggregates. Our findings provide insights into the mechanisms underlying anchorage-independent oral cancer cell aggregation and reveal previously unknown potential diagnostic and therapeutic molecules.

Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma.

Long-term senescent cells exhibit a secretome termed the senescence-associated secretory phenotype (SASP). Although the mechanisms of SASP factor induction have been intensively studied, the release mechanism and how SASP factors influence tumorigenesis in the biological context remain unclear. In this study, using a mouse model of obesity-induced hepatocellular carcinoma (HCC), we identified the release mechanism of SASP factors, which include interleukin-1ß (IL-1ß)- and IL-1ß-dependent IL-33, from senescent hepatic stellate cells (HSCs) via gasdermin D (GSDMD) amino-terminal-mediated pore. We found that IL-33 was highly induced in senescent HSCs in an IL-1ß-dependent manner in the tumor microenvironment. The release of both IL-33 and IL-1ß was triggered by lipoteichoic acid (LTA), a cell wall component of gut microbiota that was transferred and accumulated in the liver tissue of high-fat diet-fed mice, and the release of these factors was mediated through cell membrane pores formed by the GSDMD amino terminus, which was cleaved by LTA-induced caspase-11. We demonstrated that IL-33 release from HSCs promoted HCC development via the activation of ST2-positive Treg cells in the liver tumor microenvironment. The accumulation of GSDMD amino terminus was also detected in HSCs from human NASH-associated HCC patients, suggesting that similar mechanism could be involved in a certain type of human HCC. These results uncover a release mechanism for SASP factors from sensitized senescent HSCs in the tumor microenvironment, thereby facilitating obesity-associated HCC progression. Furthermore, our findings highlight the therapeutic potential of inhibitors of GSDMD-mediated pore formation for HCC treatment.

Antibody Responses to BNT162b2 Vaccination in Japan: Monitoring Vaccine Efficacy by Measuring IgG Antibodies against the Receptor-Binding Domain of SARS-CoV-2.

To fight severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), mass vaccination has begun in many countries. To investigate the usefulness of a serological assay to predict vaccine efficacy, we analyzed the levels of IgG, IgM, and IgA against the receptor-binding domain (RBD) of SARS-CoV-2 in the sera from BNT162b2 vaccinated individuals in Japan. This study included 219 individuals who received two doses of BNT162b2. The levels of IgG, IgM, and IgA against RBD were measured by enzyme-linked immunosorbent assay before and after the first and second vaccination, respectively. The relationship between antibody levels and several factors, including age, gender, and hypertension were analyzed. Virus-neutralizing activity in sera was measured to determine the correlation with the levels of antibodies. A chemiluminescent enzyme immunoassay (CLEIA) method to measure IgG against RBD was developed and validated for the clinical setting. The levels of all antibody isotypes were increased after vaccination. Among them, RBD-IgG was dramatically increased after the second vaccination. The IgG levels in females were significantly higher than in males. There was a negative correlation between age and IgG levels in males. The IgG levels significantly correlated with the neutralizing activity. The CLEIA assay measuring IgG against RBD showed a reliable performance and a high correlation with neutralizing activity. Monitoring of IgG against RBD is a powerful tool to predict the efficacy of SARS-CoV-2 vaccination and provides useful information in considering a personalized vaccination strategy for COVID-19. IMPORTANCE Mass vaccination campaigns using mRNA vaccines against SARS-CoV-2 have begun in many countries. Serological assays to detect antibody production may be a useful tool to monitor the efficacy of SARS-CoV-2 vaccination in individuals. Here, we reported the induction of antibody isotype responses after the first and second dose of the BNT162b2 vaccine in a well-defined cohort of employees in Japan. We also reported that age, gender, and hypertension are associated with differences in antibody response after vaccination. This study not only provides valuable information with respect to antibody responses after BNT162b2 vaccination in the Japanese population but also the usefulness of serological assays for monitoring vaccine efficacy in clinical laboratories to determine a personalized vaccination strategy for COVID-19.

Immunogenicity of BNT162b2 mRNA COVID-19 Vaccine in Patients with Cardiovascular Disease.

Concern has been raised about the effectiveness of the coronavirus disease 2019 (COVID-19) vaccine in the population of patients with various comorbidities such as heart disease. We investigated the humoral response to the BNT162b2 mRNA COVID-19 vaccine in patients with cardiovascular disease (CVD). We measured IgG against severe acute respiratory syndrome coronavirus 2 spike receptor-binding domain (RBD-IgG) in 85 CVD patients and 179 healthcare workers (HCWs). Blood samples were collected from patients and HCWs three times: (1) before the first dose of vaccination, (2) two weeks after the first dose of vaccination, and (3) two weeks after the second dose of vaccination. Patients with CVD showed a significantly inferior serological response to the BNT162b2 mRNA COVID-19 vaccine at 14 days after the prime dose compared to HCWs (21% vs. 95%, p < 0.001). Median RBD-IgG titers of patients with CVD at 14 days after the second dose were significantly lower than those of HCWs (137.2 U/mL (80.6-200.4 U/mL) vs. 176.2 U/mL (123.9-260.0 U/mL), p < 0.001). In multivariable analyses, CVD is significantly associated with seropositivity after first vaccination and RBD-IgG titers after second vaccination. CVD patients may have a poor humoral response to the BNT162b2 mRNA COVID-19 vaccine, need to be closely monitored, and require earlier revaccination to ensure stronger immunity and protection against infection.

Reduced TREM2 activation in microglia of patients with Alzheimer's disease.

Loss-of-function variants of triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of developing Alzheimer's disease (AD). The mechanism through which TREM2 contributes to the disease (TREM2 activation vs inactivation) is largely unknown. Here, we analyzed changes in a gene set downstream of TREM2 to determine whether TREM2 signaling is modified by AD progression. We generated an anti-human TREM2 agonistic antibody and defined TREM2 activation in terms of the downstream expression changes induced by this antibody in microglia developed from human induced pluripotent stem cells (iPSC). Differentially expressed genes (DEGs) following TREM2 activation were compared with the gene set extracted from microglial single nuclear RNA sequencing data of patients with AD, using gene set enrichment analysis. We isolated an anti-TREM2-specific agonistic antibody, Hyb87, from anti-human TREM2 antibodies generated using binding and agonism assays, which helped us identify 300 upregulated and 251 downregulated DEGs. Pathway enrichment analysis suggested that TREM2 activation may be associated with Th2-related pathways. TREM2 activation was lower in AD microglia than in microglia from healthy subjects or patients with mild cognitive impairment. TREM2 activation also showed a significant negative correlation with disease progression. Pathway enrichment analysis of DEGs controlled by TREM2 activity indicated that TREM2 activation in AD may lead to anti-apoptotic signaling, immune response, and cytoskeletal changes in the microglia. We showed that TREM2 activation decreases with AD progression, in support of a protective role of TREM2 activation in AD. In addition, the agonistic anti-TREM2 antibody can be used to identify TREM2 activation state in AD microglia.

Genetic stability of the open reading frame 2 (ORF2) of borna disease virus 1 (BoDV-1) distributed in cattle in Hokkaido.

Borna disease virus (BoDV) is a neurotropic virus that causes several infections in humans and neurological diseases in a wide range of animals worldwide. BoDV-1 has been molecularly and serologically detected in many domestic and wild animals in Japan; however, the genetic diversity of this virus and the origin of its infection are not fully understood. In this study, we investigated BoDV-1 infection and genetic diversity in samples collected from animals in Hokkaido between 2006 and 2020. The analysis was performed by focusing on the P region of BoDV-1 for virus detection. The presence of BoDV-1 RNA was observed in samples of brain tissue and various organs derived from persistently infected cattle. Moreover, after inoculation, BoDV-positive brains were isolated from neonatal rats. The gene sequences of the P region of BoDV obtained from the rat brain were in the same cluster as the P region of the virus isolated from the original bovine. Thus, genetic variation in BoDV-1 was extremely low. The phylogenetic analysis revealed that BoDV-1 isolates obtained in this study were part of the same cluster, which suggested that BoDV-1 of the same cluster was widespread among animals in Hokkaido.