A myeloid immune checkpoint, leukocyte immunoglobulin-like receptor (LILR) B4 (B4, also known as ILT3/CD85k in humans and gp49B in mice) is expressed on dendritic cells (DCs). However, a mode of regulation of DCs by B4/gp49B is not identified yet in relation to the ligand(s) as well as to the counteracting, activation-type receptor. Our recent identification of the physiological/pathological ligand for B4/gp49B as the fibronectin (FN) N-terminal 30-kDa domain poses the question of the relationship between B4/gp49B and a classical FN receptor/cellular activator, integrin, on DCs. Here we showed that FN is not constitutively tethered on the surface of bone marrow-derived cultured DCs (BMDCs) or splenic DCs, even though the FN receptor integrin and gp49B are co-expressed on these cells. Confocal laser scanning microscopic analysis, however, revealed weak correlation of fluorescent signals between gp49B and integrin β₁, suggesting their partial co-localization on the BMDC surface even in the absence of FN. We found that the plating of BMDCs onto immobilized FN induced tyrosine phosphorylation of focal adhesion kinase (FAK) and spleen tyrosine kinase (Syk). In the absence of gp49B, while the FAK phosphorylation level was virtually unchanged, that of phosphorylation of Syk was markedly augmented. These results suggested that the immobilized FN induced a crosstalk between gp49B and integrin in terms of the intracellular signaling of BMDCs, in which gp49B suppressed the integrin-mediated pro-inflammatory cascade. Our observations may provide a clue for elucidating the mechanism of the therapeutic efficacy of B4/gp49B blocking in autoimmune disease and cancer.

Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) as a novel negative immune regulator plays an important role in several human diseases. However, its influences in cervical cancer and preeclampsia (PE) remain unclear. This study aims to explore the important role of TIPE2 in cervical cancer and PE via regulating cell invasion. TIPE2 expression in the cervical cancer tissues or the placenta of PE patients was detected. Human cervical cancer cell lines and trophoblasts were transfected with adenovirus expressing human TIPE2 and green fluorescent protein (GFP) (Ad-TIPE2), or the control adenovirus expressing GFP (Ad-GFP). Xenograft models were also constructed on nude mice, aiming to clarify how TIPE2 affects in vivo growth of cervical cancer cells. TIPE2 was down-regulated in the tumor tissues or placenta of patients with cervical cancer or PE. As a result, CaSKi and Hela cells in the Ad-TIPE2 group had decreased migration and invasion, with significant up-regulations of TIPE2 and E-cadherin, but down-regulations of β-catenin and N-cadherin. Ad-TIPE2 decreased the volume and weight of xenograft tumors in the nude mice, with the down-regulation of Ki67. The quantity of cells (HTR8/SVneo and JEG3 cells) transfected with Ad-TIPE2 had increased, with up-regulations of TIPE2, matrix metalloproteinase (MMP)-2 and MMP-9. TIPE2 overexpression could reduce the invasion and migration of cervical cancer cells via inhibiting the epithelial-mesenchymal transition (EMT) process, and promote trophocyte invasion via upregulating the expression of MMPs, and it may be used as a potential therapeutic target for cervical cancer and PE.

Mongolia was listed among the 30 countries with a high tuberculosis burden in 2021. Approximately 10-11% of the tuberculosis cases are of children, which is higher than the global average (6.0%). As children are a vulnerable population, it is important to understand the current situation and prioritize the development of tuberculosis prevention strategies. However, only few studies have addressed childhood tuberculosis in Mongolia. Therefore, we aimed to describe the characteristics of childhood tuberculosis and to show its trends and estimates in Mongolia. We performed descriptive and trend analyses on secondary data from the National Center for Communicable Diseases from 2010 to 2020. A total of 4,242 childhood tuberculosis cases, compiled from nine districts of the capital city and 21 provinces, were analyzed. We found that tuberculosis occurred more frequently in school-age children, and 71.8% of the all cases were an extrapulmonary tuberculosis. Trend analysis revealed that childhood tuberculosis continuously increased with fluctuations from 2018 onwards. The central region, including the capital city of Ulaanbaatar, is the most tuberculosis-burdened. Childhood tuberculosis is estimated to increase in the central region and decrease in the others from 2021 to 2030. Our findings showed that the national childhood tuberculosis trend is increasing, although there are differences in the pattern between regions. Further studies are needed to identify the determinant factors of regional differences, and age-specific public health interventions, such as scale-up screening and preventive treatment, are in demand in high-prevalence areas.

Pain, stiffness, and swelling are the main joint symptoms of psoriatic arthritis (PsA); however, they are also common symptoms of other joint diseases. Therefore, it is challenging to distinguish PsA from other joint diseases. To evaluate the prevalence of PsA and the frequency of joint symptoms in psoriasis patients, we conducted a prefecture-wide survey using the Psoriasis Epidemiology Screening Tool (PEST), a patient questionnaire for screening PsA to assess joint symptoms. Data were collected from 764 psoriasis patients, all of whom visited hospitals (55.1%) or clinics (44.9%) in Nagano Prefecture, Japan. The proportion of psoriasis patients with PsA was 6.5% (50 of 764); four patients (1.2%) with PsA were treated in clinics, while 46 patients (10.9%) were treated in hospitals. Based on the responses to the PEST, 18.1% of patients with psoriasis had joint symptoms. In contrast, 73.2% of psoriasis patients with joint symptoms did not have PsA. The PEST showed 52% sensitivity and 93.4% specificity for PsA. In addition, fingernail alterations were common in PsA. The proportion of the population with PsA was lower than reported previously in Japan. This may have been due to the enrollment of a large number of patients treated in clinics. Many patients with PsA were treated at hospitals, which likely reflects the tendency of patients with joint symptoms to receive intensive treatment in hospitals. In addition, based on the lower sensitivity of the PEST in this study, further studies are necessary to establish the validity of the PEST.

Chronic myeloid leukemia (CML) is triggered by t(9;22)(q34;q11.2) translocation, leading to the formation of the BCR-ABL1 fusion gene. Although the development of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has dramatically improved the prognosis of CML, the disease could often relapse, presumably because leukemic stem cell fraction of CML (CML-LSC) may reside in specific niches, and also acquire an ability to resist the cytotoxic agents. Recently a study indicated that pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1, also known as SERPINE1) would cause detachment of CML-LSCs from their niche by inducing maturation of membrane-type matrix metalloprotease-1 (MT1-MMP), leading to increased susceptibility of CML-LSCs against TKIs. However, the direct antitumor effect of PAI-1 inhibition in CML remains unclear. Because PAI-1 mRNA expression was lower in CML cell line (K562) than bone marrow mononuclear cells derived from CML patients, we established K562 cell clones stably expressing exogenous PAI-1 (K562/PAI-1). We found that TM5614 treatment significantly suppressed cell proliferation and induced apoptosis in K562/PAI-1 cells, accompanied by increased activity of Furin protease, which is a known target of PAI-1. Besides processing mature MT1-MMP, Furin is in charge of cleaving the NOTCH receptor to form a heterodimer before exporting it to the cell surface membrane. In K562/PAI-1 cells, TM5614 treatment increased NOTCH1 intracellular domain (NICD) protein expression as well as NOTCH1 target of HEY1 mRNA levels. Finally, forced expression of either Furin or NICD in K562/PAI-1 cells significantly inhibited cell proliferation and induced apoptosis. Collectively, PAI-1 inhibition may have an antitumor effect by modulating the Furin/NICD pathway.

Long noncoding RNAs (LncRNAs) were reported to be implicated in the progression of gastric cancer (GC). This study aimed to explore the role of solute carrier family 25 member 21 antisense RNA 1 (SLC25A21-AS1) in radiosensitivity of GC cells. In the present study, reverse transcription quantitative polymerase chain reaction (RT-qPCR) showed that the expression of SLC25A21-AS1 and synuclein gamma (SNCG) was downregulated in GC tissues and cells, while the expression of microRNA-15a-5p (miR-15a-5p) was upregulated in GC tissues and cells. The expression of SLC25A21-AS1 was elevated in GC cells after radiation treatment. SLC25A21-AS1 overexpression enhanced GC cell radiosensitivity, inhibited cell proliferation and promoted apoptosis. SLC25A21-AS1 overexpression also facilitated the DNA damage caused by radiation in GC cells. Mechanically, SLC25A21-AS1 interacted with miR-15a-5p and negatively regulated miR-15a-5p expression in GC cells. SNCG was directly targeted by miR-15a-5p at the 3' untranslated region (3'UTR). In GC tissues, the expression of SNCG was negatively correlated with that of miR-15a-5p, but was positively correlated with that of SLC25A21-AS1. Rescue assays revealed that SNCG silencing rescued the tumor-suppressive effect of overexpressed SLC25A21-AS1 on GC cells. The enhanced radiosensitivity caused by SLC25A21-AS1 overexpression was also reduced by SNCG knockdown. In conclusion, lncRNA SLC25A21-AS1 inhibits cell malignant behaviors and enhances cell radiosensitivity in GC by elevating SNCG expression.

Coronavirus disease 2019 (COVID-19) causes a variety of pain symptoms in the acute phase. Severe chest pain suddenly occurs even without abnormalities on examination and is sometimes refractory to analgesics. Such pain is a clinical concern in care facilities with limited resources, and this is the first report on the use of saikanto for its treatment. In Miyagi Prefecture, Japan, COVID-19 patients with mild symptoms were admitted to a hotel that operated as an isolation facility, and their symptoms were observed. In this article, we report four cases in which chest pain comorbid with mild to moderate COVID-19 was successfully treated with saikanto, a traditional Japanese (Kampo) medicine. The patients presented with chest pain and underwent medical examination at the facility. Two patients had severe chest pain refractory to acetaminophen. Critical cardiopulmonary diseases were ruled out in all the patients, and three patients had features of pneumonia on chest radiograph. Medications, including saikanto, were administered to the patients. The patients’ chest pain and other symptoms improved 1-4 days after the administration of saikanto, and they left the care facility without hospitalization. The cause of the chest pain experienced by these patients is unclear, but we speculate that it could be minimal pleural inflammation or neuropathy. Previous pharmacological studies have suggested anti-inflammatory and analgesic properties of the crude drugs that constitute saikanto. This case report suggests that saikanto could be a treatment option for chest pain refractory to analgesics in patients with mild to moderate COVID-19.

Vaccination against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently underway across countries worldwide. However, the prevalence and characteristics of prolonged adverse events lasting for several months after receiving the vaccine remain largely unknown. We herein report a 46-year-old woman with prolonged diarrhea and vomiting after receiving the BNT162b2 mRNA vaccine for COVID-19. She had no notable medical history, including that of gastrointestinal diseases. She developed vomiting several hours after receiving the first vaccine dose and further developed severe diarrhea after 7 days. Several days after the second vaccine dose, her condition deteriorated, unrelieved by symptomatic therapies, including anti-diarrheal drugs. Abdominal computed tomography (CT) revealed inflammatory changes in the entire segment of the small intestine with wall thickening. The upper and lower gastrointestinal and capsule endoscopies were unremarkable. The patient’s symptoms persisted for more than 6 months after the second vaccine dose. A Vaccine Adverse Event Reporting System (VAERS) database search suggested that diarrhea is observed in approximately 3% of all vaccine recipients, but a literature review indicated that prolonged gastrointestinal symptoms lasting for several months is very rare. In summary, a case of prolonged unexplained gastrointestinal symptoms, possibly based on inflammatory changes in the small intestine, is described. A literature search revealed that this type of manifestation is very rare, and further evidence is needed to determine the causality between vaccination and gastrointestinal symptoms.

Ten years after the Great East Japan Earthquake, thousands of residents of Fukushima Prefecture were still living as evacuees. Among them, unignorable numbers of people were living outside of the prefecture. A survey was conducted with evacuees to Ibaraki, the neighboring prefecture of Fukushima, to investigate their medium- to long-term mental care needs. A questionnaire was sent to 1,470 households that had been living in Fukushima on March 11, 2011, and who were evacuated to Ibaraki by October 2016. Binary logistic regression analyses were performed to identify risk factors for major depressive disorder, post-traumatic stress disorder (PTSD), and suicidal ideation. Of the participants, 16.5% had a high risk for major depressive disorder, 39.0% exhibited a high risk for PTSD, and 19.7% indicated suicidal ideation. “Own injuries and illnesses” and “Worries about the hometown” were risk factors for major depressive disorder, PTSD, and suicidal ideation. “Not receiving compensation for damages” was a risk factor common to major depressive disorder and suicidal ideation. There is a high possibility that many people who have evacuated to other prefectures might still be suffering from psychological symptoms after the disaster. Worries about their hometowns were highly related to their mental disorders.