👤 Takashi Nagano

Innate lymphoid cells (ILCs) are rare, tissue-resident innate lymphocytes that functionally mirror CD4+ T helper cell lineages but lack antigen receptors. Type 3 ILCs (ILC3s) are enriched in the gut, airways, and mucosal lymphoid tissues, where they regulate inflammation and promote barrier integrity. To define the regulatory architecture of primary human ILC3s, we map promoter-anchored chromosomal contacts using high-resolution, low-input Promoter Capture Hi-C (PCHi-C) in these cells alongside CD4+ T cells. By combining statistical detection with a PCHi-C-adapted Activity-by-Contact approach, we link promoters to distal regulatory elements, identifying hundreds of ILC3-specific contacts. We use these maps to connect genome-wide association study (GWAS) risk variants for Crohn's disease to target genes using multiCOGS, a Bayesian framework that integrates PCHi-C with summary-statistic imputation and multivariate fine-mapping. This analysis highlights both known and unanticipated candidates, including Show less

In the tumor microenvironment, hypoxia and stromal interactions contribute to enhanced malignant behavior in cancer cells. This study aimed to assess whether pancreatic cancer cells with higher malignancy display stronger responses to hypoxia and stromal cells than their less malignant parental cells, and evaluated the underlying mechanisms, focusing on lysophosphatidic acid (LPA) receptor signaling linked to the acquisition of malignant traits. Highly invasive PANC-M10 cells, derived from the parental pancreatic cancer PANC-1 cells, were cultured at 1% O Show less

Lysophosphatidic acid (LPA) receptor-mediated signaling contributes to the pathogenesis of cancer. The tumor microenvironment (TME), composed of cancer cells and surrounding stromal cells, plays a key role in promoting malignant traits, including resistance to anticancer drugs. In this study, we investigated the roles of LPA receptor-1 (LPA Show less

Hypoxia plays a crucial role in driving tumor progression by altering cellular signaling pathways. Lysophosphatidic acid (LPA) receptor signaling regulates malignant properties in cancer cells, including motility and chemoresistance. This study aimed to compare the cellular functions of gastric cancer AGS cells under cobalt chloride (CoCl Show less

Tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, was approved in Japan for the treatment of Waldenström's macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL). We report the findings of post-marketing surveillance (PMS) of tirabrutinib that was started following its approval. We conducted an all-case PMS of patients who started tirabrutinib treatment between August 21, 2020, and January 17, 2021 for WM/LPL in Japan. Safety and effectiveness data were recorded for up to 52 weeks after the first dose of tirabrutinib. Among 152 patients who started tirabrutinib, 67.1% were male, 77.6% were ≥ 65 years old, and 61.8% started treatment with tirabrutinib at 480 mg/day (once-daily). Among these 152 patients, any-grade and grade ≥ 3 adverse drug reactions (ADRs) occurred in 58.6% and 29.6% of patients, respectively. The main ADRs were platelet count decreased (9.2%) and rash (9.2%). Grade 5 ADRs were reported in four patients (2.6%). The outcomes of most ADRs associated with the safety specifications (myelosuppression, infections, interstitial lung diseases, clinically significant skin disorders, hemorrhages, hepatic function disorders, and hypersensitivities) were resolved or improved. The effectiveness was assessed by the physicians using the VI Show less

In solid tumors, cancer cells adapt to hypoxic and nutrient deprived environments to support malignant progression. This study examined whether hypoxic and low glucose conditions enhance malignant behaviors more strongly in highly migratory MG63-R10 cells, which are derived from osteosarcoma MG-63 cells, compared to parental MG-63 cells, and further investigated whether lysophosphatidic acid (LPA) receptor signaling regulates this adaptation. MG63-R10 and MG-63 cells were cultured under hypoxic (1% O Under 1% O These results suggest that, compared to parental MG-63 cells, highly migratory osteosarcoma MG63-R10 cells adapt their malignant cellular functions to hypoxic and low-glucose conditions through LPA receptor signaling, highlighting this pathway as a potential therapeutic target in aggressive osteosarcomas. The online version contains supplementary material available at 10.1007/s12195-025-00873-y. Show less

Colorectal cancer (CRC) remains a significant global health concern, demanding a more profound comprehension of its molecular foundations for the development of improved therapeutic strategies. This study aimed to elucidate the role of protein phosphatase 6 (PP6), a member of the type 2A protein phosphatase family, in CRC. Protein phosphatase 6 functions as a heterotrimer with a catalytic subunit (PP6c), regulatory subunits (PP6Rs; PP6R1, PP6R2, and PP6R3), and scaffold subunits (ANKRD28, ANKRD44, and ANKRD52). Elevated PP6c expression has been identified in CRC tissues compared to normal mucosa, aligning with its potential involvement in CRC pathogenesis. PP6c knockdown resulted in decreased colony-forming ability and in vivo proliferation of various CRC cell lines. Transcriptome analysis revealed that PP6c knockdown resulted in altered expression of genes associated with cancer stemness. Notably, the PP6c-PP6R3 complex is a key player in regulating cancer stem cell (CSC) markers. Additionally, increased PP6c expression was observed in CSC-like cells induced by sphere formation, implicating the role of PP6c in CSC maintenance. This study highlights the role of PP6c in CRC and suggests that it is a potential therapeutic target disrupting a pathway critical for CRC progression and stem cell maintenance. Show less

Vegetable and fruit intake has been reported to be associated with decreased risk of cardiovascular disease. To date, however, no study has examined the association between vegetable and fruit intake and LOX-index, which reflects the progression of atherosclerosis and is a predictive biomarker of stroke and coronary heart disease. Here, we examined the cross-sectional association between vegetable and fruit intake and LOX-index in Japanese municipal workers. Participants were 338 workers (166 men and 172 women aged 19-71 y) with no history of serious disease who participated in a health and nutrition survey. Vegetable and fruit intake was assessed using a validated brief self-administered diet history questionnaire. LOX-index was calculated by multiplying serum concentrations of the soluble form of lectin-like oxidized LDL receptor-1 by those of LOX-1 ligands containing apolipoprotein B. Multiple regression analysis was used to estimate the geometric mean of LOX-index according to tertile of vegetable and/or fruit intake. Total vegetable and fruit intake was associated with a trend toward decreased LOX-index after adjustment for covariates (p for trend=0.067). In stratified analyses by sex, a significant inverse association between total vegetable and fruit intake and LOX-index was observed in women (p for trend=0.023), whereas such association was not observed in men (p for trend=0.70). None of the intakes of vegetables, fruit, green and yellow vegetables, or other vegetables was associated with LOX-index. Our results suggest that higher intake of total vegetables and fruit is associated with a lower LOX-index in Japanese women. Show less

Angiopoietin-like 4 (ANGPTL4) was recently shown to be associated with cancer progression but little is known about its contribution to cancer metabolism. The purpose of this study was to elucidate the role of ANGPTL4 in glucose metabolism in colorectal cancer (CRC). Immunohistochemical staining of CRC specimens classified 84 patients into two groups according to ANGPTL4 expression. Clinicopathological characteristics, gene mutation status obtained by next-generation sequencing, and fluorodeoxyglucose (FDG) uptake measured by positron emission tomography/computed tomography (PET/CT) were compared between the two groups. Furthermore, the impact of ANGPTL4 expression on cancer metabolism was investigated by a subcutaneous xenograft mouse model using the ANGPTL4 knockout CRC cell line, and glucose transporter (GLUT) expression was evaluated. There were significantly more cases of T3/4 tumours (94.3% vs. 57.1%, P < 0.001) and perineural invasion (42.9% vs. 22.4%, P = 0.046) in the ANGPTL4-high group than in the low group. Genetic exploration revealed a higher frequency of KRAS mutation (54.3% vs. 22.4%, P = 0.003) in the ANGPTL4-high tumours. All the FDG uptake parameters were significantly higher in ANGPTL4-high tumours. In vivo analysis showed a significant reduction in tumour size due to ANGPTL4 knockout with lower expression of GLUT1 and GLUT3, and suppression of AKT phosphorylation. ANGPTL4 regulates the expression of GLUTs by activating the PI3K-AKT pathway and thereby promoting glucose metabolism in CRC. These findings establish a new functional role of ANGPTL4 in cancer progression and lay the foundation for developing a novel therapeutic target. Show less

Nephronophthisis is an autosomal-recessive kidney disease that is caused by abnormalities in primary cilia. Nephronophthisis-related ciliopathies (NPHP-RCs) are a common cause of end-stage kidney disease (ESKD) in children and adolescents. NPHP-RCs are often accompanied by extrarenal manifestations, including intellectual disability, retinitis pigmentosa, or polydactyly. Although more than 100 causative genes have been identified, its diagnosis is difficult because the clinical features of each mutation often overlap. From September 2010 to August 2021, we performed genetic analysis, including next-generation sequencing (NGS), in 574 probands with kidney dysfunction and retrospectively studied cases genetically diagnosed with NPHP-RCs. RESULTS: We detected mutations related to NPHP-RCs in 93 patients from 83 families. Members of 60 families were diagnosed using NGS, and the mutations and the corresponding number of families are as follows: NPHP1 (24), NPHP3 (10), OFD1 (7), WDR35 (5), SDCCAG8 (4), BBS10 (3), TMEM67 (3), WDR19 (3), BBS1 (2), BBS2 (2), IFT122 (2), IFT140 (2), IQCB1 (2), MKKS (2), SCLT1 (2), TTC21B (2), ALMS1 (1), ANKS6 (1), BBS4 (1), BBS12 (1), CC2D2A (1), DYNC2H1 (1), IFT172 (1), and MAPKBP1 (1). A total of 39 cases (41.9%) progressed to ESKD at the time of genetic analysis, whereas 58 cases (62.3%) showed extrarenal manifestations, the most common being developmental delay, intellectual disability, and autism spectrum disorder in 44 patients. Comprehensive genetic analysis using NGS is useful for diagnosing patients with NPHP-RCs. Show less

Misty mice (m/m) have a loss of function mutation in Dock7 gene, a guanine nucleotide exchange factor, resulting in low bone mineral density, uncoupled bone remodeling and reduced bone formation. Dock7 has been identified as a modulator of osteoblast number and in vitro osteogenic differentiation in calvarial osteoblast culture. In addition, m/m exhibit reduced preformed brown adipose tissue innervation and temperature as well as compensatory increase in beige adipocyte markers. While the low bone mineral density phenotype is in part due to higher sympathetic nervous system (SNS) drive in young mice, it is unclear what effect aging would have in mice homozygous for the mutation in the Dock7 gene. We hypothesized that age-related trabecular bone loss and periosteal envelope expansion would be altered in m/m. To test this hypothesis, we comprehensively characterized the skeletal phenotype of m/m at 16, 32, 52, and 78wks of age. When compared to age-matched wild-type control mice (+/+), m/m had lower areal bone mineral density (aBMD) and areal bone mineral content (aBMC). Similarly, both femoral and vertebral BV/TV, Tb.N, and Conn.D were decreased in m/m while there was also an increase in Tb.Sp. As low bone mineral density and decreased trabecular bone were already present at 16wks of age in m/m and persisted throughout life, changes in age-related trabecular bone loss were not observed highlighting the role of Dock7 in controlling trabecular bone acquisition or bone loss prior to 16wks of age. Cortical thickness was also lower in the m/m across all ages. Periosteal and endosteal circumferences were higher in m/m compared to +/+ at 16wks. However, endosteal and periosteal expansion were attenuated in m/m, resulting in m/m having lower periosteal and endosteal circumferences by 78wks of age compared to +/+, highlighting the critical role of Dock7 in appositional bone expansion. Histomorphometry revealed that osteoblasts were nearly undetectable in m/m and marrow adipocytes were elevated 3.5 fold over +/+ (p=0.014). Consistent with reduced bone formation, osteoblast gene expression of Alp, Col1a1, Runx-2, Sp7, and Bglap was significantly decreased in m/m whole bone. Furthermore, markers of osteoclasts were either unchanged or suppressed. Bone marrow stromal cell migration and motility were inhibited in culture and changes in senescence markers suggest that osteoblast function may also be inhibited with loss of Dock7 expression in m/m. Finally, increased Oil Red O staining in m/m ear mesenchymal stem cells during adipogenesis highlights a potential shift of cells from the osteogenic to adipogenic lineages. In summary, loss of Dock7 in the aging m/m resulted in an impairment of periosteal and endocortical envelope expansion, but did not alter age-related trabecular bone loss. These studies establish Dock7 as a critical regulator of both cortical and trabecular bone mass, and demonstrate for the first time a novel role of Dock7 in modulating compensatory changes in the periosteum with aging. Show less

Fetal organs require much lipid for growth, but the cord blood had low TG concentrations, compared to adult serum. We investigated the association between the concentration of apolipoprotein A-V (apoA-V) and lipid profile in cord blood and neonatal serum. ApoA-V was identified as an important determinant of plasma triglyceride concentrations. We sought to determine the association between serum apoA-V concentrations and lipoprotein profile in preterm infants and its early postnatal change. Sixty-three neonates (35 males and 28 females; 15 term and 48 preterm) were included. Serum lipoprotein profile and apoA-V concentrations were determined at birth and 1 month. Cord blood apoA-V concentrations in appropriate-for-gestational age infants were extremely low (13.1 ± 3.4 ng/mL in term infants, 4.4 ± 0.9 ng/mL in preterm infants) compared with adult values, and those of small-for-gestational age infants were further low (6.4 ± 4.2 ng/mL, 2.2 ± 1.3 ng/mL, respectively). During the first month, serum apoA-V concentration markedly increased, and the concentration of preterm appropriate-for-gestational age infants caught up, whereas that of preterm small-for-gestational age infants did not. At birth, apoA-V concentration positively correlated with gestational age (r = 0.354, P = .0069) but not with birth weight Z-score. ApoA-V concentration had a positive association with very low-density lipoprotein triglyceride concentrations (r = 0.646, P < .0001), and the relationships still remained at 1 month (r = 0.283, P = .0348). ApoA-V in neonates was unique in its serum concentration and in the association with lipoprotein profile. Show less

The incidence of advanced hepatocellular carcinoma (HCC) is increasing worldwide, and its prognosis is extremely poor. Interferon-alpha (IFN-α)/5-fluorouracil (5-FU) therapy is reportedly effective in some HCC patients. In the present study, to improve HCC prognosis, we identified the genes that are sensitizing to these agents. The screening strategy was dependent on the concentration of ribozymes that rendered HepG2 cells resistant to 5-FU by the repeated transfection of ribozymes into the cells. After 10 cycles of transfection, which was initiated by 5,902,875 sequences of a ribozyme library, three genes including protein kinase, adenosine monophosphate (AMP)-activated, gamma 2 non-catalytic subunit (PRKAG2); transforming growth factor-beta receptor II (TGFBR2); and exostosin 1 (EXT1) were identified as 5-FU-sensitizing genes. Adenovirus-mediated transfer of TGFBR2 and EXT1 enhanced IFN-α/5-FU-induced cytotoxicity as well as 5-FU, although the overexpression of these genes in the absence of IFN-α/5-FU did not induce cell death. This effect was also observed in a tumor xenograft model. The mechanisms of TGFBR2 and EXT1 include activation of the TGF-β signal and induction of endoplasmic reticulum stress, resulting in apoptosis. In HCC patients treated with IFN-α/5-FU therapy, the PRKAG2 mRNA level in HCC tissues was positively correlated with survival period, suggesting that PRKAG2 enhances the effect of IFN-α/5-FU and serves as a prognostic marker for IFN-α/5-FU therapy. In conclusion, we identified three genes that chemosensitize the effects of 5-FU and IFN-α/5-FU on HCC cells and demonstrated that PRKAG2 mRNA can serve as a prognostic marker for IFN-α/5-FU therapy. Show less

Apolipoprotein A-V (apoA-V) is a recently discovered apolipoprotein that appears to have a role in plasma triglyceride (TG) transport. We have developed an ELISA for apoA-V using monoclonal antibodies that has a lower limit of detection of 0.3 ng/ml and linearity up to 20 ng/ml. The ELISA was then used to quantify plasma apoA-V in 196 healthy subjects and 106 patients with insulin-resistant diabetes mellitus. In the healthy subjects, total apoA-V concentration was 179.2 +/- 74.8 ng/ml, and it was greater in females than in males (P < 0.005). It was correlated positively with the plasma HDL cholesterol (r = 0.32, P < 0.0001), apoA-I (r = 0.27, P = 0.0001), and apoE (r = 0.18, P = 0.011) concentrations and negatively with plasma TG concentration (r = -0.22, P = 0.021). In relation to single nucleotide polymorphism 3 (-1131C/T) of the apoA-V gene, apoA-V concentration was higher in the T/T type than in the C/C type (P < 0.01). Plasma TG concentration was lower in the T/T type than in the C/C or C/T type (P < 0.05). ApoA-V concentration was lower in the diabetic patients (69.4 +/- 44.3 ng/ml; P < 0.01) than in the healthy controls. Show less