👤 Yoshinori L Doi

Physical inactivity strongly predicts poor prognosis in chronic obstructive pulmonary disease (COPD) but is often underrecognized. We investigated whether combining patient-reported outcomes (PROs) with myokine profiling enhances detection of inactivity in COPD. In this multicentre cross-sectional study, 73 patients with stable COPD underwent PRO assessment (modified Medical Research Council dyspnea scale (mMRC), dyspnea-specific PROs (PROMs-D), COPD Assessment Test (CAT), Shortness of Breath Daily Activities Questionnaire (SOBDA-Q), and Kihon Checklist (KCL)), serum myokine measurement, and accelerometer-based physical activity evaluation, stratified into 1.0-1.5 METs (low-intensity/sedentary), ≥ 3.0 METs (moderate), total activity (METs·h), and step count. Correlation and logistic regression analyses were performed. mMRC and PROMs-D correlated negatively with moderate activity and step count. Among myokines, growth differentiation factor-15 (GDF-15), fatty acid binding protein 3 (FABP3), and brain-derived neurotrophic factor (BDNF) showed moderate associations with physical activity: GDF-15 and BDNF with low-intensity, GDF-15 with moderate, and FABP3 and BDNF with step count. Combined PRO-myokine models outperformed single markers, with areas under the curve of 0.77 for low-intensity activity, 0.82 for moderate activity, and 0.86 for step count. In conclusion, integrating PROs and myokines improves the specificity and accuracy of inactivity detection in COPD. This multidimensional strategy may facilitate early, personalized interventions. Show less

Malignant phyllodes tumors (MPTs) are rare fibroepithelial breast tumors with no standard treatment for metastatic or recurrent cases. Comprehensive genomic profiling (CGP) has been conducted for MPT; however, its association with treatment remains unclear. A retrospective study was conducted on patients with advanced or recurrent MPTs treated with chemotherapy between 2013 and 2022 at two hospitals, analyzing clinical data, CGP, treatment outcomes, and survival. Five patients with metastatic MPTs who had received chemotherapy were identified. The median age was 55 years (range, 50-66), and all patients were female. As first-line treatment, four patients received doxorubicin plus ifosfamide (AI) combination therapy, while one received doxorubicin monotherapy. Among those treated with AI therapy, the best responses were partial response in three patients and stable disease in one. The median progression-free survival (PFS) for patients treated with AI therapy was 5.3 months. Of the five patients two proceeded to second-line therapy, and one patient received up to fourth-line treatment. Next-generation sequencing-based CGP testing was performed in four cases. One patient with an FGFR1-N546K-mutated MPT achieved a relatively long PFS of 6.8 months with pazopanib therapy, a multi-kinase inhibitor targeting FGFR1 among other kinases, as fourth-line therapy. AI therapy is useful for advanced or recurrent MPTs. The observed clinical benefit of pazopanib in a patient with FGFR1 N546K-mutated MPT suggests that FGFR1 kinase domain mutations may be a relevant factor in responsiveness of FGFR1-targeted therapy. Further data accumulation is warranted. Show less

Hospitalization-associated disability (HAD) is linked to poor post-discharge outcomes in older individuals with heart failure (HF). We investigated whether HAD could be predicted by physical activity measured using a wearable device. We retrospectively analyzed data from 104 older individuals with HF whose physical activity was recorded for 3 consecutive days after initiating cardiac rehabilitation. Physical activity was categorized as sedentary behavior (≤1.5 metabolic equivalents [METs]), light-intensity physical activity (LPA; 1.6-2.9 METs), and moderate-to-vigorous physical activity (≥3.0 METs). HAD was observed in 31 (29.8%) individuals. LPA duration was significantly shorter in the HAD than non-HAD group (mean [±SD] 45.7±24.9 vs. 121.2±67.4 min/day; P<0.0001). In receiver operating characteristic curve analysis, the optimal LPA cut-off was 68 min/day, with 87.1% sensitivity and 80.8% specificity (area under the curve=0.888; P<0.0001). Physical activity measured using a wearable device may be useful in predicting HAD in older individuals with HF. Show less

Aberrant fibroblast growth factor receptor (FGFR)-driven signaling, predominantly arising from FGFR2 amplification, plays a key role in gastric cancer pathogenesis. This open-label, phase 2 study evaluated the efficacy and safety of futibatinib, an irreversible FGFR1-4 inhibitor, in patients with gastric or gastroesophageal junction (GEJ) cancer harboring FGFR2 amplifications. Patients were treated with futibatinib 20 mg orally once daily in a 28-day cycle. The primary endpoint was objective response rate (ORR) per independent central review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Among 28 treated patients, the ORR per independent central review was 17.9 %, comprising five patients with a partial response (median duration of response, 3.9 months), and an additional nine patients with stable disease for a disease control rate of 50.0 %. Median PFS per independent central review and median OS were 2.9 and 5.9 months, respectively. The most common treatment-related adverse events (any grade) were hyperphosphatemia (89.3 %), decreased appetite (32.1 %), and increased aspartate aminotransferase (21.4 %). Only one (3.6 %) patient discontinued study treatment due to an adverse event. Futibatinib demonstrated modest antitumor activity with a safety profile consistent with previous reports in patients with gastric or GEJ cancer harboring FGFR2 amplifications, potentially warranting further investigation. Show less

Limited evidence exists on the role of lipoprotein(a) [Lp(a)] in the progression of atherosclerotic coronary plaques as assessed by intravascular imaging modality, particularly under low-density lipoprotein cholesterol (LDL-C) lowering therapy. In this study, we aimed to evaluate the clinical significance of Lp(a) as a residual risk factor for coronary plaque progression, using serial intravascular ultrasound (IVUS) in statin-treated patients with coronary artery disease (CAD). This observational cohort study included statin-treated patients from two clinical prospective trials (the ENTERPRISE trial and Extended-ESTABLISH trial) in which coronary plaques were assessed using serial grayscale IVUS at baseline and at 6-12 months follow-up. The primary endpoints were defined as absolute changes in normalized total atheroma volume (TAV Show less

Familial hypercholesterolemia (FH) causes corneal arcus (CA) and xanthomas via lipid particle deposition. Lipoprotein(a) [Lp(a)] consists of an apolipoproteinB100 and apolipoprotein(a). As apolipoprotein(a) accumulates within extracellular connective tissues, it may associate with CA and tendon xanthoma. To elucidate the association between elevated Lp(a) and FH-related physical features and evaluate their independent and joint prognostic utility on cardiovascular risk. We retrospectively analyzed 484 clinically diagnosed FH patients, evaluating both Lp(a) and physical features. Physical features were compared in individuals with and without Lp(a) ≥ 30 mg/dL. The occurrence of major adverse cardiovascular events (MACE = cardiovascular death + acute coronary syndrome + ischemic stroke) was compared in those stratified according to Lp(a) ≥ 30 mg/dL and physical features. The median value of Lp(a) was 18.4 mg/dL; subjects with Lp(a) ≥ 30 mg/dL were more likely to exhibit CA and greater Achilles tendon thickness (ATT). Receiver operating characteristic analysis suggested 14.0 mm as an optimal cut-off value of ATT predicting Lp(a) ≥ 30 mg/dL (C-statistic = 0.58). Even after adjusting for age, sex, untreated low-density lipoprotein cholesterol level, and FH-related pathogenic variants, the co-existence of CA and ATT ≥ 14.0 mm was independently associated with Lp(a) ≥30 mg/dL (odds ratio = 2.31; 95% CI = 1.22-4.38; P = .010). During a 15-year observational period (median = 1835 days), MACE occurred more frequently in subjects with Lp(a) ≥ 30 mg/dL (log-rank P = .026). This Lp(a)-associated cardiovascular risk was further elevated among those with both CA and ATT ≥ 14.0 mm (log-rank P = .042), whereas the presence of physical stigmata did not worsen cardiovascular outcome when Lp(a) was < 30 mg/dL. Assessment of CA and ATT in FH identifies those more likely to have higher Lp(a) levels. The presence of these triads is associated with the highest risk of MACE and potentially guides intensification of antiatherosclerotic therapies. Show less

FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1-4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0-1 (or equivalent for adolescents aged 12-17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%) were male. The data cutoff was Aug 15, 2022. At a median follow-up of 17·9 months (IQR 13·6-23·9), an objective response was observed in 64 (30% [95% CI 24-36]) of 217 patients across 16 distinct tumour types. The most common grade 3 or higher treatment-emergent adverse events related to erdafitinib were stomatitis (25 [12%]), palmar-plantar erythrodysaesthesia syndrome (12 [6%]), and hyperphosphataemia (11 [5%]). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis in four (2%) patients and diarrhoea in two (1%). There were no treatment-related deaths. RAGNAR results show clinical benefit for erdafitinib in the tumour-agnostic setting in patients with advanced solid tumours with susceptible FGFR alterations who have exhausted other treatment options. These results support the continued development of FGFR inhibitors in patients with advanced solid tumours. Janssen Research & Development. Show less

In diabetes mellitus (DM) patients, the morbidity of infectious disease is increased, and these infections can easily progress from local to systemic infection. Sepsis is a characteristic of organ failure related to microcirculation disorders resulting from endothelial cell injury, whose most frequent comorbidity in patients is DM. The aim of the present study was to evaluate the influence of infection on DM-induced microvascular damage on inflammation and pulmonary endothelial structure using an experimental endotoxemia model. Lipopolysaccharide (LPS; 15 mg/kg) was injected intraperitoneally into 10-week-old male C57BLKS/J Iar Show less

Hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in sarcomere genes. Regarding the clinical implications of genetic information, little is known about the lifelong clinical effect of sarcomere mutations in Japanese HCM patients. We studied 211 consecutive Japanese patients with HCM who had agreed to genetic testing between 2003 and 2013. Genetic analyses were performed by direct DNA sequencing in the 6 common sarcomere genes (MYH7,MYBPC3,TNNT2,TNNI3,TPM1,ACTC). Through variant filtering, 21 mutations were identified in 67 patients. After excluding 8 patients whose variants were determined as having uncertain significance, finally 203 patients (130 men, age at study entry: 61.8±14.1 years) were investigated for clinical presentation and course. At the time of study entry, patients with mutations were younger, had more frequent non-sustained ventricular tachycardia, had greater interventricular wall thickness, were more frequently in the dilated phase and less frequently had apical HCM. Through their lifetimes, a total of 98 HCM-related morbid events occurred in 72 patients. Survival analysis revealed that patients with sarcomere gene mutations experienced those morbid events significantly more frequently, and this tendency was more prominent for lethal arrhythmic events. In our HCM cohort, patients with sarcomere gene mutations had poorer lifelong outcome. Genetic information is considered important for better management of HCM. Show less

Hypertrophic cardiomyopathy (HCM), which is inherited as an autosomal dominant trait, is the most prevalent hereditary cardiac disease. Although there are several reports on the systematic screening of mutations in the disease-causing genes in European and American populations, only limited information is available for Asian populations, including Japanese. Genetic screening of disease-associated mutations in 8 genes for sarcomeric proteins, MYH7, MYBPC3, MYL2, MYL3, TNNT2, TNNI3, TPM1, and ACTC, was performed by direct sequencing in 112 unrelated Japanese proband patients with familial HCM; 37 different mutations, including 13 novel ones in 5 genes, MYH7, MYBPC3, TNNT2, TNNI3, and TPM1, were identified in 49 (43.8%) patients. Among them, 3 carried compound heterozygous mutations in MYBPC3 or TNNT2. The frequency of patients carrying the MYBPC3, MYH7, and TNNT2 mutations were 19.6%, 10.7%, and 8.9%, respectively, and the most frequently affected genes in the northeastern and southwestern parts of Japan were MYBPC3 and MYH7, respectively. Several mutations were found in multiple unrelated proband patients, for which the geographic distribution suggested founder effects of the mutations. This study demonstrated the frequency and distribution of mutations in a large cohort of familial HCM in Japan. Show less

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal-dominant pattern of inheritance mainly caused by single heterozygous mutations in sarcomere genes. Although multiple gene mutations have recently been reported in Western countries, clinical implications of multiple mutations in Japanese subjects are not clear. A comprehensive genetic analysis of 5 sarcomere genes (cardiac β-myosin heavy chain gene [MYH7], cardiac myosin-binding protein C gene [MYBPC3], cardiac troponin T gene [TNNT2], α-tropomyosin gene [TPM1] and cardiac troponin I gene [TNNI3]) was performed in 93 unrelated patients and 14 mutations were identified in 28 patients. Twenty-six patients had single heterozygosity (20 in MYBPC3, 4 in MYH7, 1 in TNNT2, 1 in TNNI3), whereas 2 proband patients with familial HCM had double heterozygosity: 1 with P106fs in MYBPC3 and R869C in MYH7 and 1 with R945fs in MYBPC3 and E1049D in MYH7. From the results of the family survey and the previous literature on HCM mutations, P106fs, R945fs and R869C seemed to be pathological mutations and E1049D might be a rare polymorphism. The proband patient with P106fs and R869C double mutation was diagnosed as having HCM at an earlier age (28 years of age) than her relatives with single mutation, and had greater wall thickness with left ventricular outflow obstruction. One double mutation was identified in a Japanese cohort of HCM patients. Further studies are needed to clarify the clinical significance of multiple mutations including phenotypic severity. Show less

Mutations in the cardiac myosin-binding protein C gene (MYBPC3) have been reported to be associated with delayed expression of hypertrophic cardiomyopathy (HCM) and a relatively good prognosis. The aim of this study was to evaluate clinical manifestations in patients with familial HCM caused by a novel nonsense mutation, S297X, in MYBPC3. We analyzed the sarcomere protein genes in 93 probands with HCM. The nonsense mutation S297X in MYBPC3 was present in nine subjects from two unrelated families. Eight of those nine subjects with this mutation were found to be phenotype-positive and the remaining individual was not affected phenotypically. The age range at diagnosis was 9-75 years. There was no family history of sudden death in either family. At presentation, there were various left ventricular hypertrophy (LVH) patterns, including Maron type III hypertrophy from the LV base to apex, hypertrophy confined to the anterolateral wall at the basal LV wall. Two patients showed a significant LV outflow tract gradient and one patient showed intra-right-ventricular obstruction. During follow-up, one patient was repeatedly hospitalized for the treatment of heart failure after development of paroxysmal atrial fibrillation at the age of 86 years and the remaining eight subjects were in relatively stable condition and did not require hospitalization for the treatment of HCM-related events. The novel mutation S297X in MYBPC3 causes HCM in a broad range of ages and heterogeneous clinical manifestations, though the clinical course in patients with this mutation seems to be benign. Show less

Bone marrow- (BM-) derived cells can differentiate into smooth muscle-like cells (SMLC), resulting in vascular pathogenesis. However, the molecular mechanism of the differentiation remains unknown. We have recently reported that Notch signaling promotes while a Notch target HERP1 inhibit the differentiation of mesenchymal cells to SMC. During the differentiation of BM-derived mononuclear cells into smooth muscle alpha-actin (SMA)-positive cells, expression of Jagged1 and SMC-specific Notch3 was increased. Blocking Notch with gamma-secretase inhibitor prevented the induction of SMA. Wire-mediated vascular injury was produced in femoral arteries in mice transplanted with green fluorescent protein (GFP)-positive cells. Many double-positive cells for GFP/Jagged1 or GFP/Notch3 were detected in the thickened neointima. In contrast, only a few SMA-positive cells were positive for GFP in neointima where HERP1, a suppressor for Notch, were abundantly expressed. In conclusion, Notch-HERP1 pathway plays an important role in differentiation of BM-derived mononuclear cells into SMLC. Show less

Myocardin is a coactivator of serum response factor (SRF) required for vascular smooth muscle cell (VSMC) differentiation. HERP1 is a transcriptional repressor, which is abundantly expressed in vascular system and is known to function as a target gene of Notch. However, the role of HERP1 in the pathogenesis of vascular lesions remains unknown. The present study characterizes the expression of HERP1 in normal and diseased vessels, and tests the hypothesis that HERP1 inhibits SRF/myocardin-dependent SMC gene expression. Immunohistochemistry revealed that HERP1 and myocardin expression was localized to SMC in the neointima of balloon-injured rat aorta and in human coronary atherosclerotic lesions. Expression of both HERP1 and myocardin was elevated in cultured VSMCs compared with medial SMC. Overexpressed HERP1 inhibited the myocardin-induced SMC marker gene expression in 10T1/2 cells. HERP1 protein interfered with the SRF/CArG-box interaction in vivo and in vitro. Immunoprecipitation assays showed that HERP1 physically interacts with SRF. HERP1 expression was associated with the SMC proliferation and dedifferentiation in vitro and in vivo. HERP1 may play a role in promoting the phenotypic modulation of VSMCs during vascular injury and atherosclerotic process by interfering with SRF binding to CArG-box through physical association between HERP1 and SRF. Show less

This review discusses the regulation of the intestinal and hypothalamic apolipoprotein A-IV (apo A-IV) gene and protein expression. Apo A-IV is a glycoprotein secreted together with triglyceride-rich lipoproteins by the small intestine. Intestinal apo A-IV synthesis is stimulated by fat absorption, probably mediated by chylomicron formation. This stimulation of intestinal apo A-IV synthesis is attenuated by intravenous leptin infusion. Chronic ingestion of a high-fat diet blunts the intestinal apo A-IV in response to dietary lipid. Intestinal apo A-IV synthesis is also stimulated by members of the pancreatic polypeptide family, including peptide YY (PYY), neuropeptide Y (NPY), and pancreatic polypeptide (PP). Recently, apo A-IV was demonstrated to be present in the hypothalamus as well. Hypothalamic apo A-IV level was reduced by food deprivation and restored by lipid feeding. Intracerebroventricular administration of apo A-IV antiserum stimulated feeding and decreased the hypothalamic apo A-IV mRNA level, implying that feeding is intimately regulated by endogenous hypothalamic apo A-IV. Central administration of NPY significantly increased hypothalamic apo A-IV mRNA levels in a dose-dependent manner. Show less

Apolipoprotein AIV (apo AIV) is a circulating signal released from intestinal cells in response to lipid feeding and contributes to the anorectic effect of a lipid meal. We have demonstrated that apo AIV is also synthesized in the hypothalamus, and that hypothalamic apo AIV gene expression is regulated physiologically. Neuropeptide Y (NPY) is a hypothalamic neuropeptide with broad regulatory actions in the central nervous system. In the present studies, the effects of intracerebroventricular (i.v.t.) administration of NPY and of intraduodenal lipid infusion on hypothalamic apo AIV gene expression were determined using competitive RT-PCR in fasted rats. I.v.t. injection of NPY alone significantly increased apo AIV mRNA levels in the hypothalamus in a dose-dependent manner. Intraduodenal infusion of lipid also stimulated the gene expression of hypothalamic apo AIV, but no further significant increment occurred when i.v.t. injection of NPY was combined with lipid infusion. These results suggest that NPY and lipid may regulate apo AIV gene expression in the rat hypothalamus. Show less

We determined apolipoprotein AIV (apo AIV) content in intestinal epithelial cells using immunohistochemistry when leptin was administered intravenously. Most of the apo AIV immunoreactivity in the untreated intestine was located in the villous cells as opposed to the crypt cells. Regional distribution of apo AIV immunostaining revealed low apo AIV content in the duodenum and high content in the jejunum that gradually decreases caudally toward the ileum. Intraduodenal infusion of lipid (4 h) significantly increased apo AIV immunoreactivity in the jejunum and ileum. Simultaneous intravenous leptin infusion plus duodenal lipid infusion markedly suppressed apo AIV immunoreactivity. Duodenal lipid infusion increased plasma apo AIV significantly (measured by ELISA), whereas simultaneous leptin infusion attenuated the increase. These findings suggest that leptin may regulate circulating apo AIV by suppressing apo AIV synthesis in the small intestine. Show less

Apolipoprotein AIV (apo AIV) is a satiety protein secreted by the small intestine. We demonstrate for the first time that apo AIV protein and apo AIV mRNA are present in rat hypothalamus, a site intimately involved in the integration of signals for regulation of food intake and energy metabolism. We further characterized the regulation of hypothalamic apo AIV mRNA levels. Food-deprived animals showed a pronounced decrease in gene expression of apo AIV in the hypothalamus, with a concomitant decrease in the jejunum. Refeeding fasted rats with standard laboratory chow for 4 h evokes a significant increase of apo AIV mRNA in jejunum but not in hypothalamus. However, lipid refeeding to the fasted animals restored apo AIV mRNA levels both in hypothalamus and jejunum. Intracerebroventricular administration of apo AIV antiserum not only stimulated feeding, but also decreased apo AIV mRNA level in the hypothalamus. These data further confirm the central role of apo AIV in the regulation of food intake. Show less