Search Results (156)

Adrenomedullin (AM) is a bioactive peptide that is strongly induced during severe inflammation, including pneumonia and sepsis, and serves as an organ-protective factor. The plasma concentration of AM is markedly increased in the novel coronavirus disease COVID-19 and is closely related to the severity of the disease and prognosis of patients. We performed two investigator-initiated trials to evaluate the efficacy and safety of AM in patients with moderate-to-severe COVID-19. This multicenter, double-blind, placebo-controlled phase-2a trial evaluated COVID-19 patients with severe (n = 33) and moderate (n = 31) pneumonia in Japan. Patients were randomly assigned to receive either 15 ng/kg/min AM or placebo. The primary endpoint was the duration of mechanical ventilation (MV) for severe pneumonia and oxygen support for moderate pneumonia. The main secondary endpoint was clinical status up to 30 days after the intervention. No differences in primary or secondary endpoints were observed between the AM and placebo groups in patients with severe or moderate pneumonia. In the severe pneumonia group, three patients in the placebo group died due to respiratory failure, and one patient in the AM group died due to respiratory failure. The respiratory function test at 30 days in the moderate pneumonia group tended to be better than that in the AM group and approached significance (p = 0.073). Although mild adverse events caused by the vasodilatory effects of AM were noted, the safety of AM for treating pneumonia was confirmed. In these trials, we did not observe a definitive efficacy of AM in moderate to severe pneumonia. Alternative strategies for the treatment of AM in pneumonia require further research. Full article

Background/Objectives: Prolonged use of denosumab in patients with metastatic breast cancer has raised concerns about the development of medication-related osteonecrosis of the jaw (MRONJ). However, the threshold at which the risk increases remains unclear. Methods: This retrospective cohort study analyzed patients with breast cancer and bone metastases who received denosumab between May 2012 and August 2024. Associations between cumulative denosumab administration and MRONJ were evaluated using univariate and multivariate logistic regression analyses. A receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff for cumulative doses. Results: MRONJ developed in 101 patients (31.2%). Multivariate analysis identified cumulative denosumab administration (odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.03–1.06; p < 0.001) and a history of tooth extraction (OR: 4.40, 95% CI: 2.23–8.71; p < 0.001) as independent risk factors for MRONJ. ROC analysis determined an optimal cutoff of 32 cumulative doses, with an area under the curve of 0.83 (95% CI: 0.78–0.88; p < 0.0001). Conclusions: Cumulative denosumab administration and history of tooth extraction were independent risk factors for MRONJ in patients with breast cancer and bone metastases. The risk of MRONJ increased after 32 cumulative doses, providing a clinically actionable threshold for risk assessment and patient monitoring. Full article

Background/Objectives: While sodium–glucose cotransporter 2 (SGLT2) inhibitors have demonstrated additional non-glycemic benefits for renal protection in individuals with type 2 diabetes, less evidence is available for those with type 1 diabetes (T1D). To determine whether the adjunctive use of the SGLT2 inhibitor ipragliflozin confers kidney protection in individuals with T1D, we retrospectively analyzed data from a real-world cohort examined at 25 centers in Japan. Methods: We enrolled 359 subjects aged 20–74 years with T1D (IPRA group: 159 ipragliflozin users; control [CTRL] group: 200 non-users). The primary outcome was changes in the estimated glomerular filtration rate (eGFR) from baseline to 24 months after the initiation of ipragliflozin. The secondary outcomes were all other changes, including the urinary albumin–creatinine ratio (UACR) and urinary protein–creatinine ratio (UPCR). Results: The IPRA group’s eGFR decline slopes were 0.79 mL/min/1.73 m²/year milder than the CTRL group’s after propensity score matching, but this difference was not significant. The subjects complicated by chronic kidney disease (CKD) defined as UACR ≥ 30 mg/g and/or UPCR ≥ 0.5 g/g and/or eGFR < 60 mL/min/1.73 m² showed changes in UPCR (g/g) from baseline to 24 months that were significantly lower in the IPRA group (−0.27 ± 1.63) versus the CTRL group (0.18 ± 0.36) (p = 0.016). No significant increase in adverse events (including severe hypoglycemia and hospitalization due to ketosis/ketoacidosis or cardiovascular diseases) was observed in the IPRA group. Conclusions: Adjunctive treatment with ipragliflozin exerted potential renal benefits by decreasing proteinuria in T1D subjects with CKD. Further investigations are required to determine whether its additional benefits exceed the increased risk of ketoacidosis. Full article

Background/Objectives: Hypoxic–ischemic encephalopathy (HIE), affecting 1.3–1.7/1000 live births, is treated with conventional therapeutic hypothermia (TH) but carries significant mortality and neurological impairment. Here, we compared intravascular cooling with extracorporeal membrane oxygenation (ECMO) and conventional TH in neonates with moderate to severe HIE. Methods: We retrospectively analyzed single-center neonates born in 2000–2022. Neonates with a 10 min Apgar score ≤ 3 or umbilical artery pH ≤ 6.7, along with persistent pulmonary hypertension of the newborn and an oxygenation index of ≥25 to <40, were divided into ECMO (n = 17) and conventional TH (n = 18) groups and administered the Kyoto Scale of Psychological Development at 18 months. Results: Neonatal and maternal characteristics were similar between the groups. A significantly higher proportion of the ECMO group (70.6% vs. 33.3%) achieved a developmental quotient ≥ 70. Conclusions: Intravascular cooling with ECMO may improve the neurodevelopmental outcomes of neonates with HIE, severe acidosis, and low Apgar scores. Full article

Hepatitis E virus (HEV) is a zoonotic pathogen with multiple hosts, posing significant public health risks, especially in regions like Japan where game meat consumption is prevalent. This study investigated HEV infection and viral shedding in wild boars, sika deer, and Japanese serows across Japan. A total of 1896 serum samples were tested for anti-HEV antibodies, 1034 for HEV RNA, and 473 fecal samples for viral shedding. Anti-HEV antibodies were detected in wild boars from all seven prefectures studied, while HEV RNA was detected in wild boars from Fukuoka, Oita, and Miyazaki in southern Japan, as well as Yamaguchi prefecture. Genetic analysis revealed subtypes 3b, 4a, and 4g, with 3b being the most prevalent. Subtype 3b exhibited distinct geographical clustering, whereas 4g persisted exclusively in Yamaguchi for over 12 years. Infectious HEV particles were confirmed in wild boar feces, highlighting the risk of environmental contamination and zoonotic transmission. Sika deer showed no evidence of HEV infection, and only one Japanese serow tested positive for antibodies without detectable RNA. These findings underscore the importance of ongoing surveillance to assess the zoonotic risks from game meat consumption and prevention of HEV transmission to humans. Full article

Background: Prescribing antiviral agents for severe acute respiratory syndrome coronavirus 2 requires careful consideration based on the patient’s risk factors for severe disease progression and their vaccination status. However, effective interventions ensuring the appropriate use of antiviral agents by physicians have yet to be fully established. Thus, this study evaluated the impact of an educational film on antiviral prescription rates for coronavirus disease 2019 (COVID-19). Methods: This prospective, nationwide, web-based survey enrolled 1500 physicians. They were instructed to view a short educational film and assess the necessity of prescribing antiviral agents in 16 fictitious scenarios featuring adult patients with COVID-19 with varying risk factors for severe disease and vaccination statuses. We compared the antiviral prescription rates before and after viewing the educational film. Results: There was a significant increase in the antiviral prescription rates after viewing the educational film, particularly nirmatrelvir/ritonavir prescribed in cases involving immunocompromised patients (from 31.3% to 49.4%) and those with obesity (from 15.1% to 33.7%) who were unvaccinated and had no risk of drug interactions. However, viewing the educational film made little to no impact on the prescription rates for the patients with hypertension and hyperlipidemia or those with no underlying conditions. Conclusions: Short educational films may promote the appropriate use of antiviral agents for COVID-19. However, their impact on altering prescription behavior appears limited and varies according to the clinical context. Full article

Background/Objectives: This study aimed to investigate the effectiveness of etanercept biosimilar 1 under real-world clinical conditions in patients with rheumatoid arthritis (RA), using not only clinical evaluation but also musculoskeletal ultrasound (MSUS). Methods: This multicenter, interventional, open-label, single-arm clinical trial conducted a 24-week follow-up. Patients with RA with moderate to high disease activity received weekly subcutaneous injections of etanercept biosimilar 1 at 50 mg/dose for 24 weeks. The effectiveness was evaluated with clinical indices and MSUS. Results: Twenty-three patients were evaluated during the study period. The primary endpoint involves a change in the Global OMERACT-EULAR Synovitis Score by MSUS in bilateral second–fifth metacarpophalangeal joints from baseline, demonstrating median (IQR) values of 0 (−4, 1), including 4 (1, 9.8) and 2 (0, 5) at baseline and 24 weeks, respectively. The clinical endpoints exhibited a good treatment response, with 15 (68%) and 18 (86%) patients achieving low disease activity or remission at 12 weeks and 24 weeks, respectively. Additionally, MSUS scores improved at both 12 and 24 weeks compared to baseline. The patients who achieved power doppler remission (total power doppler score = 0) at 24 weeks demonstrated a shorter disease duration and no previous use of biological disease-modifying antirheumatic drugs compared to those with no power doppler remission. Conclusions: Etanercept biosimilar 1 exhibited significant improvements not only in clinical indices but also in MSUS assessment, indicating its effectiveness at the structural level. Full article

Mammalian heme oxygenase (HO) catalyzes heme degradation using reducing equivalents supplied by NADPH–cytochrome P450 reductase (CPR). The tertiary structure of the catalytic domain of a constitutively expressed isoform of HO, HO-2, resembles that of the inductive isoform, HO-1, whereas HO-2 has two heme regulatory motifs (HRM) at the proximal portion of the C-terminus, where the disulfide linkage reflects cellular redox conditions and the second heme binding site is located. Here, we report the results of crosslinking experiments, which suggest that HRM is located near the FMN-binding domain of the CPR when it is complexed with HO-2. The enzymatic assay and reduction kinetics results suggest that heme-bound HRM negatively regulates HO-2 activity in vitro. Cellular redox conditions and free heme concentrations may regulate HO-2 activity. Full article

Background and Objectives: In previous studies, we reported that the assessment of the cumulative thermal dose in the crystalline lens, conducted through computational modeling utilizing a supercomputer and the biothermal transport equation, exhibited a significant association with the incidence of nuclear cataracts. In this study, we have investigated the types of proteins that expressed underlying 35.0 °C (normal-temp) and 37.5 °C (warming-temp) by using the shotgun liquid chromatography (LC) with tandem mass spectrometry (MS/MS)-based global proteomic approach. Materials and Methods: We have discussed the changes in protein expression in warmed iHLEC-NY2 cells using Gene Ontology analysis and a label-free semiquantitative method based on spectral counting. Results: In iHLEC-NY2, 615 proteins were detected, including 307 (49.9%) present in both lenses cultured at normal-temp and warming-temp, 130 (21.1%) unique to the lens cultured at normal-temp, and 178 (29.0%) unique to the lens cultured at warming-temp. Furthermore, LC–MS/MS analysis showed that warming decreased the expression of actin, alpha cardiac muscle 1, actin-related protein 2, putative tubulin-like protein alpha-4B, ubiquitin carboxyl-terminal hydrolase 17-like protein 1, ubiquitin-ribosomal protein eL40 fusion protein, ribosome biogenesis protein BMS1 homolog, histone H2B type 1-M, and histone H2A.J. in iHLEC-NY2. Conclusions: The decreases in the specific protein levels of actin, tubulin, ubiquitin, ribosomes, and histones may be related to cataract development under warming conditions. This investigation could provide a critical framework for understanding the correlation between temperature dynamics and the development of nuclear cataracts. Full article

Background: Current influenza A vaccines primarily induce neutralizing antibodies targeting the variable hemagglutinin (HA) head domain, limiting their effectiveness against diverse or emerging influenza A virus (IAV) subtypes. The conserved HA stem domain, particularly the long α-helix (LAH) epitope, is a focus of universal vaccine research due to its cross-protective potential. Additionally, Fc-mediated functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are recognized as important protective immune mechanisms. This study evaluated IgG responses to the HA head, stem, and LAH regions and assessed cross-reactive potential through neutralization, ADCC, and ADCP assays. Methods: IgG responses to the HA head, stem, and LAH regions were measured in vaccinated individuals. Functional assays were conducted for neutralization, ADCC, and ADCP to evaluate the association between antibody levels and immune function. Results: The results showed that HA head-specific IgG increased significantly after vaccination in 50 individuals, whereas stem-specific IgG increased by 72% and LAH-specific IgG by 12–14%. Among the induced antibody subclasses, IgG1 was predominantly increased. Neutralization titers were detected in viruses of the same strain as the vaccine strain, but not in classical or pandemic strains (H5N1, H7N9). HA stem-specific IgG1 antibody titers showed a significant correlation with ADCC/ADCP activity breadth, but no correlation was observed with neutralization breadth. Conclusions: These findings suggest that although current influenza vaccines can induce HA stem-targeted cross-reactive antibodies, their quantity may be insufficient for broad cross-protection, underscoring the need for improved vaccine strategies. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important common comorbidity in subjects with type 2 diabetes, and liver fibrosis is a factor directly related to its prognosis. Glucagon-like peptide-1 receptor agonists are useful treatment options for MASLD; however, the efficacy of oral semaglutide in treating liver steatosis/fibrosis has not been fully elucidated. Methods: A secondary analysis of a multicenter, retrospective, observational study investigating the efficacy and safety of oral semaglutide in Japanese subjects with type 2 diabetes in a real-world clinical setting (the Sapporo-Oral SEMA study) was conducted. Subjects in the original cohort were divided into groups as follows: subjects with suspected MASLD (alanine aminotransferase > 30 U/L) were placed in an overall group; a subpopulation from an overall group at high risk for hepatic fibrosis (fibrosis-4 (FIB-4) index ≥ 1.3 or platelet count < 200,000/µL) was placed in a high-risk group; and the remaining subjects were placed in a low-risk group. Changes in the hepatic steatosis index and FIB-4 index after oral semaglutide induction were explored using a paired t-test or the Wilcoxon signed-rank test. Results: Overall, 169 subjects (including 131 that switched from other medications) were analyzed, and 67 and 102 subjects were selected for the high-risk and low-risk groups, respectively. Oral semaglutide significantly improved the hepatic steatosis index (from 46.1 to 44.6, p < 0.001) and FIB-4 index (from 1.04 to 0.96, p < 0.001) as well as several metabolic parameters in all cohorts. The efficacy of semaglutide in treating liver fibrosis was confirmed by the addition of, and switching from, existing agent groups. Furthermore, improvement in the FIB-4 index was significantly negatively correlated with the baseline FIB-4 index. Conclusions: The induction of oral semaglutide might be a useful treatment option for subjects with type 2 diabetes at high risk for liver fibrosis, even when switching from conventional medications for diabetes. Full article

Background: Cell-free DNA (cfDNA) is present in healthy individuals but is elevated in those undergoing physical exertion, trauma, sepsis, and certain cancers. Maintaining cfDNA concentrations is vital for immune homeostasis and preventing inflammatory responses. Understanding cfDNA release and clearance is essential for using cfDNA as a biomarker in clinical diagnostics. We focused on the fragment size of cfDNA and investigated cfDNA dynamics and half-life, particularly the 100–250 base pair fragments. Methods: Healthy, adult men (n = 5; age 40 ± 4.1 years) were subjected to a 30 min treadmill exercise. Blood samples were collected at 0, 5, 10, 15, 30, and 60 min post-exercise using PAXgene^® Blood ccfDNA tubes to stabilize and prevent nuclease-mediated cfDNA degradation and minimize genomic DNA contamination risk. The cfDNA concentration was measured using an electrophoresis-based technique (4150 TapeStation system) to quantify the concentration based on cfDNA fragment size. Results: The results showed a cfDNA half-life of 24.2 min, with a transient increase in 100–250 base pair cfDNA fragments post-exercise, likely due to nuclease activity. These levels rapidly reverted to the baseline within an hour. Conclusions: The rapid clearance of cfDNA underscores its potential as a biomarker for real-time disease monitoring and the evaluation of treatment efficacy. This study is expected to standardize cfDNA investigations, enhancing diagnosis and treatment monitoring across various disease conditions. Full article

Background: FOLFIRI (5-FU + leucovorin + irinotecan) plus ramucirumab is one of the standards in second-line metastatic colorectal cancer (CRC) patients progressing after treatment with oxaliplatin/fluoropyrimidine with bevacizumab, but there is no evidence on its efficacy without prior bevacizumab. Moreover, VEGF-D has not been confirmed as a predictive biomarker for ramucirumab’s efficacy, either. Methods: The RAINCLOUD study was a multicenter, single-arm, phase II trial conducted in Japan. Patients with recurrent CRC pretreated with fluoropyrimidine and oxaliplatin without bevacizumab were analyzed. The primary endpoint was progression-free survival (PFS). The secondary endpoints measured were overall survival (OS), overall response rate (ORR), and safety. Results: A total of 48 patients were enrolled from 15 sites between September 2017 and September 2020. Their median age was 63.5 years (25~77), 20.1% had a right-sided tumor, and 68.8% had RAS-mutant cancer. The median PFS was 8.9 months (90% CI: 6.3–11.8), so the primary endpoint was met. Their median OS and ORR were 22.3 months (95% CI: 17.4-NA) and 41.7% (95% CI: 4.9–7.6), respectively. An incidence of grade 3/4 adverse events that reached over 5% applied to neutropenia (44%), leucopenia (10%), and hypertension (8%). In the biomarker analysis, the serum VEGF-D levels post-treatment were higher than those pre-treatment, but the PFS in those with high VEGF-D levels trended towards being worse than that in those with low VEGF-D (7.6M/5.6M (p = 0.095; HR: 0.56)). Instead, those with low TSP-2 had a better PFS than those with high TSP-2 (7.5M/4.3M (p = 0.022; HR: 0.45)). Conclusions: Our data suggested that FOLFIRI plus ramucirumab was effective and tolerable for CRC refractory to fluoropyrimidine and oxaliplatin without anti-angiogenesis. Serum VEGF-D levels may not be predictive but TSP-2 may be a potential prognostic biomarker for ramucirumab’s efficacy. Full article

Recent studies have shown that long noncoding RNAs (lncRNAs) play pivotal roles in the development and progression of cancer. In the present study, we aimed to identify lncRNAs associated with lymph node metastasis in pancreatic ductal adenocarcinoma (PDAC). We analyzed data from The Cancer Genome Atlas (TCGA) database to screen for genes overexpressed in primary PDAC tumors with lymph node metastasis. Our screen revealed 740 genes potentially associated with lymph node metastasis, among which were multiple lncRNA genes located in the HOXA locus, including HOXA11-AS. Elevated expression of HOXA11-AS was associated with more advanced tumor stages and shorter overall survival in PDAC patients. HOXA11-AS knockdown suppressed proliferation and migration of PDAC cells. RNA-sequencing analysis revealed that HOXA11-AS knockdown upregulated interferon lambda (IFNL) family genes and downregulated high-mobility group box (HMGB) family genes in PDAC cells. Moreover, HMGB3 knockdown suppressed proliferation and migration by PDAC cells. These results suggest that HOXA11-AS contributes to PDAC progression, at least in part, through regulation of IFNL and HMGB family genes and that HOXA11 AS is a potential therapeutic target in PDAC. Full article

It is known that swift heavy ion (SHI) irradiation induces the shape elongation of metal nanoparticles (NPs) embedded in transparent insulators, which results in anisotropic optical absorption. Here, we report another type of the optical anisotropy induced in CaF₂ crystals without including intentionally embedded metal NPs. The CaF₂ samples were irradiated with 200 MeV Xe¹⁴⁺ ions with an incident angle of 45° from the surface normal. With the increasing fluence, an absorption band at ~550 nm, which is ascribed to Ca aggregates, increases both the intensity and the anisotropy. XTEM observation clarified the formation of the continuous line structures and the discontinuous NP chains parallel to the SHI beam. Numerical simulations of the optical absorption spectra suggested the NP chains but not the continuous line structures as the origin of the anisotropy. The optical anisotropy in CaF₂ irradiated with SHIs is different from the shape elongation of NPs. Full article