Search Results (282)

Background/Objectives: We define severe postpartum hemorrhage (PPH) with macroscopic hematuria as clinical disseminated intravascular coagulation (DIC), a life-threatening condition. We also report a methodology using machine learning, a subtype of artificial intelligence, for developing the boundary criterion for predicting hematuria on the fibrinogen–fibrin/fibrinogen degradation product (FDP) plane. A positive FDP–fibrinogen/3–60 (mg/dL) value indicates hematuria; otherwise, non-hematuria is observed. We aimed to validate this criterion using severe placental abruption (PA), and to examine the activation of the coagulation–fibrinolytic system in clinical DIC. Methods: Of 17,285 deliveries across nine perinatal centers in Japan between 2020 and 2024, 13 had severe PA without hematuria, 18 had severe PPH without hematuria, and 3 had severe PPH with hematuria, i.e., clinical DIC. We calculated the values of the criterion formula for 13 cases of severe PA to validate the boundary criterion and compared the laboratory tests for coagulation–fibrinolytic activation among the three groups. Results: The calculated values using the criterion for the 13 PA without hematuria ranged from −108.91 to −5.87 and all were negative. In cases of clinical DIC, fibrinogen levels (median, 62 mg/dL) were lower (p < 0.05), while levels of FDP (96 mg/dL), the thrombin–antithrombin complex (120 ng/mL), and the plasmin-α₂–plasmin inhibitor complex (28.4 μg/mL) were significantly higher than in the other two groups. Conclusions: This study demonstrated the validity of the boundary criterion for predicting hematuria using severe PA. The coagulation–fibrinolytic test results suggested that PPH cases with hematuria were assumed to have clinical DIC, indicating that this criterion may be considered for diagnosing DIC during delivery. However, further additional patient data are needed to confirm the usefulness of this criterion because of the very low number of hematuria cases. Full article

Background: This Phase 2 trial evaluated the efficacy, tolerability, and safety of [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) in patients with ≥1 measurable lesion and progressive prostate-specific membrane antigen-positive (PSMA+) metastatic castration-resistant prostate cancer (mCRPC) in Japan. Methods: This study comprises four parts; data from three parts are presented here. Part 1 evaluated safety and tolerability; Parts 2 (post-taxane) and 3 (pre-taxane/taxane-naive) assessed the overall response rate (ORR; primary endpoint), overall survival (OS), radiographic progression-free survival (rPFS), disease control rate (DCR), PFS, and safety; and Part 4 is the expansion part. Patients received 7.4 GBq (±10%) ¹⁷⁷Lu-PSMA-617 Q6W for up to six cycles. Results: Of the 35 patients who underwent a [⁶⁸Ga]Ga-PSMA-11 (⁶⁸Ga-PSMA-11) PET/CT scan, 30 received ¹⁷⁷Lu-PSMA-617 (post-taxane, n = 12; pre-taxane, n = 18). No dose-limiting toxicity was noted in Part 1 (n = 3). Post- and pre-taxane patients had a median of three and five cycles, respectively. The primary endpoint, ORR, met the pre-specified threshold, with the lower limit of the 90% confidence interval (CI) above the threshold of 5% for post-taxane and 12% for pre-taxane. Post- and pre-taxane patients had an ORR of 25.0% (90% CI: 7.2–52.7) and 33.3% (90% CI: 15.6–55.4), respectively. In post- and pre-taxane patients, the DCR was 91.7% and 83.3%, the median rPFS was 3.71 and 12.25 months, and the median PFS was 3.71 and 5.59 months, respectively. The median OS was 14.42 and 12.94 months in post- and pre-taxane patients, respectively. The most common adverse events were constipation, decreased appetite, decreased platelet count, anemia, and nausea. Conclusions: The primary endpoint (ORR) was met. The safety profile of ¹⁷⁷Lu-PSMA-617 was consistent with the VISION and PSMAfore studies, with no new safety signals in the Japanese patients with mCRPC. Full article

Persistent SARS-CoV-2 infections involve prolonged viral replication and immune system interactions, potentially driving viral evolution and immune escape. This study examines viral characteristics and host gene expression changes in persistent infections. The nasopharyngeal samples from four patients with persistent SARS-CoV-2 infections at Tottori University Hospital, Japan, were analyzed. Viral isolates were cultured, and infectivity was assessed using TCID₅₀ assays. To investigate host responses, RNA sequencing (RNA-seq) was performed to identify differentially expressed genes (DEGs), and Gene Ontology (GO) enrichment analysis mapped affected biological pathways. Viral genome sequencing detected mutations associated with prolonged infection. The results showed significant infectivity differences between early- and late-phase infection. Gene expression analysis revealed a strong early phase of pro-inflammatory response (IL6, TNF, IL1B, CXCL10) followed by immune suppression. GO enrichment analysis highlighted inflammation and cytokine-mediated immune pathways. Genomic sequencing identified mutations in ORF1ab and the spike (S) protein, potentially aiding immune escape. The findings underscore that SARS-CoV-2 adapts during persistent infections, altering infectivity and immune responses. These highlight the need for continued monitoring of prolonged infections to mitigate immune escape and viral evolution. Full article

Background/Objectives: There is still no clear consensus regarding the efficacy of exercise interventions in maintaining or improving cognitive function among independent older adults, as well as individuals with mild cognitive impairment (MCI) or dementia. This review explores the potential mechanisms underlying cognitive decline prevention and dementia mitigation from the perspective of motor learning theory, with a particular focus on aerobic-oriented open-skill exercise (OSE) and electronic sports (e-sports). Methods: Comprehensive literature searches were conducted using databases such as PubMed, Scopus, Web of Science, CiNii, and J-Stage (all available years) to identify studies examining the relationship between OSE, e-sports, and cognitive function. Results: Although various intervention studies have investigated aerobic exercise, resistance training, and other multifactorial exercise programs, a unified conclusion has not been reached regarding their effectiveness in enhancing cognitive function in the general elderly population or in patients with MCI or dementia. However, sports involving dynamic interaction with opponents (OSE) have shown a positive association with the maintenance and enhancement of cognitive abilities. Furthermore, e-sports present an accessible exercise modality, unrestricted by age, gender, time, or location, and are expected to support cognitive health in older adults. Conclusions: Aerobic-oriented OSE appears more effective than closed-skill exercise in preventing age-related cognitive decline and dementia. Additionally, e-sports may offer a comprehensive approach to brain health by integrating cognitive stimulation, physical engagement, social interaction, and stress reduction, though caution is advised regarding potential mental health concerns stemming from excessive use. Full article

UL16-binding protein 2 (ULBP2), a ligand for the activating receptor NKG2D, plays a dual role in tumor immunity, promoting immune activation or suppression, depending on the context. To investigate its impact on CD4⁺CD25⁺ T cell-targeted immunotherapies, we used a syngeneic CT26 colon cancer model engineered to express ULBP2 and compared tumor growth and tumor-infiltrating lymphocyte (TIL) profiles in control and ULBP2-expressing tumors treated with anti-CD4, anti-CD25, or anti-CTLA-4 antibodies. Tumor growth was uniformly assessed on day 21 post-transplantation, and TIL analysis was performed in groups with evaluable residual tumors. Anti-CD4 antibody significantly suppressed tumor growth in mock-transfected tumors, while no significant suppression was observed in ULBP2-expressing tumors. Anti-CD25 antibody had limited efficacy in mock tumors and tended to promote tumor growth in ULBP2-expressing tumors. Following these treatments, ULBP2 expression was associated with reduced NKG2D expression in CD8⁺ effector memory T cells, particularly PD-1^high subsets. In contrast, anti-CTLA-4 antibody treatment induced marked tumor regression irrespective of ULBP2 expression. These findings suggest that ULBP2–NKG2D signaling may contribute to altered CD8⁺ T cell phenotypes under T cell-modulatory conditions, potentially impacting the outcome of CD4⁺CD25⁺ T cell-targeted therapies and providing insights for optimizing immunotherapeutic strategies. Full article

Hans Selye’s stress concept, first introduced in the 1930s, has undergone substantial evolution, extending beyond biology and medicine to influence diverse academic disciplines. Initially, Selye’s General Adaptation Syndrome (GAS) described nonspecific physiological responses to stressors exclusively in mammals, without addressing other biological systems. Consequently, the concept of stress developed independently in biology and medicine, shaped by distinct physiological contexts. This review provides a historical overview of stress research, highlights both parallels and divergences between the stress responses of plants and animals, and integrates insights from traditional Eastern philosophies. We propose an updated GAS framework that incorporates the dynamic balance among reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) within the broader context of oxidative stress. We highlight the ionotropic glutamate receptor (iGluR) family and the transient receptor potential (TRP) channel superfamily as minimal molecular architectures for achieving GAS. This perspective expands the classical stress paradigm, providing new insights into redox biology, interspecies stress adaptation, and evolutionary physiology. 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

The electric field enhancement effect induced by localized surface plasmon resonance (LSPR) plays a critical role in imaging and sensing applications. In particular, nanocube structures with narrow gaps provide large hotspot areas, making them highly promising for high-sensitivity applications. This study predicts the electric field enhancement effect of structures combining silver nanocubes and a 10 nm thick silver thin film using the finite-difference time-domain (FDTD) method. We demonstrate that the interaction between the silver nanocubes and silver thin film allows control over sharp LSPR peaks in the visible wavelength range. Specifically, the structure with a spacer layer between the silver nanocubes and the silver thin film is suitable for multimodal imaging, while the direct contact structure of the silver nanocubes and the silver thin film shows potential as a highly sensitive refractive index sensor. The 10 nm thick silver thin film enables backside illumination due to its transparency in the visible wavelength region, making it compatible with inverted microscopes and allowing for versatile applications, such as living cell imaging and observations in liquid media. These structures are particularly expected to contribute to advancements in bioimaging and biosensing. Full article

Microglia and macrophages are critical mediators of immune responses in the central nervous system. Their roles range from homeostatic maintenance to the pathogenesis of autoimmune demyelinating diseases such as multiple sclerosis and neuromyelitis optica spectrum disorder. This review explores the origins of microglia and macrophages, as well as their mechanisms of activation, interactions with other neural cells, and contributions to disease progression and repair processes. It also highlights the translational relevance of insights gained from animal models and the therapeutic potential of targeting microglial and macrophage activity in multiple sclerosis and neuromyelitis optica spectrum disorder. Full article

UL-16 binding protein 2 (ULBP2), a human NKG2D ligand, has been identified as a poor prognostic factor in several cancers based on recent comprehensive analyses of immune-related genes using the Cancer Genome Atlas datasets. Despite its clinical significance, the functional role of ULBP2 in vivo remains largely unknown. In this study, we investigated the role of ULBP2 in modulating anti-tumor immunity using murine melanoma cell lines engineered to stably express surface-expressed or soluble ULBP2. Subcutaneous transplantation of ULBP2-expressing melanoma cells into syngeneic mice resulted in accelerated tumor growth, mediated by surface-expressed ULBP2, through the suppression of NKG2D-dependent immune responses. In vitro experiments revealed that sustained exposure to tumor-expressed ULBP2 reduced NKG2D expression and cytotoxic activity of splenocytes. In contrast, soluble ULBP2 did not significantly affect tumor growth or immune responses. These findings suggest that surface-expressed ULBP2 plays a pivotal role in tumor immune evasion and highlight its potential as a therapeutic target to enhance anti-tumor immunity. Full article

Background/Objectives: The effectiveness of robot-assisted radical prostatectomy (RARP) with extended pelvic lymph node dissection (ePLND) in improving oncological outcomes for patients with high- or very-high-risk prostate cancer (HR/VHR-PCa) remains a subject of debate. This study aimed to compare the efficacy of neoadjuvant chemohormonal therapy (NCHT) and ePLND in reducing biochemical recurrence (BCR) in patients with HR/VHR-PCa undergoing RARP. Methods: This retrospective, multicenter cohort study included 1182 patients with HR/VHR-PCa who underwent RARP at six Japanese institutions. Patients were stratified into three groups: those who received NCHT followed by RARP without ePLND (Group 1), those who received neoadjuvant hormonal therapy (NHT) followed by RARP with ePLND (Group 2), and those who underwent RARP with ePLND (Group 3). The primary endpoint was the rate of BCR, while the secondary endpoint was biochemical recurrence-free survival (BRFS) following RARP. Results: Of the 1182 patients, 154 patients were included in Group 1, 97 patients were included in Group 2, and 470 patients were included in Group 3. By the end of the follow-up period, 243 patients (33.8%) had experienced BCR, 27 (3.7%) had progressed to castration-resistant prostate cancer, and 5 (0.7%) had died from PCa. Over a median follow-up period of 41.4 months, BCR occurred in 16.5% of patients in Group 1, 36.1% of patients in Group 2, and 38.9% in Group 3 (p < 0.001). The 3-year BRFS rate was 63.6% in Group 1, 53.1% in Group 2, and 63.9% in Group 3. Conclusions: The findings of this study indicate that NCHT in patients with HR/VHR-PCa undergoing RARP without ePLND may reduce the risk of postoperative BCR compared to those undergoing RARP with ePLND. Full article

Changes in the level of metabolites, small molecules that are intermediates produced by metabolism or catabolism, are associated with developing diseases. Metabolite signatures in body fluids such as plasma, cerebrospinal fluid, urine, and saliva are associated with Parkinson’s disease. Here, we discuss alteration of metabolites in the TCA cycle, pentose phosphate pathway, kynurenic network, and redox system. We also summarize the efforts of many research groups to differentiate between metabolite profiles that characterize PD motor progression and dyskinesia, gait and balance, and non-motor symptoms such as depression and cognitive decline. Understanding how changes in metabolites lead to progression in PD may allow for the identification of individuals at the earliest stage of the disease and the development of new therapeutic strategies. Full article

Decreases in chlorophyll control the degradation of green plants during leaf senescence and fruit ripening processes. Our previous daily monitoring of the natural senescence processes of Japanese maple (Acer palmatum) leaves demonstrated initial slow and later fast chlorophyll (Chl) decrease rates. In this study, Chl decrease processes were monitored by in situ visible and near-infrared spectroscopy during heating of maple leaves to 30–200 °C. The initial decreases with time in the 640–720 nm band area, due mainly to chlorophyll a after the water decrease, were fitted by first-order kinetics. The obtained rate constants k₁ from 200 to 60 °C showed a quasi-linear trend on an Arrhenius plot with an activation energy Ea of 38 kJ·mol⁻¹, while those from 60 to 30 °C had a different trend with an Ea of 91 kJ·mol⁻¹. Since the previous natural faster Chl decrease rates are on the extension of the higher-temperature trend, this process might occur without the protection of proteins in the photosynthetic system. On the other hand, the previous natural slower Chl decrease rates are on the extension of the lower-temperature trend, and might have protein protection. Full article

Background/Objectives: Previously, we reported that high molecular weight hyaluronic acid (HMW-HA) exerts chondroprotective effects by enhancing dual specificity protein phosphatase 10/mitogen-activated protein kinase (MAPK) phosphatase 5 (DUSP10/MKP5) expression and suppressing inflammatory cytokine-induced matrix metalloproteinase-13 (MMP13) expression in a human immortalized chondrocyte line (C28/I2 cells) via inhibition of MAPKs. The aim of this study was to elucidate the molecular mechanisms underlying the enhancement of DUSP10/MKP5 expression by HMW-HA in C28/I2 cells. Methods: C28/I2 cells were treated with HMW-HA, and the activation of intracellular signaling molecules was determined using Western blot analysis. The expression levels of mRNAs and microRNAs (miRNAs) were evaluated through real-time quantitative reverse transcription PCR analysis. Results: HMW-HA treatment induced Akt phosphorylation via interaction with CD44, and pretreatment with specific inhibitors of phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) signaling attenuated the HMW-HA-induced expression of DUSP10/MKP5. HMW-HA suppressed the expression of miR-92a, miR-181a, and miR-181d. Loss-of-function and gain-of-function analyses of these miRNAs indicate that miR-92a, miR-181a, and miR-181d negatively regulate DUSP10/MKP5 expression. Moreover, HMW-HA-induced Akt phosphorylation was partially suppressed by miR-181a and miR-181d mimics. Finally, we found that HMW-HA activates RhoA-associated protein kinase (ROK) signaling, which contributes to Akt phosphorylation. Conclusions: These findings suggest that the induction of DUSP10/MKP5 expression by HMW-HA binding to CD44, leading to MMP13 suppression, involves multiple regulatory mechanisms, including PI3K/Akt and RhoA-activated ROK signaling, in addition to miRNA-mediated regulation. Elucidating these detailed molecular mechanisms may reveal novel biological activities that contribute to the therapeutic efficacy of HMW-HA against osteoarthritis. Full article

Seawater intrusion into soils caused by global climate change and tsunami disasters is a significant factor contributing to soil salinization in coastal vegetation areas, posing a critical threat to agriculture and food security. This study aimed to evaluate the seawater tolerance of Vigna marina, a wild Vigna species, through comparative laboratory experiments with Vigna radiata (mung bean) and Vigna angularis (adzuki bean). Unlike V. radiata and V. angularis, the seeds of V. marina exhibited significant buoyancy in seawater, remaining afloat for at least 30 days. After this prolonged seawater incubation, V. marina seeds maintained a 100% germination rate, whereas V. radiata and V. angularis failed to germinate under the same conditions. The photosynthetic activity of V. marina seedlings, evaluated via the Fv/Fm parameter, remained stable even after seven days of seawater irrigation. In contrast, V. radiata and V. angularis perished under seawater irrigation. Furthermore, V. marina seedlings exhibited sustained growth under seawater irrigation, showing consistent increases in both fresh and dry weight. These findings confirm that V. marina possesses remarkable tolerance to seawater, a critical characteristic for cultivation in areas affected by seawater intrusion. Full article