👤 Hideaki Tahara

Agricultural or gardening activity (also known as hobby farming) is a simple strategy that may be effective for maintaining health and preventing lifestyle-related diseases. However, its preventive effect on the development of conditions associated with neurovascular aging (e.g., stroke and dementia) remains unclear. To comprehensively investigate the preventive role of regular agricultural or gardening physical activity (AGPA) in neurovascular aging and its underlying mechanisms using two approaches. We conducted an experimental study in which we assessed arterial stiffness, cognitive performance (Flanker and Stroop tests), and circulating biomarkers (e.g., plasmin-α2-plasmin inhibitor complexes, nitric oxide, brain-derived neurotrophic factor) in 12 male students (average age: 22 ± 1 years) before and after three 40-min interventions (resting, cycling, and simulated AGPA) under controlled conditions. We also conducted a cross-sectional study, in which we recruited 161 (79 in the AGPA group and 82 in the control group) hospital-based older individuals (average age: 78 ± 5 years) and assessed their history of stroke, cognitive function, and brain magnetic resonance imaging (MRI) findings. In the experimental study, simulated AGPA reduced arterial stiffness, improved executive cognitive function, and elevated circulating plasmin-α2-plasmin inhibitor complexes, nitric oxide, and brain-derived neurotrophic factor. Brain MRI-assessed cerebral white matter hyperintensities caused by reduced blood flow to brain tissue and stroke prevalence were lower, and cognitive scores (as assessed by the Hasegawa Dementia Scale-Revised) were higher in the AGPA group than in the control group. Our findings suggest that regular AGPA is associated with markers of slower neurovascular aging in older individuals. AGPA induces a combination of general physical activity-related and specific AGPA-related effects; moreover, it may offer similar or even greater benefits than physical activity alone. Therefore, habitual AGPA may serve as an effective preventive strategy for neurovascular aging. Show less

The benefit of the addition of perioperative pembrolizumab to standard care with surgery and adjuvant therapy for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) is unclear. In this phase 3, open-label trial, we randomly assigned participants with locally advanced HNSCC in a 1:1 ratio to receive 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab (both at a dose of 200 mg every 3 weeks) in addition to standard care (pembrolizumab group) or standard care alone (control group). Standard care was surgery and adjuvant radiotherapy with or without concomitant cisplatin. The primary end point was event-free survival, sequentially assessed in participants whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS) of 10 or more (CPS-10 population), participants whose tumors expressed PD-L1 with a CPS of 1 or more (CPS-1 population), and all the participants. A higher CPS indicates a higher proportion of cells that express PD-L1. A total of 363 participants (234 with a CPS of ≥10 and 347 with a CPS of ≥1) were assigned to the pembrolizumab group and 351 (231 with a CPS of ≥10 and 335 with a CPS of ≥1) to the control group. Surgery was completed in approximately 88% of the participants in each group. At the first interim analysis, the median follow-up was 38.3 months. Event-free survival at 36 months was 59.8% in the pembrolizumab group and 45.9% in the control group (hazard ratio for progression, recurrence, or death, 0.66; 95% confidence interval [CI], 0.49 to 0.88; two-sided P = 0.004) in the CPS-10 population; 58.2% and 44.9%, respectively (hazard ratio, 0.70; 95% CI, 0.55 to 0.89; two-sided P = 0.003), in the CPS-1 population; and 57.6% and 46.4%, respectively (hazard ratio, 0.73; 95% CI, 0.58 to 0.92; two-sided P = 0.008), in the total population. Grade 3 or higher treatment-related adverse events occurred in 44.6% of the participants in the pembrolizumab group and in 42.9% of those in the control group, including death in 1.1% and 0.3%, respectively. Potentially immune-mediated adverse events of grade 3 or higher occurred in 10.0% of the participants in the pembrolizumab group. The addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced HNSCC. Neoadjuvant pembrolizumab did not affect the likelihood of surgical completion. No new safety signals were identified. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-689 ClinicalTrials.gov number, NCT03765918.). Show less

MicroRNA-140 (miR-140) is specifically expressed in developing cartilage tissues. We have previously reported that miR-140 plays an important role during palatal cartilage development by modulating platelet-derived growth factor receptor alpha (pdgfra) in zebrafish. However, the regulatory mechanism of miR-140 in cartilage is still unknown. Using developing zebrafish, sox9a mutant (sox9a-/-) and sox9b mutant (sox9b-/-) zebrafish and SOX9 small interfering RNA in human chondrocytes, T/C-28 cells, we found that miR-140 is regulated by the cartilage master transcription regulator Sox9 in zebrafish and mammalian cells. Show less