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While the seroprevalence of SARS-CoV-2 in healthy people does not differ significantly among age groups, those aged 65 years or older exhibit strikingly higher COVID-19 mortality compared to younger individuals. To further understand differing COVID-19 manifestations in patients of different ages, three age groups of ferrets are infected with SARS-CoV-2. Although SARS-CoV-2 is isolated from all ferrets regardless of age, aged ferrets (≥3 years old) show higher viral loads, longer nasal virus shedding, and more severe lung inflammatory cell infiltration, and clinical symptoms compared to juvenile (≤6 months) and young adult (1–2 years) groups. Furthermore, direct contact ferrets co-housed with the virus-infected aged group shed more virus than direct-contact ferrets co-housed with virus-infected juvenile or young adult ferrets. Transcriptome analysis of aged ferret lungs reveals strong enrichment of gene sets related to type I interferon, activated T cells, and M1 macrophage responses, mimicking the gene expression profile of severe COVID-19 patients. Thus, SARS-CoV-2-infected aged ferrets highly recapitulate COVID-19 patients with severe symptoms and are useful for understanding age-associated infection, transmission, and pathogenesis of SARS-CoV-2. Here, Kim et al. characterize SARS-CoV-2 infection in juvenile, young, and old aged ferrets to provide a further understanding of differences in COVID-19 severity in humans at different ages. Aged ferrets have higher viral loads, shed virus longer, and mimic the transcriptomic profile of severely infected patients.

p21-Activated kinase 4 (PAK4), a member of the PAK family, regulates a wide range of cellular functions, including cell adhesion, migration, proliferation, and survival. Dysregulation of its expression and activity thus contributes to the development of diverse pathological conditions. PAK4 plays a pivotal role in cancer progression by accelerating the epithelial–mesenchymal transition, invasion, and metastasis. Therefore, PAK4 is regarded as an attractive therapeutic target in diverse types of cancers, prompting the development of PAK4-specific inhibitors as anticancer drugs; however, these drugs have not yet been successful. PAK4 is essential for embryonic brain development and has a neuroprotective function. A long list of PAK4 effectors has been reported. Recently, the transcription factor CREB has emerged as a novel effector of PAK4. This finding has broad implications for the role of PAK4 in health and disease because CREB-mediated transcriptional reprogramming involves a wide range of genes. In this article, we review the PAK4 signaling pathways involved in prostate cancer, Parkinson’s disease, and melanogenesis, focusing in particular on the PAK4-CREB axis. Gene expression: The role of a regulatory enzyme in disease An enzyme that regulates an important controller of gene expression may offer a therapeutic target for cancer and other diseases. cAMP response element-binding protein (CREB) interacts with various other proteins to switch a myriad of target genes on and off in different cells. A review by Eung-Gook Kim, Eun-Young Shin and colleagues at Chungbuk National University, Cheongju, South Korea, explores the interplay between CREB and an enzyme called p21-activated kinase 4 (PAK4) in human health and disease. PAK4, for example, has been shown to promote CREB’s gene-activating function in prostate cancer, and PAK4 overexpression is a feature of numerous other tumor types. Disruptions in PAK4-mediated regulation of CREB activity have also been observed in neurons affected by Parkinson’s disease. The authors see strong clinical promise in further exploring the biology of the PAK4-CREB pathway.

Background The association between systemic sclerosis and the development of bronchiectasis is unclear. This study aimed to compare the risk of bronchiectasis between individuals with systemic sclerosis and those without using a nationwide longitudinal dataset. Methods Using the Korean National Health Insurance Service dataset between 2010 and 2017, we identified 4845 individuals aged ≥ 20 years with systemic sclerosis and 24,225 without systemic sclerosis who were matched 1:5 by age and sex. They were followed up until the date of a bronchiectasis diagnosis, death, or December 31, 2019, whichever came first. Results During a median follow-up period of 6.0 (interquartile range, 3.2–8.7) years, 5.3% of the systemic sclerosis cohort and 1.9% of the matched cohort developed bronchiectasis, with incidence rates of 9.99 and 3.23 per 1000 person-years, respectively. Even after adjusting for potential confounders, the risk of incident bronchiectasis was significantly higher in the systemic sclerosis cohort than in the matched cohort (adjusted hazard ratio 2.63, 95% confidence interval 2.22–3.12). A subgroup analysis of individuals with systemic sclerosis revealed that the risk of incident bronchiectasis was notably higher in younger individuals aged 20–39 years ( P for interaction = 0.048) and in those without other coexisting connective tissue diseases ( P for interaction = 0.006) than in their counterparts. Conclusions The risk of incident bronchiectasis is higher in individuals with systemic sclerosis than those without. Bronchiectasis should be considered one of the pulmonary manifestations related to systemic sclerosis.

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that influence cancer progression via extracellular matrix (ECM) remodeling and secretion of growth factors and cytokines. Endothelial-to-mesenchymal transition (EndMT) is emerging as an important axis among the heterogeneous origins of CAFs. This review introduces the diverse methods used to induce EndMT in cancer—mouse tumor models, conditioned-medium treatment, co-culture, targeted gene perturbation, ligand stimulation, exosome exposure, irradiation, viral infection, and three-dimensional (3D) culture systems—and summarizes EndMT cell-type evidence uncovered using transcriptomic and proteomic technologies. Hallmark EndMT features include spindle-like morphology, increased motility, impaired angiogenesis and barrier function, decreased endothelial markers (CD31, VE-cadherin), and increased mesenchymal markers (α-SMA, FN1). Reported mechanisms include signaling via TGF-β, cytoskeletal/mechanical stress, reactive oxygen species, osteopontin, PAI-1, IL-1β, GSK-3β, HSP90α, Tie1, TNF-α, HSBP1, and NOTCH. Cancer-induced EndMT affects tumors and surrounding TME—promoting tumor growth and metastasis, expanding cancer stem cell-like cells, driving macrophage differentiation, and redistributing pericytes—and is closely associated with poor survival and therapy resistance. Finally, we indicate each study’s stance: some frame cancer-induced EndMT as a source of CAFs, whereas others, from an endothelial perspective, emphasize barrier weakening and promotion of metastasis.

Although remimazolam is an ultra-short-acting benzodiazepine with a shorter elimination half-life and faster recovery time than midazolam, studies evaluating its safety and efficacy during bronchoscopy are limited. This study aimed to compare the safety and efficacy of remimazolam with those of midazolam for bronchoscopy. This prospective randomized parallel-group study was conducted at a single institution. The primary outcome was the time from the end of the procedure to full alertness. Other procedural time parameters, satisfaction profiles, and adverse effects were thoroughly evaluated. The time taken to reach peak sedation and the time from the end of the procedure to full alertness was significantly shorter in the remimazolam group than in the midazolam group (median [interquartile range], 2 min [1–4] vs. 3 min [2–5], P  = 0.006; and median, 2 min [1–5] vs. 5 min [1–12], P  = 0.035, respectively). In patients with non-biopsy procedures (n = 79), participant satisfaction was significantly higher in the remimazolam group than in the midazolam group (median rated scale, 10 vs. 7, P  = 0.042). Physician satisfaction and willingness to repeat the procedure were similar between groups. Although the incidence of adverse effects was similar between the groups and there was no significant difference, the midazolam group had a higher antidote administration rate than the remimazolam group (15.7% vs. 4.1%, P  = 0.092). Remimazolam is effective and safe for achieving adequate sedation, with a shorter onset time and faster neuropsychiatric recovery than midazolam. It may be a new option for sedation during bronchoscopy. Trial registration : The trial registration number is NCT05994547, and the date of first registration is 16/08/2023.

Senescence, a hallmark of aging, is a factor in age-related diseases (ARDs). Therefore, targeting senescence is widely regarded as a practicable method for modulating the effects of aging and ARDs. Here, we report the identification of regorafenib, an inhibitor of multiple receptor tyrosine kinases, as a senescence-attenuating drug. We identified regorafenib by screening an FDA-approved drug library. Treatment with regorafenib at a sublethal dose resulted in effective attenuation of the phenotypes of βPIX knockdown- and doxorubicin-induced senescence and replicative senescence in IMR-90 cells; cell cycle arrest, and increased SA-β-Gal staining and senescence-associated secretory phenotypes, particularly increasing the secretion of interleukin 6 (IL-6) and IL-8. Consistent with this result, slower progression of βPIX depletion-induced senescence was observed in the lungs of mice after treatment with regorafenib. Mechanistically, the results of proteomics analysis in diverse types of senescence indicated that growth differentiation factor 15 and plasminogen activator inhibitor-1 are shared targets of regorafenib. Analysis of arrays for phospho-receptors and kinases identified several receptor tyrosine kinases, including platelet-derived growth factor receptor α and discoidin domain receptor 2, as additional targets of regorafenib and revealed AKT/mTOR, ERK/RSK, and JAK/STAT3 signaling as the major effector pathways. Finally, treatment with regorafenib resulted in attenuation of senescence and amelioration of porcine pancreatic elastase-induced emphysema in mice. Based on these results, regorafenib can be defined as a novel senomorphic drug, suggesting its therapeutic potential in pulmonary emphysema. Lung disease: existing drug could block emphysema progression An existing drug that can inhibit the deterioration of cell activity due to aging could provide a novel treatment for the debilitating lung disease emphysema. Aging-related diseases, including emphysema, are exacerbated by cellular senescence, the loss of cell division and growth due to aging. ‘Senomorphic’ drugs could halt senescence and stop the progression of aging-related diseases. Eung-Gook Kim and Eun-Young Shin at Chungbuk National University, Cheongju, South Korea, and co-workers screened an approved drug library for senomorphic drug candidates to treat emphysema. Their search highlighted regorafenib, a drug that is used to treat colorectal and gastrointestinal cancers. In experiments on mouse models, regorafenib exhibited a strong inhibitory effect on different types of senescence by regulating the expression of multiple proteins and inhibiting key signaling pathways. The drug blocked emphysema progression in the lungs of mice.

Bronchiectasis show various ventilatory disorders in pulmonary function. The characteristics and severity of patients with bronchiectasis according to these pulmonary dysfunctions are still very limited. This study aimed to evaluate the clinical, radiologic feature and the disease severity of patients with bronchiectasis according to spirometric patterns. We retrospectively evaluated 506 patients with bronchiectasis who underwent pulmonary lung function test (PFT) at a referral hospital between 2014 to 2021. The results showed that cylindrical type was the most common (70.8%) type of bronchiectasis on chest Computed tomography (CT), and 70% of patients had bilateral lung involvement. On the other hand, obstructive ventilatory disorder was the most common (51.6%), followed by normal ventilation (30%) and restrictive ventilatory disorder (18.4%). The modified Medical Research Council (mMRC) was highest in patients with obstructive ventilatory disorders, Modified Reiff score [median (interquartile range)] [6 (3–10), P < 0.001], FACED (FEV 1 , Age, Chronic colonization, Extension, and Dyspnea) score [3 (1–4), P < 0.001], and Bronchiectasis Severity (BSI) score [8 (5–11), P < 0.001] showed significantly highest values of obstructive ventilatory disorder rather than restrictive ventilatory disorder and normal ventilation. More than half of patients with bronchiectasis had obstructive ventilatory disorder. Bronchiectasis with obstructive ventilatory disorders has more dyspnea symptom, more disease severity and more radiologic severity. There was no significant association between spirometric pattern and radiologic type, but the more severe the radiologic severity, the more severe the lung function impairment.

SARS‐CoV‐2 infection can lead to severe COVID‐19, particularly in elderly individuals and those with compromised immunity. Cellular senescence has been implicated as a key pathogenic mechanism. This study investigated the therapeutic potential of regorafenib, a previously characterized senomorphic drug, for severe COVID‐19. SARS‐CoV‐2 virus‐infected K18‐hACE2 mice, overexpressing the human ACE2 receptor, exhibited 100% mortality by 10 days post infection. Regorafenib treatment significantly improved survival rates, approximately 43% remaining alive. Mechanistically, regorafenib effectively suppressed type I and II interferon and cytokine signaling. Notably, regorafenib inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, a key driver of the cytokine storm associated with severe COVID‐19. Our findings elucidate the molecular mechanisms underlying therapeutic effects of regorafenib and suggest its potential use as a promising treatment option for severe COVID‐19. Regorafenib treatment significantly enhanced survival in SARS‐CoV‐2‐infected K18‐hACE2 mice. Mechanistically, it suppressed type I and II interferon and cytokine signaling through inhibiting NLRP3 inflammasome activation, a critical driver of the cytokine storm in severe COVID‐19. These findings elucidate the molecular mechanisms of regorafenib's therapeutic effects and highlight its potential as a treatment for severe COVID‐19.

Cases of laboratory-confirmed SARS-CoV-2 reinfection have been reported in a number of countries. Further, the level of natural immunity induced by SARS-CoV-2 infection is not fully clear, nor is it clear if a primary infection is protective against reinfection. To investigate the potential association between serum antibody titres and reinfection of SARS-CoV-2, ferrets with different levels of NAb titres after primary SARS-CoV-2 infection were subjected to reinfection with a heterologous SARS-CoV-2 strain. All heterologous SARS-CoV-2 reinfected ferrets showed active virus replication in the upper respiratory and gastro-intestinal tracts. However, the high NAb titre group showed attenuated viral replication and rapid viral clearance. In addition, direct-contact transmission was observed only from reinfected ferrets with low NAb titres (<20), and not from other groups. Further, lung histopathology demonstrated the presence of limited inflammatory regions in the high NAb titre groups compared with control and low NAb groups. This study demonstrates a close correlation between a low NAb titre and SARS-CoV-2 reinfection in a recovered ferret reinfection model.

Background The molecular pathophysiology underlying the development of bronchiectasis with exacerbation at the proteomic level has not been clarified using bronchoalveolar lavage fluid samples. This study aimed to evaluate the bronchoalveolar lavage fluid inflammatory profiles associated with exacerbation of bronchiectasis. Methods We analyzed the bronchoalveolar lavage fluid specimens from 4 patients in the exacerbation status and 4 patients in a stable status using liquid chromatography-tandem mass spectrometry. Results A total of 1,577 proteins were identified using proteomic analysis, with 127 differentially expressed proteins. Of 127 differentially expressed proteins, 23 proteins showed more than 2-fold differences between exacerbation and stable status groups. The exacerbation status was associated with 18 upregulated proteins (TPI1, CRP, BPI, ORM1, PTPRE, S100A9, BPY2, TPM4, ERVFC1-1, CYS1, CLEC3B, S100A8, PSAT1, NDUFA10, MDGA1, SPRR3, ALDOA, and PSMB2) and five downregulated proteins (MUC5B, HSPE1, KLK13, IGHA1, and MUC5AC). Pathway analysis revealed that the neutrophil degranulation pathway (R-HSA-6798695) was the most enriched pathway in these proteins, followed by the C-type lectin receptor pathway (R-HSA-5621481). Conclusion The bronchoalveolar lavage fluid protein expression in patients in the exacerbation status of bronchiectasis was significantly different from that in patients in the stable status, indicating that neutrophil degranulation and C-type lectin receptor pathways are the most enriched pathways during exacerbation.