Subarachnoid hemorrhage (SAH) is a stroke subtype with high mortality and poor functional outcomes. Prompt occlusion of a ruptured aneurysm at an early stage is crucial to prevent rebleeding, which can result in even higher mortality and more severe disabilities. The most critical initial decision in SAH management is the choice of treatment method with surgical clipping or endovascular coiling. We aimed to develop an evidence-based clinical guideline to select the optimal initial treatment in patients with SAH. We developed this guideline based on evidence from systematic reviews and meta-analyses via a de novo process. A systematic literature review was conducted across four databases (MEDLINE, Embase, Cochrane, and KoreaMed) to answer two population, intervention, comparison, outcome questions comparing clipping and coiling. The risk of bias was assessed using ROB 2.0 and the Newcastle-Ottawa Scale. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagrams and meta-analyses were generated for functional outcome and mortality. We included six randomized control trials (RCTs) and 58 observational studies. Meta-analysis of RCTs showed that coiling improved functional outcomes compared to clipping (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.86–0.97). No significant mortality difference was observed in RCTs (OR, 1.38; 95% CI, 0.91–2.09), but non-RCTs favored clipping for reduced mortality (OR, 0.77; 95% CI, 0.69–0.86). However, it is difficult to generalize these findings to all clinical situations, as patients with SAH have a highly variable clinical course. Final treatment decision should be tailored to the individual patient’s status, including aneurysm location, morphology, and the expertise available at the treatment center. Such decisions are best made by specialists such as a board-certified physician and should be explained to the patient and their caregivers, along with the rationale for selecting the most appropriate treatment at the given hospital. Korea has many certified endovascular neurosurgeons, cerebrovascular surgeons, and certified cerebrovascular centers. Proper selection of the most suitable treatment method by certified physicians and centers would greatly benefit patient outcomes and healthcare professionals.

The mothership (MS) model, where patients are directly transferred to a thrombectomy-capable center, and the drip-and-ship (DS) model, where thrombolysis is initiated at the nearest primary stroke center before transfer for thrombectomy, are the primary transport modes for patients with stroke. We aimed to establish guidelines for selecting the appropriate transfer strategy based on emergent large vessel occlusion (LVO). We developed this guideline based on evidence from systematic reviews and meta-analyses via a de novo process. A systematic literature review was conducted across four databases (MEDLINE, Embase, Cochrane, and KoreaMed) to answer three Population, Intervention, Comparison, and Outcome questions comparing MS and DS models. The risk of bias was assessed using the Newcastle-Ottawa Scale. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagrams and meta-analyses were generated for functional outcomes, mortality, and successful recanalization. Twenty-six non-randomized controlled studies showed that the MS model improved good functional outcomes by approximately 14% compared with the DS model (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.00–1.30). Fifteen studies reported that mortality in the MS and DS models showed no significant differences (OR, 0.97; 95% CI, 0.84–1.11). Twenty-four studies revealed no significant difference in successful recanalization between the MS and DS models (OR, 0.87; 95% CI, 0.68–1.10). The MS model should be considered first to improve the functional outcome of patients with LVO. However, if thrombectomy cannot be performed immediately after thrombolysis, or if a thrombectomy-enabled hospital is not nearby, the DS model should be considered by stroke specialists depending on transportation time and regional factors. We suggest a mixed approach with the DS model based on specific circumstances or regions to ensure the optimum treatment of patients with acute ischemic stroke (AIS). Appropriate transport for patients with LVO improves the prognosis of AIS.

Purpose: A widely distributed cell cycle inhibitor, p27, regulates cyclin-dependent kinase-cyclin complexes. Although the prognostic value of p27 has been established for various types of carcinomas, its role in luminal breast cancer remains poorly understood. This study aimed to explore the functional enrichment of p27 and identify potential drug targets in patients with luminal-type breast cancer. Methods: Clinicopathological data were collected from 868 patients with luminal-type breast cancer. Additionally, publicly available data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset (1,500 patients) and the Gene Expression Omnibus database (855 patients) were included in the analysis. Immunohistochemical staining for p27, differential gene expression analysis, disease ontology analysis, survival prediction modeling using machine learning (ML), and in vitro drug screening were also performed. Results: Low p27 expression correlated with younger age, advanced tumor stage, estrogen receptor/progesterone receptor negativity, decreased cluster of differentiation 8+ T cell count, and poorer survival outcomes in luminal-type breast cancer. The METABRIC data revealed that reduced cyclin-dependent kinase inhibitor 1B (CDKN1B) expression (encoding p27) was associated with cell proliferation-related pathways and epigenetic polycomb repressive complex 2. Using ML, p27 emerged as the second most significant survival factor after N stage, thereby enhancing survival model performance. Additionally, luminal-type breast cancer cell lines with low CDKN1B expression demonstrated increased sensitivity to specific anticancer drugs such as voxtalisib and serdemetan, implying a potential therapeutic synergy between CDKN1B-targeted approaches and these drugs. Conclusion The integration of ML and bioinformatic analyses of p27 has the potential to enhance risk stratification and facilitate personalized treatment strategies for patients with breast cancer.

Purpose: A widely distributed cell cycle inhibitor, p27, regulates cyclin-dependent kinase-cyclin complexes. Although the prognostic value of p27 has been established for various types of carcinomas, its role in luminal breast cancer remains poorly understood. This study aimed to explore the functional enrichment of p27 and identify potential drug targets in patients with luminal-type breast cancer. Methods: Clinicopathological data were collected from 868 patients with luminal-type breast cancer. Additionally, publicly available data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset (1,500 patients) and the Gene Expression Omnibus database (855 patients) were included in the analysis. Immunohistochemical staining for p27, differential gene expression analysis, disease ontology analysis, survival prediction modeling using machine learning (ML), and in vitro drug screening were also performed. Results: Low p27 expression correlated with younger age, advanced tumor stage, estrogen receptor/progesterone receptor negativity, decreased cluster of differentiation 8+ T cell count, and poorer survival outcomes in luminal-type breast cancer. The METABRIC data revealed that reduced cyclin-dependent kinase inhibitor 1B (CDKN1B) expression (encoding p27) was associated with cell proliferation-related pathways and epigenetic polycomb repressive complex 2. Using ML, p27 emerged as the second most significant survival factor after N stage, thereby enhancing survival model performance. Additionally, luminal-type breast cancer cell lines with low CDKN1B expression demonstrated increased sensitivity to specific anticancer drugs such as voxtalisib and serdemetan, implying a potential therapeutic synergy between CDKN1B-targeted approaches and these drugs. Conclusion The integration of ML and bioinformatic analyses of p27 has the potential to enhance risk stratification and facilitate personalized treatment strategies for patients with breast cancer.

Background: Tumor spread through air spaces (STAS) is a recently discovered risk factor for lung adenocarcinoma (LUAD). The aim of this study was to investigate specific genetic alterations and anticancer immune responses related to STAS. By using a machine learning algorithm and drug screening in lung cancer cell lines, we analyzed the effect of Janus kinase 2 (JAK2) on the survival of patients with LUAD and possible drug candidates. Methods: This study included 566 patients with LUAD corresponding to clinicopathological and genetic data. For analyses of LUAD, we applied gene set enrichment analysis (GSEA), in silico cytometry, pathway network analysis, in vitro drug screening, and gradient boosting machine (GBM) analysis. Results: The patients with STAS had a shorter survival time than those without STAS (P < 0.001). We detected gene set-related downregulation of JAK2 associated with STAS using GSEA. Low JAK2 expression was related to poor prognosis and a low CD8+ T-cell fraction. In GBM, JAK2 showed improved survival prediction performance when it was added to other parameters (T stage, N stage, lymphovascular invasion, pleural invasion, tumor size). In drug screening, mirin, CCT007093, dihydroretenone, and ABT737 suppressed the growth of lung cancer cell lines with low JAK2 expression. Conclusion In LUAD, low JAK2 expression linked to the presence of STAS might serve as an unfavorable prognostic factor. A relationship between JAK2 and CD8+ T cells suggests that STAS is indirectly related to the anticancer immune response. These results may contribute to the design of future experimental research and drug development programs for LUAD with STAS.

Background: and Purpose In young patients (aged 18–60 years) with patent foramen ovale (PFO)- associated stroke, percutaneous closure has been found to be useful for preventing recurrent ischemic stroke or transient ischemic attack (TIA). However, it remains unknown whether PFO closure is also beneficial in older patients. Methods: Patients aged ≥60 years who had a cryptogenic stroke and PFO from ten hospitals in South Korea were included. The effect of PFO closure plus medical therapy over medical therapy alone was assessed by a propensity-score matching method in the overall cohort and in those with a high-risk PFO, characterized by the presence of an atrial septal aneurysm or a large shunt. Results: Out of the 437 patients (mean age, 68.1), 303 (69%) had a high-risk PFO and 161 (37%) patients underwent PFO closure. Over a median follow-up of 3.9 years, recurrent ischemic stroke or TIA developed in 64 (14.6%) patients. In the propensity score-matched cohort of the overall patients (130 pairs), PFO closure was associated with a significantly lower risk of a composite of ischemic stroke or TIA (hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.24–0.84; P=0.012), but not for ischemic stroke. In a subgroup analysis of confined to the high-risk PFO patients (116 pairs), PFO closure was associated with significantly lower risks of both the composite of ischemic stroke or TIA (HR: 0.40; 95% CI: 0.21–0.77; P=0.006) and ischemic stroke (HR: 0.47; 95% CI: 0.23–0.95; P=0.035). Conclusion Elderly patients with cryptogenic stroke and PFO have a high recurrence rate of ischemic stroke or TIA, which may be significantly reduced by device closure.

Purpose: A widely distributed cell cycle inhibitor, p27, regulates cyclin-dependent kinase-cyclin complexes. Although the prognostic value of p27 has been established for various types of carcinomas, its role in luminal breast cancer remains poorly understood. This study aimed to explore the functional enrichment of p27 and identify potential drug targets in patients with luminal-type breast cancer. Methods: Clinicopathological data were collected from 868 patients with luminal-type breast cancer. Additionally, publicly available data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset (1,500 patients) and the Gene Expression Omnibus database (855 patients) were included in the analysis. Immunohistochemical staining for p27, differential gene expression analysis, disease ontology analysis, survival prediction modeling using machine learning (ML), and in vitro drug screening were also performed. Results: Low p27 expression correlated with younger age, advanced tumor stage, estrogen receptor/progesterone receptor negativity, decreased cluster of differentiation 8+ T cell count, and poorer survival outcomes in luminal-type breast cancer. The METABRIC data revealed that reduced cyclin-dependent kinase inhibitor 1B (CDKN1B) expression (encoding p27) was associated with cell proliferation-related pathways and epigenetic polycomb repressive complex 2. Using ML, p27 emerged as the second most significant survival factor after N stage, thereby enhancing survival model performance. Additionally, luminal-type breast cancer cell lines with low CDKN1B expression demonstrated increased sensitivity to specific anticancer drugs such as voxtalisib and serdemetan, implying a potential therapeutic synergy between CDKN1B-targeted approaches and these drugs. Conclusion The integration of ML and bioinformatic analyses of p27 has the potential to enhance risk stratification and facilitate personalized treatment strategies for patients with breast cancer.

The development of drug-resistant influenza and new pathogenic virus strains underscores the need for antiviral therapeutics. Currently, neuraminidase (NA) inhibitors are commonly used antiviral drugs approved by the US Food and Drug Administration (FDA) for the prevention and treatment of influenza. Here, we show that vitisin B (VB) inhibits NA activity and suppresses H1N1 viral replication in MDCK and A549 cells. Reactive oxygen species (ROS), which frequently occur during viral infection, increase virus replication by activating the NF-κB signaling pathway, downmodulating glucose-6-phosphate dehydrogenase (G6PD) expression, and decreasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response activity. VB decreased virus-induced ROS generation by increasing G6PD expression and Nrf2 activity, and inhibiting NF-κB translocation to the nucleus through IKK dephosphorylation. In addition, VB reduced body weight loss, increased survival, decreased viral replication and the inflammatory response in the lungs of influenza A virus (IAV)-infected mice. Taken together, our results indicate that VB is a promising therapeutic candidate against IAV infection, complements existing drug limitations targeting viral NA. It modulated the intracellular ROS by G6PD, Nrf2 antioxidant response pathway, and NF-κB signaling pathway. These results demonstrate the feasibility of a multi-targeting drug strategy, providing new approaches for drug discovery against IAV infection.

Background: Fractional flow reserve (FFR) based on computed tomography (CT) has been shown to better identify ischemia-causing coronary stenosis. However, this current technology requires high computational power, which inhibits its widespread implementation in clinical practice. This prospective, multicenter study aimed at validating the diagnostic performance of a novel simple CT based fractional flow reserve (CT-FFR) calculation method in patients with coronary artery disease. Methods: Patients who underwent coronary CT angiography (CCTA) within 90 days and invasive coronary angiography (ICA) were prospectively enrolled. A hemodynamically significant lesion was defined as an FFR ≤ 0.80, and the area under the receiver operating characteristic curve (AUC) was the primary measure. After the planned analysis for the initial algorithm A, we performed another set of exploratory analyses for an improved algorithm B. Results: Of 184 patients who agreed to participate in the study, 151 were finally analyzed.Hemodynamically significant lesions were observed in 79 patients (52.3%). The AUC was 0.71 (95% confidence interval [CI], 0.63–0.80) for CCTA, 0.65 (95% CI, 0.56–0.74) for CT-FFR algorithm A (P = 0.866), and 0.78 (95% CI, 0.70–0.86) for algorithm B (P = 0.112). Diagnostic accuracy was 0.63 (0.55–0.71) for CCTA alone, 0.66 (0.58–0.74) for algorithm A, and 0.76 (0.68–0.82) for algorithm B. Conclusion This study suggests the feasibility of automated CT-FFR, which can be performed on-site within several hours. However, the diagnostic performance of the current algorithm does not meet the a priori criteria for superiority. Future research is required to improve the accuracy.

Background and Objectives: Studies evaluating the nature of ischemic burden of chronic total occlusion (CTO) vessels are still lacking. Methods: A total of 165 patients with single vessel CTO >2.5 mm in an epicardial coronary artery who underwent single photon emission computed tomography (SPECT) were enrolled in the study. Ischemic burden was calculated with the use of semi-quantitative SPECT analysis, and was defined as the summed difference score (SDS) divided by the maximal limit of the score (=SDS/68). Results: The mean age of the participants was 59.5 years and the CTO of the left anterior descending coronary artery (LAD), left circumplex coronary artery (LCX), and right coronary artery (RCA) accounted for 93 (56.4%), 18 (10.9%), and 54 (32.7%) patients, respectively. The median ischemic burden of the total population was 8.8%, and it was highest in the LAD CTO (10.3%) compared with the LCX (5.9%) and RCA CTO (5.9%, p<0.001). High-ischemic burden (ischemic burden >10%) was observed in 66 patients (40.0%), and in 47 patients (50.5%) of the LAD CTO. Ischemic burden was different according to the CTO location only in LAD CTO. The statistically significant predictors for high-ischemic burden were hypertension, baseline ejection fraction >45%, LAD CTO, proximal CTO location, and de novo CTO. Japanese-CTO score and Rentrop scale collateral grade were not associated with high-ischemic burden. Conclusions Only 40% of patients with single vessel CTO had ischemic burden >10%. For CTO vessels, measurement of ischemic burden using SPECT prior to revascularization may be helpful in identifying beneficial subjects.