Alzheimer’s disease (AD) is characterized by progressive cognitive deterioration and significant depression. However, the mechanisms linking depression to AD pathology remain unclear. Here, we investigated whether Notch2 signaling mediates depressionlike behaviors in presenilin-2 (PS2) N141I mutant mice, an early-onset AD model. PS2 wild-type (WT) and mutant (MT) mice aged 12-15 months were subjected to unpredictable chronic mild stress (UCMS) for 4 weeks, followed by sucrose preference, tail-hanging, and forced swimming tests. Behavioral assessments showed that UCMS exacerbated anhedonia and immobility only in PS2 MT mice. Molecular analysis revealed concomitant increases in plasma corticosterone, hippocampal γ-secretase activity, and Notch2 expression, and elevated total and phosphorylated glucocorticoid receptor levels in PS2 MT-UCMS mice. Gene expression profiling of human hippocampal datasets confirmed upregulation of NOTCH2 in Alzheimer’s disease and depression.Pharmacological inhibition of γ-secretase and Notch signaling with DAPT normalizes depressive behavior, reduces corticosterone release, attenuates GR phosphorylation, and inhibits Notch2 signaling in PS2 MT mice. These findings identify Notch2 as a pivotal mediator linking chronic stress to molecular changes associated with depression and AD, and suggest that targeting Notch2 signaling may provide therapeutic benefits for comorbid mood and neurodegenerative disorders.

Purpose: Current guidelines recommend vaccination at least 2 weeks before chemotherapy initiation to optimize the immune response despite limited evidence. Our previous study indicated no differences in short-term immune response for the 13-valent pneumococcal conjugate vaccine (PCV13) according to the vaccination timing. This study aims to investigate the long-term efficacy of PCV13 and clinical factors associated with the respective antibody response. Materials and Methods: Patients with gastric or colorectal cancer who received adjuvant chemotherapy were enrolled and divided into two groups: vaccinated 2 weeks before chemotherapy (arm A) and vaccinated concurrently with chemotherapy (arm B). Serum samples were collected before vaccination and in one month, 3 years, and 5 years. Immune responses were measured using enzyme-linked immunosorbent assay and multiplex opsonophagocytosis assay. Results: Including 63 patients, both groups showed an initial increase in the geometric mean titers of opsonophagocytic activity and the geometric mean concentrations of serotype-specific IgG levels after one month, followed by a decline at 3 and 5 years, particularly for serotypes 1, 14, 18C, and 19A. Despite the decline, global protection was maintained for 5 years, although global response decreased. The two arms did not show significant differences in immunogenicity nor in factors such as vaccination timing, age, cancer type, or chemotherapy regimen. Conclusion Vaccination timing is not a significant factor for the immunogenicity of PCV13 in cancer patients undergoing adjuvant chemotherapy. Global protection against pneumococcal infection was sustained for > 5 years, and global response remained in over half of patients.

Purpose: This study evaluates the Korean Cancer Study Group Geriatric Score-7 (KG-7) frailty screening tool’s effectiveness in elderly multiple myeloma (MM) patients to prevent under and overtreatment. Materials and Methods: This prospective pilot cohort study included 100 elderly patients aged 70 and older with newly diagnosed MM who had not undergone transplantation from August 2020 to January 2022. Results: The median age was 77 years, and 73.0% of patients were classified at International Staging System stages 2 or 3. Using a 5-point cutoff on the KG-7 index (non-frail, score ≥ 5; frail, score < 5), 31% were categorized as frail. After a median follow-up of 26.8 months, the 3-year overall survival rate was 73.0%. There was no statistically significant association between any frailty index and the risk of death. However, frail patients defined by the simplified frailty index (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.09 to 5.95; p=0.030) and by KG-7 (HR, 2.43; 95% CI, 1.03 to 5.86; p=0.043) had a significantly higher risk of grade 3-4 non-hematologic toxicity, whereas the International Myeloma Working Group definition did not. Over a 24-month tracking period, vulnerability as measured by KG-7 either improved or deteriorated. Conclusion The pilot study, which had a limited number of participants, did not demonstrate KG-7’s effectiveness in predicting survival; however, it successfully predicted severe non-hematologic toxicities. We plan to conduct larger studies in elderly MM patients to determine whether KG-7 can help tailor their treatment regimens.

Background: The effects of propofol, a commonly used intravenous anesthetic, on the breast cancer tumor microenvironment are not well understood. This study examined the influence of propofol on natural killer group 2, member D (NKG2D) ligand expression, matrix metalloproteinase (MMP)-mediated immune evasion, and natural killer (NK) cell-mediated cytotoxicity in breast cancer cells. Methods: We studied three human breast cancer cell lines representing distinct receptor subtypes: MCF-7 (estrogen receptor - and progesterone receptor-positive), MDA-MB-453 (human epidermal growth factor receptor 2-positive), and HCC-70 (triple-negative). Cells were treated with propofol at concentrations of 0 μg/ml (control; C), 4 μg/ml (P4), or 8 μg/ml (P8). Assessments included mRNA and protein expression of NKG2D ligands, NK cell cytotoxicity, protein levels of MMP-1 and MMP-2, and concentrations of soluble NKG2D ligands. Results: In MCF-7 and HCC-70 cell lines, propofol upregulated the mRNA and protein expression of NKG2D ligands in a dose-dependent manner, enhancing NK cell-mediated lysis. In contrast, in MDA-MB-453 cell lines, propofol downregulated the mRNA and protein expression of NKG2D ligands, resulting in diminished NK cell-mediated lysis. Across all receptor subtypes, propofol did not affect the expression of MMP-1 or MMP-2 or the concentration of soluble NKG2D ligands. Conclusions Our results demonstrate that propofol exerts receptor subtype-dependent effects on NK cell-mediated immunosurveillance in breast cancer cell lines, potentially mediated by changes in the transcription of NKG2D ligands rather than by alterations in MMP expression or their proteolytic activity.

Background and Objectives: We evaluated 20-year trends in heart failure (HF) epidemiology in Korea to quantify changes in its burden from 2002 to 2023. Methods: A nationwide analysis was conducted using a random 50% sample from the Korean National Health Information Database linked to mortality records (2002–2023). HF was defined using diagnostic codes recorded as a primary or secondary condition. We calculated crude and age-standardized rates of prevalence, incidence, hospitalization, and mortality. Survival was assessed using the Kaplan–Meier method, stratified by inpatient versus outpatient diagnosis.Trends in heart transplantation and left ventricular assist device implantations were also examined. Results: By 2023, approximately 1,750,228 individuals had HF (3.41% prevalence). The age-standardized prevalence has more than doubled from 2002 to 2023. The crude incidence increased over time; the age-standardized incidence remained stable in men and declined in women.Hospitalization rates for any cause or secondary HF diagnoses have increased substantially, whereas primary HF hospitalization rates have remained relatively stable. The annual mortality rate in patients with HF was approximately 6.0% in 2023, being markedly higher in older adults.Although short-term survival has improved, particularly in hospitalized patients, long-term survival remains limited. Use of advanced therapies significantly increased. Conclusions The burden of HF in Korea has increased substantially over the past two decades, driven primarily by population aging and improved survival rather than increasing age-adjusted incidence. Despite therapeutic advances, hospitalization and long-term mortality rates remain high, highlighting the need for comprehensive HF strategies in aging societies.

Purpose: Despite the widespread use of liquid skin adhesives (LSA), concerns persist regarding the increase in wound care costs. This study aimed to investigate the cost-effectiveness of LSA for surgical wound management. Methods: In this prospective, open-label, single-center randomized controlled trial, adults aged 19 years and older who were scheduled for elective minimally invasive colorectal surgeries were included. The participants were randomly divided into 2 groups: an n-butyl cyanoacrylate skin adhesive was used in the experimental group (LSA group), while a surgical skin stapler was employed in the control group (stapler group). The primary outcome measure was the sum of the total time required for wound management. Results: A total of 58 patients were randomly assigned to 2 groups, with 29 patients in each group. The findings revealed comparable wound complication rates in the 2 groups (8 out of 29 in the LSA group vs. 5 out of 29 in the stapler group, P = 0.530). Notably, the LSA group had a significantly shorter wound management time (median 235 seconds vs. 1,201 seconds, P < 0.001) and similar wound management cost (median US dollar [USD] 50.6 vs. USD 54.6, P = 0.529) compared to the stapler group. Subgroup analysis showed that the LSA group had a shorter management time for uncomplicated wounds and a lower cost for complicated wounds. Conclusion LSA not only provides a safe alternative but also offers a resource-efficient option for wound management compared to staplers.

To investigate the relationship between depression and AD, water avoidance stress (WAS) was induced for 10 days in both Tg2576 mice and wild-type (WT) mice. After WAS, memory function and depressive-like behavior were investigated in Tg2576 mice. Tg2576 WAS mice exhibited more depressive-like behaviors than WT WAS and Tg2576 control (CON) mice. Strikingly, Tg2576 CON mice showed more depressive-like behaviors than WT mice. Moreover, corticosterone and phospho-glucocorticoid receptor (p-GR) levels were also higher in Tg2576 WAS mice in comparison to Tg2576 CON mice. Spinster homologue 2 (SPNS2) is a member of non-ATP-dependent transporter. The role of SPNS2 was widely known as a sphingosine-1-phosphate (S1P) transporter, which export intracellular S1P from cells. Using GEO database to analyze SPNS2 gene expression changes in patients with AD and depression, we show that SPNS2 gene expression correlates with AD and depression. Interestingly, Tg2576 WAS mice displayed significantly increased levels of SPNS2 w1hen compared to Tg2576 CON counterparts. SPNS2 levels were also higher in Tg2576 CON mice in comparison with WT CON mice. Remarkably, we found a decrease in S1P brain levels and an increase in S1P serum levels of Tg2576 WAS mice in comparison with Tg2576 CON mice. Accordingly, WAS induced group further decreased S1P levels in the brains. However, the level in the serum further increased in comparison with non-induced group. Therefore, these results suggest that AD and depression could be associated, and that Tg2576 transgenic mice are more susceptible to stress-induced depression through the release of S1P by SPNS2 up-regulation.

Microplastics (MP) are pervasive environmental pollutants with potential adverse effects on human health, particularly concerning neurotoxicity. This study investigates the accumulation and neurotoxic effects of MP in cerebral organoids and mouse brains. Utilizing in vitro cerebral organoids and in vivo mouse models, we examined the penetration of MP, revealing that smaller MP (50 nm) infiltrated deeper into the organoids compared to larger ones (100 nm). Exposure to 50 nm MP resulted in a significant reduction in organoid viability. Furthermore, total RNA sequencing indicated substantial alterations in neurotoxicity-related gene expression.In vivo, MP-treated mice exhibited notable DNA fragmentation in the hippocampus and cortex, alongside elevated levels of inflammatory markers and neurotoxic metabolites, such as kynurenine (KYN) and 3-hydroxykynurenine (3-HK). Our findings suggest that MP may promote neurotoxicity through the kynurenine pathway, leading to heightened levels of neurotoxic compounds like quinolinic acid. This research highlights the potential for MP to induce neuroinflammatory responses and disrupt normal brain function, underscoring the need for further investigation into the long-term effects of MP exposure on neurological health.

Tofacitinib, which is used to treat rheumatoid arthritis (RA), is primarily metabolized by the hepatic cytochrome P450 (CYP) enzymes, CYP3A1/2 and CYP2C11. Acetaminophen (APAP), which is frequently used for pain relief in patients with RA, can induce acute liver injury (ALI) when taken in excess, profoundly affecting drug metabolism. Resveratrol (RVT) is a polyphenolic compound with hepatoprotective properties. This study investigated the protective effects of RVT against APAP-induced ALI in rats, and explored its influence on the pharmacokinetics of tofacitinib. In ALI rats, both intravenous and oral administration of tofacitinib resulted in a significant (207% and 181%) increase in the area under the plasma concentration-time curve (AUC), primarily driven by a substantial reduction (66.1%) in non-renal clearance (CLNR) compared to that in control (CON) rats. Notably, RVT administration in ALI rats provided effective liver protection, partially restoring liver function, as evidenced by normalized glutamate oxaloacetate transaminase levels and the pharmacokinetic parameters, AUC and CLNR, closer to those observed in untreated CON rats (117% and 81.9%, respectively). These findings highlight the importance of considering the potential interactions between RVT or polyphenol-rich natural products and medications in patients with ALI in clinical practice.