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: Molecular characteristics of synchronous colorectal cancers (SCRCs) remain incompletely elucidated, despite their importance in targeted therapy selection. We compared the molecular characteristics and somatic mutations between SCRCs. Materials and Methods: This retrospective study (2012-2014) included 98 consecutive patients with surgically resected SCRCs. Molecular characteristics, including microsatellite instability (MSI) and tumor-infiltrating lymphocytes (TILs), were analyzed for all cancer lesions. The intertumoral heterogeneity of SCRCs was evaluated using whole-exome sequencing (WES) for 18 cancers from nine patients with at least one MSI-high (MSI-H) tumor. Results: Twelve patients had at least one MSI-H tumor; five showed discordant MSI status. Mucinous adenocarcinoma frequency and TIL density were higher in patients with at least one MSI-H tumor than in those with only microsatellite-stable tumors. WES revealed that, except one patient (6.5%), most synchronous cancers shared few variants in each patient (0.09%-0.36%). The concordance rates for BRAF, KRAS, NRAS, and PIK3CA, in synchronous cancers from each patient were 66.7%, 66.7%, 66.7%, and 55.6%, respectively. Conclusion Although synchronous cancers shared a mutated gene, the mutation subtypes differed. SCRCs exhibited 5.1% MSI status discordance rate and a high discordance rate in somatic mutational variants. As intertumoral heterogeneity may affect the targeted therapy response, molecular analysis of all tumors is recommended for patients with SCRCs.

Purpose: Adjuvant chemotherapy (AC) is recommended for muscle-invasive or lymph node-positive upper urinary tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). However, disease recurrences are frequently observed in pT1 disease, and AC may increase the risk of overtreatment in pT2 UTUC patients. This study aimed to validate a risk-adapted scoring model for selecting UTUC patients with ≤pT2 disease who would benefit from AC. Materials and Methods: We retrospectively analyzed 443 ≤pT2 UTUC patients who underwent RNU. A risk-adapted scoring model was applied, categorizing patients into low- or high-risk groups. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were analyzed according to risk group. Results: Overall, 355 patients (80.1%) and 88 patients (19.9%) were categorized into the low- and high-risk groups, respectively, with the latter having higher pathological stages, concurrent carcinoma in situ, and synchronous bladder tumors. Disease recurrence occurred in 45 patients (10.2%), among whom 19 (5.4%) and 26 (29.5%) belonged to the low- and high-risk groups, respectively (p<0.001). High-risk patients had significantly shorter RFS (64.3% vs. 93.6% at 60 months; hazard ratio [HR] 13.66; p<0.001) and worse CSS (80.7% vs. 91.5% at 60 months; HR 4.25; p=0.002). Multivariate analysis confirmed that pT2 stage and the high-risk group were independent predictors of recurrence and cancer-specific death (p<0.001). Decision curve analysis for RFS showed larger net benefits with our model than with the T stage model. Conclusions The risk-adapted scoring model effectively predicts recurrence and identifies optimal candidates for AC post RNU in non-metastatic UTUC.

Background: Despite the critical role of vitamin D in various biological processes, its impact on frailty—a condition closely linked to biological age—remains inconclusive. This study aimed to explore the association between serum 25-hydroxyvitamin D (25[OH] D) levels and frailty status in older Korean adults, utilizing a comprehensive frailty index (FI) and a nationally representative dataset. Methods: This cross-sectional study included 6,589 participants aged ≥65 years from the Korea National Health and Nutrition Examination Survey (2008–2012). Frailty was assessed using a deficit accumulation FI based on 38 physical, cognitive, psychological, and social items. Results: After adjusting for potential confounders, frail men showed 6.8% lower serum 25(OH)D concentrations compared to nonfrail controls (P=0.007). Men in the lowest serum 25(OH)D quartile (≤39.3 nmol/L) exhibited a 5.3% higher FI (P=0.047) and 1.71-fold increased odds of frailty (P=0.005), compared to those in the highest quartile (>63.3 nmol/L). Similarly, men with vitamin D deficiency (<30 nmol/L) exhibited a 9.6% higher FI compared to those with sufficient vitamin D levels (≥50 nmol/L; P=0.004). However, no significant association between serum 25(OH)D concentration and frailty was observed in women across any analysis. Conclusion These findings suggest that low serum 25(OH)D concentrations are a potential risk factor for frailty, particularly in men. Further research is warranted to determine whether vitamin D supplementation in such high-risk older adults could help mitigate frailty.

Bovine borreliosis, caused by Borrelia theileri which is transmitted via hard tick bites, is associated with mild clinical symptoms, such as fever, lethargy, hemoglobinuria, anorexia, and anemia. Borrelia theileri infects various animals, such as cattle, deer, horses, goats, sheep, and wild ruminants, in Africa, Australia, and South America. Notably, no case of B. theileri infection has been reported in Korean cattle to date. In this study, 101 blood samples were collected from a Korean indigenous cattle breed, among which 1.98% tested positive for B. theileri via nested PCR. The obtained sequences exhibited high homology with B. theileri strains identified in other regions. Phylogenetic analysis of 16S rRNA confirmed the B. theileri group affiliation; however, flagellin B sequences exhibited divergence, potentially due to regional evolutionary differences. This study provides the first molecular confirmation of B. theileri infection in Korean livestock. Further isolation and nucleotide sequence analyses are necessary to better understand the presence of B. theileri strains in cows in Korea.

BACKGROUND: Current tendon and ligament reconstruction surgeries rely on scar tissue healing which differs from native bone-to-tendon interface (BTI) tissue. We aimed to engineer Synovium-derived mesenchymal stem cells (Sy-MSCs) based scaffold-free fibrocartilage constructs and investigate in vivo bone–tendon interface (BTI) healing efficacy in a rat anterior cruciate ligament (ACL) reconstruction model. METHODS: Sy-MSCs were isolated from knee joint of rats. Scaffold-free sy-MSC constructs were fabricated and cultured in differentiation media including TGF-b-only, CTGF-only, and TGF-b + CTGF. Collagenase treatment on tendon grafts was optimized to improve cell-to-graft integration. The effects of fibrocartilage differentiation and collagenase treatment on BTI integration was assessed by conducting histological staining, cell adhesion assay, and tensile testing. Finally, histological and biomechanical analyses were used to evaluate in vivo efficacy of fibrocartilage construct in a rat ACL reconstruction model. RESULTS: Fibrocartilage-like features were observed with in the scaffold-free sy-MSC constructs when applying TGF-band CTGF concurrently. Fifteen minutes collagenase treatment increased cellular attachment 1.9-fold compared to the Control group without affecting tensile strength. The failure stress was highest in the Col + D + group (22.494 ± 13.74 Kpa) compared to other groups at integration analysis in vitro. The ACL Recon + FC group exhibited a significant 88% increase in estimated stiffness (p = 0.0102) compared to the ACL Recon group at the 4-week postoperative period. CONCLUSION Scaffold-free, fibrocartilage engineering together with tendon collagenase treatment enhanced fibrocartilaginous BTI healing in ACL reconstruction.

The prevalence of thyroid cancer in pregnant women is unknown; however, given that thyroid cancer commonly develops in women, especially young women of childbearing age, new cases are often diagnosed during pregnancy. This recommendation summarizes the follow-up and treatment when thyroid cancer is diagnosed during pregnancy and when a woman with thyroid cancer becomes pregnant. If diagnosed in the first trimester, surgery should be postponed until after delivery, and the patient should be monitored with ultrasound. If follow-up before 24–26 weeks of gestation shows that thyroid cancer has progressed, surgery should be considered. If it has not progressed at 24–26 weeks of gestation or if papillary thyroid cancer is diagnosed after 20 weeks of pregnancy, surgery should be considered after delivery.

Surgical resection is typically the primary treatment for differentiated thyroid cancer (DTC), followed by radioactive iodine (RAI) and thyroid-stimulating hormone suppression therapies based on the cancer stage and risk of recurrence. Nevertheless, further treatment may be necessary for patients exhibiting persistent disease following RAI therapy, residual disease refractory to RAI, or unresectable locoregional lesions. This guideline discusses the role of external beam radiotherapy and chemotherapy following surgical resection in patients with DTC. External beam radiotherapy is ineffective if DTC has been entirely excised (Grade 2). Adjuvant external beam radiotherapy may be optionally performed in patients with incomplete surgical resection or frequently recurrent disease (Grade 2). In patients at high risk of recurrence following surgery and RAI therapy, adjuvant external beam radiotherapy may be optionally considered (Grade 3). However, external beam radiotherapy may increase the risk of serious adverse events after tyrosine kinase inhibitor therapy. Therefore, careful consideration is needed when prescribing external beam radiotherapy for patients planning to undergo tyrosine kinase inhibitor therapy. There is no evidence supporting the benefits of the routine use of adjuvant chemotherapy for DTC treatment (Grade 2).

Only a small percentage of patients (2-5%) with differentiated thyroid cancer (DTC) exhibit distant metastasis at the initial diagnosis or during the disease course. The most common metastatic sites of DTC are the lungs, followed by the bones. Radioactive iodine (RAI) therapy is considered the primary treatment for RAI-avid distant metastatic DTC. Depending on the characteristics of metastatic lesions, local treatment such as surgical resection, radiofrequency ablation, and external beam radiation therapy may be considered for some patients with metastatic DTC. Slowly growing and asymptomatic metastases can be monitored with follow-up while receiving thyroid-stimulating hormone (TSH) suppression therapy. In patients with a limited number of lung metastases and good performance status, surgical removal of the metastatic lesions may be considered. Systemic therapy should be considered for patients with progressive RAI refractory DTC. In this clinical guideline, we aim to outline the treatment principles for patients with lung, bone, and brain metastases of DTC.

The primary treatment for differentiated thyroid cancer (DTC) with distant metastasis is high-dose radioactive iodine (RAI) therapy, which can have various effects depending on the iodine uptake of thyroid cancer cells. The iodine uptake of metastatic lesions decreases over time, and approximately 40-70% of patients eventually develop RAI refractory disease. Although the prognosis of patients with RAI refractory DTC is very poor, clinical outcomes vary depending on the location and progression of metastatic lesions. Therefore, it is crucial to determine which patients should receive active systemic therapy with tyrosine kinase inhibitor (TKI) and how to apply local treatment before or during systemic therapy. This guideline covers the definition, treatment principles, systemic anticancer agents, and complications of progressive RAI-refractory DTC. RAI refractory DTC is defined as (1) the absence of RAI uptake on whole body scan, (2) presence of RAI uptake in some lesions but not in others, or (3) disease progression despite RAI uptake. Treatment options for RAI refractory DTC include surgery, external beam radiation therapy, locoregional therapies such as high-intensity focused ultrasound ablation, and systemic anticancer therapy.In patients with minimal symptoms and progression, active surveillance without specific treatment may be considered. Systemic treatment should be considered for patients with multiple progressive lesions by RECIST criteria. Furthermore, testing for cancer gene mutations, including BRAF, NTRK, and RET genes, is recommended for personalized therapy. Systemic therapy should be decided based on shared decision-making between the patient and specialist, considering anticipated benefits and risks. Regular assessment of treatment responses and evaluation of adverse events is essential, with dose adjustment based on these assessments. The optimal time of use, clinical approaches for the prevention and control of adverse events, and individualized treatment approaches based on patient characteristics will be of great help in the treatment of patients with RAI-refractory DTC.