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Objective: The presence of extrathyroidal extension (ETE) in differentiated thyroid cancer (DTC) patients is an important predictor of their prognosis. Therefore, the tumor stage of DTC is divided into extensive ETE and gross ETE only affecting the strap muscle (Gross strap muscles invasion; gSMI). However, insufficient evidence exists regarding the association of gSMI with the prognosis, especially in relation to tumor size., Methods: Related literature was searched in MEDLINE, Embase, Cochrane Library and KoreaMed. All processes were performed in accordance with PRISMA guidelines, and the process was conducted by two independent reviewers. The meta-analysis was performed using a random-effect model considering the diversity of studies. RoBANS version 2.0, an evaluation tool for non-randomized studies, was used to evaluate the quality of the selected research. Clinical data from observational studies that analyzed the relationship between the degree of ETE and prognosis were collected, and a meta-analysis was performed., Results: Eighteen observational studies were included in this study. A subgroup analysis was performed for each outcome. The recurrence rate (odds ratio [OR]: 2.498), disease-specific mortality (risk ratio [RR]: 2.984), overall mortality (RR: 1.361) and lymph node (LN) metastasis (OR: 5.355) were significantly higher in patients with gSMI than in those with no ETE. However, in an analysis limited to tumors 4 cm or smaller, no significant difference in prognostic outcomes was seen, except for LN metastasis., Conclusion: gSMI has a negative impact on the prognosis; however, this correlation diminishes when the tumor size is small. Thus, a more cautious approach is warranted during the treatment process.

Objective: To examine whether simple laboratory tests can guide selection between tocilizumab (TCZ) and tumor necrosis factor inhibitors (TNFi) in biologic-naive patients with rheumatoid arthritis (RA), by investigating their influence on drug retention., Methods: Data of RA patients prescribed TCZ or TNFi as the initial biologics from March 2013 to December 2021 were obtained from the KOrean College of Rheumatology BIOlogics and Targeted Therapy (KOBIO) registry. Propensity score matching was performed to adjust for baseline confounding factors. Hazards of drug discontinuation for TCZ were calculated compared to those for TNFi. Interaction analyses with a Bonferroni-corrected p-value threshold were conducted to determine whether the hemoglobin level, C-reactive protein level, erythrocyte sedimentation rate, and platelet count affected the hazards of drug discontinuation., Results: Overall, 893 patients were analyzed, of whom 315 and 578 were treated with TCZ and TNFi, respectively. The hazards of drug discontinuation in all patients were lower for TCZ than for TNFi (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.44~0.66). Notably, only the presence of anemia indicated a significant interaction (p for interaction=0.010); the HRs for drug discontinuation were 0.41 (95% CI 0.30~0.55) and 0.70 (95% CI 0.53~0.92) in the anemic and non-anemic groups, respectively. In the anemic subgroup, biologics were discontinued because of a lack of efficacy in 35.0% of TNFi initiators and 7.4% of TCZ initiators.Conclusion The drug discontinuation rate in biologic-naïve patients with RA was significantly lower for TCZ than for TNFi, particularly in those with anemia., Competing Interests: CONFLICT OF INTEREST BSK has been an editorial board member since May 2022, but has no role in the decision to publish this article. The authors declare that they have no competing interests., (Copyright © 2024 by The Korean College of Rheumatology. All rights reserved.)

Metastasis is the primary stumbling block to the treatment of bladder cancer (BC). In order to spread, tumor cells must acquire increased migratory and invasive capacity, which is tightly linked with pseudopodia formation. Here, we unravel the effects of sulforaphane (SFN), an isothiocyanate in cruciferous vegetables, on the assembly of pseudopodia and BC metastasis, and its molecular mechanism in the process. Our database analysis revealed that in bladder tumor, pseudopodia-associated genes, CTTN, WASL and ACTR2/ARP2 are upregulated. SFN caused lamellipodia to collapse in BC cells by blocking the CTTN-ARP2 axis. SFN inhibited invadopodia formation and cell invasion by reducing WASL in different invasive BC cell lines. The production of ATP, essential for the assembly of pseudopodia, was significantly increased in bladder tumors and strongly inhibited by SFN. Overexpressing AKT1 reversed the downregulation of ATP in SFN-treated bladder cancer cells and restored filopodia and lamellipodia morphology and function. Bioluminescent imaging showed that SFN suppressed BC metastases to the lung of nude mice while downregulating Cttn and Arp2 expression. Our study thus reveals mechanisms of SFN action in inhibiting pseudopodia formation and highlights potential targeting options for the therapy of metastatic bladder cancer., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Context: Epidemiological studies indicated that cruciferous vegetable intake is associated with positive health outcomes. However, the role of cruciferous vegetables may have differential impacts on various cancers., Objective: This meta-analysis aims to review recent epidemiological studies on the link between cruciferous vegetables and various cancers. It seeks to identify the optimal intake dose and timing of cruciferous vegetables influencing their association with cancer risk., Data Sources: Studies on cruciferous vegetables and cancer were searched in PubMed, NCBI, Web of Science, and Elsevier databases from 1978 to June 2023., Data Extraction: Extracted data from 226 relevant case-control and cohort studies were expressed by standardized mean difference and 95% CI, followed by the subgroup analysis to eliminate heterogeneity., Results: Intake of cruciferous vegetables can prevent cancers, with an odds ratio of 0.77 and risk ratio (RR) of 0.96. The intake levels of cruciferous vegetables associated with the risk of colorectal cancer, lung cancer, upper gastrointestinal cancer, gynecological cancer (ovarian cancer and endometrial cancer), bladder cancer, renal cancer, and prostate cancer were found to be 5.41 servings/week, 5.41 servings/week, 5.5 servings/week, 7.4 servings/week, 5.5 servings/week, 4.85 servings/week, and 3 servings/week, respectively. In a cohort followed for 2 to 15 years, limited consumption of cruciferous vegetables was correlated with a higher cancer RR. In the Asian population, cruciferous vegetables had a significant relationship with lung cancer, head and neck squamous cell carcinoma, and esophageal cancer. Conversely, cruciferous vegetables are predominantly associated with colorectal, renal, gynecological, and prostate cancer in the American population., Conclusion: This study highlights the complex link between cruciferous vegetables and cancer, influenced by factors such as cancer type, region, intake level, and follow-up duration., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Object: To investigate the factors associated with cause-specific discontinuation of long-term anti-tumor necrosis factor (TNF) agent use in patients with ankylosing spondylitis (AS)., Methods: AS patients who initiated first-line anti-TNF treatment between 2004 and 2018 and continued treatment for at least two years were enrolled in the study. Enrolled patients were observed until the last visit, discontinuation of treatment, or September 2022. Reasons for discontinuation of the first-line anti-TNF agent were categorized into the following: (1) clinical remission, (2) loss of efficacy, (3) adverse events, and (4) other reasons including loss to follow-up, cost, or reimbursement issues. A cumulative incidence function curve was used to visualize the cumulative failure rates over time for each specific reason. Univariable and multivariable cause-specific hazard models were utilized to identify factors associated with cause-specific discontinuation of the first-line anti-TNF agent., Results: A total of 429 AS patients was included in the study, with 121 treated with adalimumab (ADA), 176 with etanercept (ETN), 89 with infliximab (INF), and 43 with golimumab (GLM). The median overall survival on the first-line anti-TNF agent was 10.6 (7.9-14.5) years. Among the patients, 103 (24.0%) discontinued treatment, with 36 (34.9%) due to inefficacy, 31 (30.1%) due to clinical remission, 15 (14.6%) due to adverse events, and 21 (20.4%) due to other reasons. Patients treated with ETN had a lower risk of discontinuation due to clinical remission compared to those receiving ADA (hazard ratio [HR] 0.45 [0.21-0.99], P = 0.048). Higher baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; HR 1.31 [1.04-1.65], P = 0.023) and INF use were linked to a higher risk of treatment discontinuation for inefficacy compared to ADA use (HR 4.53 [1.45-14.16], P = 0.009). Older age was related to an increased risk of discontinuation due to infection-related adverse events (HR 1.07 [1.02-1.12], P = 0.005), and current smoking was a risk factor for discontinuation due to other reasons (HR 6.22 [1.82-21.28], P = 0.004)., Conclusion: AS patients on their first anti-TNF treatment for at least two years demonstrated a favorable long-term treatment retention rate, with a 24.0% discontinuation rate over a 10.6-year overall survival period. The predictors for discontinuation varied by causes, underscoring the complexity of treatment response and the importance of personalized approaches to treatment management., (© 2024. The Author(s).)

Aim: Ankylosing spondylitis (AS) predominantly affects the spine and sacroiliac joints, with rare renal involvement. We investigated the incidence rate and risk factors for chronic kidney disease (CKD) in patients with AS and its relationship with long-term nonsteroidal anti-inflammatory drug (NSAID) use., Methods: We retrospectively analyzed data of patients diagnosed with AS from the Korean National Health Insurance service. The 3-month, 6-month, and 1-year Assessment of SpondyloArthritis International Society (ASAS) NSAID Intake Scores were categorized into four groups, as follows: =0, >0 and ≤33.3, 33.3-66.6, and >66.6., Results: Of the 12 000 patients with AS, 150 were identified with CKD, and the incidence rate was 4.64 per 10 000 patient-years. Factors significantly associated with CKD included age ≥60 years, Charlson Comorbidity Index, hypertension, and diabetes mellitus. In the nested case-control analysis, among the ASAS NSAIDs Intake Scores for 0-365 days from diagnosis, the ≥66.6 group had a significantly lower odds ratio than those of the =0 group., Conclusion: The present study established the incidence rate of CKD in Korean patients with AS. Though older age and comorbidities were found to be associated with a higher CKD risk, long-term NSAID use was associated with a lower risk. Therefore, the optimal use of NSAIDs in inflammatory diseases requires extensive research., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

The SUV max is a measure of FDG uptake and is related with tumor aggressiveness in thyroid cancer, however, its association with molecular pathways is unclear. Here, we investigated the relationship between SUV max and gene expression profiles in 80 papillary thyroid cancer (PTC) patients. We conducted an analysis of DEGs and enriched pathways in relation to SUV max and tumor size. SUV max showed a positive correlation with tumor size and correlated with glucose metabolic process. The genes that indicate thyroid differentiation, such as SLC5A5 and TPO, were negatively correlated with SUV max . Unsupervised analysis revealed that SUV max positively correlated with DNA replication(r = 0.29, p = 0.009), pyrimidine metabolism(r = 0.50, p < 0.0001) and purine metabolism (r = 0.42, p = 0.0001). Based on subgroups analysis, we identified that PSG5, TFF3, SOX2, SL5A5, SLC5A7, HOXD10, FER1L6, and IFNA1 genes were found to be significantly associated with tumor aggressiveness. Both high SUV max PTMC and macro-PTC are enriched in pathways of DNA replication and cell cycle, however, gene sets for purine metabolic pathways are enriched only in high SUV max macro-PTC but not in high SUV max PTMC. Our findings demonstrate the molecular characteristics of high SUV max tumor and metabolism involved in tumor growth in differentiated thyroid cancer., (© 2024. The Author(s).)

Neutrophil heterogeneity is involved in autoimmune diseases, sepsis, and several cancers. However, the link between neutrophil heterogeneity and T-cell immunity in thyroid cancer is incompletely understood. We investigated the circulating neutrophil heterogeneity in 3 undifferentiated thyroid cancer (UTC), 14 differentiated thyroid cancer (DTC) (4 Stage IV, 10 Stage I-II), and healthy controls (n = 10) by transcriptomic data and cytometry. Participants with UTC had a significantly higher proportion of immature high-density neutrophils (HDN) and lower proportion of mature HDN in peripheral blood compared to DTC. The proportion of circulating PD-L1 + immature neutrophils were significantly increased in advanced cancer patients. Unsupervised analysis of transcriptomics data from circulating HDN revealed downregulation of innate immune response and T-cell receptor signaling pathway in cancer patients. Moreover, UTC patients revealed the upregulation of glycolytic process and glutamate receptor signaling pathway. Comparative analysis across tumor types and stages revealed the downregulation of various T-cell-related pathways, such as T-cell receptor signaling pathway and T-cell proliferation in advanced cancer patients. Moreover, the proportions of CD8+ and CD4+ T effector memory CD45RA+ (TEMRA) cells from peripheral blood were significantly decreased in UTC patients compared to DTC patients. Finally, we demonstrated that proportions of tumor-infiltrated neutrophils were increased and related with poor prognosis in advanced thyroid cancer using data from our RNA-seq and TCGA (The Cancer Genome Atlas) data. In conclusion, observed prevalence of circulating immature high-density neutrophils and their immunosuppressive features in undifferentiated thyroid cancers underscore the importance of understanding neutrophil dynamics in the context of tumor progression in thyroid cancer., (© 2024. The Author(s).)

The relationship between saturated fatty acids (SFA) and bladder cancer (BC) risk has been conflicting. Our aim was to investigate the relationship between erythrocyte membrane SFA and BC risk. A total of 404 participants were enrolled in the study (including 112 cases and 292 controls). A validated food frequency questionnaire was used to assess the food intake. The constitutive composition of fatty acids in the erythrocyte membrane was measured by gas chromatography. After adjustment for BC risk factors, SFA had no significant association with BC risk. However, C18:0 was positively linked with BC risk with an odds ratio (OR; 95% CI) of 2.99 (1.37-6.53). In contrast, very-long-chain saturated fatty acids (VLCSFA), especially C24:0, were negatively related to BC risk with an OR (95% CI) of 0.28 (0.12-0.65) for VLCSFA and 0.33 (0.15-0.75) for C24:0. Higher total odd-chain SFA (C15:0 and C17:0) were associated with a lower risk of BC with OR (95% CI) of 0.18 (0.076-0.44), 0.18 (0.068-0.47), 0.34 (0.14-0.81), respectively. After subgroup analysis, the protective effects C15:0 and C17:0 were still remained. Receiver operating characteristic analysis displayed that the combination of C15:0 and C17:0 indexes increased the accurate predictive rate of BC risk. Further mediation effect analysis showed that C15:0 and C17:0 could be used as partial mediation effectors for milk and dairy products and bladder carcinogenesis. Overall, the combination of odd-chain SFA (C15:0 and C17:0) in the erythrocyte membrane could serve as a reliable mediator and predictor, indicating a relationship between a high intake of milk and dairy products and a lower risk of BC., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

After the first outbreak, SARS-CoV-2 infection continues to occur due to the emergence of new variants. There is limited information available on the comparative evaluation of evolutionary characteristics of SARS-CoV-2 among different countries over time, and its relatedness to epidemiological and socio-environmental factors within those countries. We assessed comparative Bayesian evolutionary characteristics for SARS-CoV-2 in eight countries from 2020 to 2022 using BEAST version 2.6.7. Additionally, the relatedness between virus evolution factors and both epidemiological and socio-environmental factors was analyzed using Pearson's correlation coefficient. The estimated substitution rates in the gene encoding S protein of SARS-CoV-2 exhibited a continuous increase from 2020 to 2022 and were divided into two distinct groups in 2022 ( p value < 0.05). Effective population size ( Ne ) generally showed decreased patterns by time. Notably, the change rates of the substitution rates were negatively correlated with the cumulative vaccination rates in 2021. A strict and rapid vaccination policy in the United Arab Emirates dramatically reduced the evolution of the virus, compared to other countries. Also, the average yearly temperature in countries were negatively correlated with the substitution rates. The changes of six epitopes in SARS-CoV-2 were related to various socio-environmental factors. We figured out comparative virus evolutionary traits and the association of epidemiological and socio-environmental factors especially cumulative vaccination rates and average temperature., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Objective: Active surveillance (AS) is generally accepted as an alternative to immediate surgery for papillary thyroid carcinoma (PTC) measuring ≤1.0 cm (cT1a) without risk factors. This study investigated the clinicopathologic characteristics of PTCs measuring ≤2.0 cm without cervical lymph node metastasis (cT1N0) by tumor size group to assess the feasibility of AS for PTCs between 1.0 cm and 1.5 cm (cT1b≤1.5)., Design: This study enrolled clinically T1N0 patients with preoperative ultrasonography information (n= 935) from a cohort of 1259 patients who underwent lobectomy and were finally diagnosed with PTC from June 2020 to March 2022., Results: The cT1b≤1.5 group (n = 171; 18.3 %) exhibited more lymphatic invasion and occult central lymph node (LN) metastasis with a higher metastatic LN ratio than the cT1a group (n = 719; 76.9 %). However, among patients aged 55 years or older, there were no significant differences in occult central LN metastasis and metastatic LN ratio between the cT1a, cT1b≤1.5, and cT1b>1.5 groups. Multivariate regression analyses revealed that occult central LN metastasis was associated with age, sex, tumor size, extrathyroidal extension, and lymphatic invasion in patients under 55, while in those aged 55 or older, it was associated only with age and lymphatic invasion., Conclusion: For PTC patients aged 55 years or older with cT1b≤1.5, AS could be a viable option due to the absence of a significant relationship between tumor size and occult central LN.

Objective: Ankylosing spondylitis (AS) is chronic inflammatory arthritis causing structural damage and radiographic progression to the spine due to repeated and continuous inflammation over a long period. This study establishes the application of machine learning models to predict radiographic progression in AS patients using time-series data from electronic medical records (EMRs)., Methods: EMR data, including baseline characteristics, laboratory findings, drug administration, and modified Stoke AS Spine Score (mSASSS), were collected from 1,123 AS patients between January 2001 and December 2018 at a single center at the time of first (T1), second (T2), and third (T3) visits. The radiographic progression of the (n+1)th visit (Pn+1=(mSASSSn+1-mSASSSn)/(Tn+1-Tn)≥1 unit per year) was predicted using follow-up visit datasets from T1 to Tn. We used three machine learning methods (logistic regression with the least absolute shrinkage and selection operation, random forest, and extreme gradient boosting algorithms) with three-fold cross-validation., Results: The random forest model using the T1 EMR dataset best predicted the radiographic progression P2 among the machine learning models tested with a mean accuracy and area under the curves of 73.73% and 0.79, respectively. Among the T1 variables, the most important variables for predicting radiographic progression were in the order of total mSASSS, age, and alkaline phosphatase., Conclusion: Prognosis predictive models using time-series data showed reasonable performance with clinical features of the first visit dataset when predicting radiographic progression., Competing Interests: CONFLICT OF INTEREST B.S.K. has been an editorial board member since May 2022, but has no role in the decision to publish this article. The authors declare that they have no competing interests., (Copyright © 2024 by The Korean College of Rheumatology. All rights reserved.)

Background: The clinicopathological impact of chronic lymphocytic thyroiditis on patients with papillary thyroid carcinoma patients is still controversial. This study aimed to evaluate the clinicopathologic differences and risk factors for central lymph node metastasis based on the presence of coexistent chronic lymphocytic thyroiditis in patients with low- to intermediate-risk papillary thyroid carcinoma., Methods: The medical records of 1,022 patients with low- to intermediate-risk papillary thyroid carcinoma who underwent lobectomy and central neck dissection between June 2020 and March 2022 were reviewed. Differences in clinicopathological factors were analyzed in patients with papillary thyroid carcinoma with or without chronic lymphocytic thyroiditis. Furthermore, risk factors for central lymph node metastasis in patients with low- to intermediate-risk papillary thyroid carcinoma with or without chronic lymphocytic thyroiditis were evaluated., Results: Among the 1,022 patients with low to intermediate-risk papillary thyroid carcinoma, 102 (10.0%) had coexisting chronic lymphocytic thyroiditis. Female sex (odds ratio = 3.536, P = .001, 95% confidence interval 1.781-8.069), a multifocal tumor (odds ratio = 2.162, P = .001, 95% confidence interval 1.358-3.395), and angiolymphatic invasion (odds ratio = 0.365, P < .001, 95% confidence interval 0.203-0.625) were independent factors associated with patients who had coexisting chronic lymphocytic thyroiditis compared to those without chronic lymphocytic thyroiditis. There were 358 (35%) patients who had central lymph node metastasis. Multivariate analysis showed that younger age (odds ratio = 0.667, P = .013, 95% confidence interval 0.482-0.555), male sex (odds ratio = 0.549, P < .001, 95% confidence interval 0.402-0.751), tumor size >1 cm (odds ratio = 1.454, P = .022, 95% confidence interval 1.053-2.003), extrathyroidal extension (odds ratio = 1.874, P < .001, 95% confidence interval 1.414-2.486), and angiolymphatic invasion (odds ratio = 3.094, P < .001, 95% confidence interval 2.339-4.101) were risk factors for central lymph node metastasis. Angiolymphatic invasion (odds ratio = 11.184, P < .001, 95% confidence interval 3.277-46.199) was identified as the sole independent risk factor for central lymph node metastasis in patients with papillary thyroid carcinoma with coexisting chronic lymphocytic thyroiditis., Conclusion: Our data suggest that patients with low to intermediate-risk papillary thyroid carcinoma with coexistent chronic lymphocytic thyroiditis exhibit different clinical features than patients with papillary thyroid carcinoma without chronic lymphocytic thyroiditis. Additionally, the presence of chronic lymphocytic thyroiditis may be considered a potential factor against central lymph node metastasis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a representative cause of dementia and is caused by neuronal loss, leading to the accumulation of aberrant neuritic plaques and the formation of neurofibrillary tangles. Oxidative stress is involved in the impaired clearance of amyloid beta (Aβ), and Aβ-induced oxidative stress causes AD by inducing the formation of neurofibrillary tangles. Hwangryunhaedok-tang (HHT, Kracie K-09 ® ), a traditional herbal medicine prescription, has shown therapeutic effects on various diseases. However, the studies of HHT as a potential treatment for AD are insufficient. Therefore, our study identified the neurological effects and mechanisms of HHT and its key bioactive compounds against Alzheimer's disease in vivo and in vitro. In a 5xFAD mouse model, our study confirmed that HHT attenuated cognitive impairments in the Morris water maze (MWM) test and passive avoidance (PA) test. In addition, the prevention of neuron impairment, reduction in the protein levels of Aβ, and inhibition of cell apoptosis were confirmed with brain tissue staining. In HT-22 cells, HHT attenuates tBHP-induced cytotoxicity, ROS generation, and mitochondrial dysfunction. It was verified that HHT exerts a neuroprotective effect by activating signaling pathways interacting with Nrf2, such as MAPK/ERK, PI3K/Akt, and LKB1/AMPK. Among the components, baicalein, a bioavailable compound of HHT, exhibited neuroprotective properties and activated the Akt, AMPK, and Nrf2/HO-1 pathways. Our findings indicate a mechanism for HHT and its major bioavailable compounds to treat and prevent AD and suggest its potential.

The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Woohwangchungsimwon (WCW) is a traditional medicine used in East Asian countries to treat central nervous system disorders. Reported pharmacological properties include antioxidant effects, enhanced learning and memory, and protection against ischemic neuronal cell death, supporting its use in treating neurodegenerative diseases like Alzheimer's disease (AD)., Aim of the Study: The study aims to assess the effects of co-treatment with WCW and donepezil on cognitive functions and serum metabolic profiles in a scopolamine-induced AD model., Materials and Methods: Cell viability and reactive oxygen species (ROS) levels were measured in amyloid β-peptide 25-35 (Aβ 25-35 )-induced SH-SY5Y cells. An AD model was established in ICR mice by intraperitoneal scopolamine administration. Animals underwent the step-through passive avoidance test (PAT) and Morris water maze (MWM) test. Hippocampal tissues were collected to examine specific protein expression. Serum metabolic profiles were analyzed using nuclear magnetic resonance (NMR) spectroscopy., Results: Co-treatment with WCW and donepezil increased cell viability and reduced ROS production in Aβ 25-35 -induced SH-SY5Y cells compared to that with donepezil treatment alone. Co-treatment improved cognitive functions and was comparable to donepezil treatment alone in the PAT and MWM tests. Pathways related to tyrosine, phenylalanine, and tryptophan biosynthesis, phenylalanine metabolism, and cysteine and methionine metabolism were altered by co-treatment. Levels of tyrosine and methionine, major serum metabolites in these pathways, were significantly reduced after co-treatment., Conclusions: Co-treatment with WCW and donepezil shows promise as a therapeutic strategy for AD and is comparable to donepezil alone in improving cognitive function. Reduced tyrosine and methionine levels after co-treatment may enhance cognitive function by mitigating hypertyrosinemia and hyperhomocysteinemia, known risk factors for AD. The serum metabolic profiles obtained in this study can serve as a foundation for developing other bioactive compounds using a scopolamine-induced mouse model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Despite its rarity and limited documentation, therapeutic neck dissection (ND) for cervical lymph node (LN) metastases from distant primary sites is increasingly practiced, potentially enhancing survival rates. However, the optimal ND extent remains unclear. This study aimed to determine the safety of excluding upper neck levels from ND., Methods: We retrospectively analyzed 25 patients who underwent ND for cervical LN metastases from remote primary tumors between 2015 and 2021 (12 with primary lung tumors, four with ovary, three with mammary gland, three with esophagus, two with thymus, and one with colon)., Results: Assessing clinical characteristics and occult metastasis rates, we observed LN metastases predominantly at levels III and IV. Occult metastases occurred in 14 out of 25 patients, primarily at neck levels III and IV (55.0% and 50.0%, respectively). The five-year disease-specific survival rate for all patients was 44.3%. While no statistically significant impact of occult metastasis on prognosis was confirmed, an association between the postoperative LN ratio and poor prognosis was revealed., Conclusions: Our findings suggest that prophylactic NDs at levels I, II, and Va may not be essential for managing cervical LN metastases from remote primary malignancies. This could lead to a more tailored and less invasive therapeutic strategy.