Strategies for the development of in vitro models of spinal cord ischemia-reperfusion injury: Oxygen-glucose deprivation and reoxygenation.

BACKGROUND: In vitro models tailored for spinal cord ischemia-reperfusion injury are pivotal for investigation of the mechanisms underlying spinal cord injuries. We conducted a two-phased study to identify the optimal conditions for establishing an in vitro model of spinal cord ischemia-reperfusion injury using primary rat spinal motor neurons. NEW METHOD: In the first phase, cell cultures were subjected to oxygen deprivation (OD) only, glucose deprivation (GD) only, or simultaneous deprivation of oxygen and glucose [oxygen-glucose deprivation (OGD)] for different durations (1, 2, and 6 h). In the second phase, different durations of re-oxygenation (1, 12, and 24 h) were applied after 1 h of OGD to determine the optimal duration simulating reperfusion injury. RESULTS AND COMPARISON WITH EXISTING METHOD(S): GD for 6 h significantly reduced cell viability (91 % of control, P<0.001) and increase cytotoxicity (111 % of control, P<0.001). OGD for 1 h and 2 h, resulted in a significant decrease in cell viability (80 % of control P<0.001, respectively), and increase in cytotoxicity (130 % of control, P<0.001, respectively). Re-oxygenation for 1, 12, and 24 h worsened ischemic injury following 1 h of OGD (all P<0.05). CONCLUSIONS: Our results may provide a valuable guide to devise in vitro models of spinal cord ischemia-reperfusion injury using primary spinal motor neurons.

ACCELERATED CELL DEATH 6 is a crucial genetic factor shaping the natural diversity of age- and salicylic acid-induced leaf senescence in Arabidopsis.

Leaf senescence is a crucial process throughout evolution, vital for plant fitness as it facilitates the gradual shift of energy allocation between photosynthesis and catabolism overtime. This onset is influenced by a complex interplay of genetic and environmental factors, making senescence a key adaptation mechanism for plants in their natural habitats. Our study investigated the genetic mechanism underlying age-induced leaf senescence in Arabidopsis natural populations. Using a phenome high-throughput investigator, we comprehensively analyzed senescence responses across 234 Arabidopsis accessions and identified that environmental factors (e.g., ambient temperature) and physiological factors (e.g., defense responses) are substantially linked to senescence phenotypes. Through genome-wide association mapping, we identified the ACCELERATED CELL DEATH 6 (ACD6) locus as a potential regulator of senescence variation among natural accessions. Knocking out ACD6 in accessions with early and delayed senescence phenotypes resulted in varying degrees of delay in age-induced senescence, highlighting the accession-dependent regulatory role of ACD6 in leaf senescence. Furthermore, our findings suggest ACD6's involvement in senescence regulation via the salicylic acid signaling pathway. In summary, our study sheds light on the genetic regulation of leaf senescence in Arabidopsis natural populations, with the discovery of ACD6 as a potential candidate for genetic modification to enhance plant adaptation and survival.

Internal quality prediction technology for 'Sulhyang' strawberry fruit using organic analysis and hyperspectral imaging.

In recent years, hyperspectral imaging combined with machine learning techniques has garnered significant attention for its potential in assessing fruit maturity. This study proposes a method for predicting strawberry fruit maturity based on the harvest time. The main features of this study are as follows. 1) Selection of wavelength band associated with strawberry growth season; 2) Extraction of efficient parameters to predict strawberry maturity 3) Prediction of internal quality attributes of strawberries using extracted parameters. In this study, experts cultivated strawberries in a controlled environment and performed hyperspectral measurements and organic analyses on the fruit with minimal time delay to facilitate accurate modeling. Data augmentation techniques through cross-validation and interpolation were effective in improving model performance. The four parameters included in the model and the cumulative value of the model were available for quality prediction as additional parameters. Among these five parameter candidates, two parameters with linearity were finally identified. The predictive outcomes for firmness, soluble solids content, acidity, and anthocyanin levels in strawberry fruit, based on the two identified parameters, are as follows: The first parameter, ps, demonstrated RMSE performances of 1.0 N, 2.3 %, 0.1 %, and 2.0 mg per 100 g fresh fruit for firmness, soluble solids content, acidity, and anthocyanin, respectively. The second parameter, p3, showed RMSE performances of 0.6 N, 1.2 %, 0.1 %, and 1.8 mg per 100 g fresh fruit, respectively. The proposed non-destructive analysis method shows the potential to overcome the challenges associated with destructive testing methods for assessing certain internal qualities of strawberry fruit.

Anti-Streptococcus mutans and anti-inflammatory effects of ginsenoside Compound K and enzyme-treated red ginseng extract (BTEX-K).

OBJECTIVES: Dental caries, or tooth decay, is an oral health issue worldwide. Oral healthcare researchers are considering how to develop safe and effective preventive measures and treatments for dental caries. This study evaluated the potential applications of Compound K and BTEX-K, a Compound K-rich red ginseng extract, for the prevention and treatment of dental caries. Moreover, this study briefly confirmed its inhibitory effect on inflammation, an important factor in dental health. METHODS: The amount of organic acids produced by bacteria in biofilm was determined using in vitro and in vivo assays. The ability of these extracts to promote tooth remineralization and microhardness was evaluated using an in vivo mouse assay. We evaluated their anti-inflammatory potential by inhibiting proinflammatory cytokine expression and lipopolysaccharide-induced nitrous oxide production in cell lines. RESULTS: Compound K (10-20 µg/mL) and BTEX-K (50-100 µg/mL) effectively inhibited the growth of Streptococcus mutans bacteria, demonstrating significant antibacterial properties. They can potentially prevent biofilm formation by reducing lactic acid production in the teeth. These compounds showed a strong ability to promote tooth remineralization and improve the microhardness of acid-producing bacteria. They also possess potent anti-inflammatory properties that downregulate proinflammatory cytokine (interleukin-6, interleukin-1ß, inducible nitric oxide synthase) expression, suppress nuclear factor-kappa B transcription factor activation (∼1.6 times), and reduce nitrous oxide production in lipopolysaccharide-induced RAW264.7 cells. CONCLUSIONS: Compounds K and BTEX-K may provide a novel approach to dental caries prevention as well as inflammation prevention and treatment.

Predicting stroke volume variation using central venous pressure waveform: a deep learning approach.

Objective. This study evaluated the predictive performance of a deep learning approach to predict stroke volume variation (SVV) from central venous pressure (CVP) waveforms.Approach. Long short-term memory (LSTM) and the feed-forward neural network were sequenced to predict SVV using CVP waveforms obtained from the VitalDB database, an open-source registry. The input for the LSTM consisted of 10 s CVP waveforms sampled at 2 s intervals throughout the anesthesia duration. Inputs of the feed-forward network were the outputs of LSTM and demographic data such as age, sex, weight, and height. The final output of the feed-forward network was the SVV. The performance of SVV predicted by the deep learning model was compared to SVV estimated derived from arterial pulse waveform analysis using a commercialized model, EV1000.Main results. The model hyperparameters consisted of 12 memory cells in the LSTM layer and 32 nodes in the hidden layer of the feed-forward network. A total of 224 cases comprising 1717 978 CVP waveforms and EV1000/SVV data were used to construct and test the deep learning models. The concordance correlation coefficient between estimated SVV from the deep learning model were 0.993 (95% confidence interval, 0.992-0.993) for SVV measured by EV1000.Significance. Using a deep learning approach, CVP waveforms can accurately approximate SVV values close to those estimated using commercial arterial pulse waveform analysis.

Coadministration of 6-Shogaol and Levodopa Alleviates Parkinson's Disease-Related Pathology in Mice.

Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the nigrostriatal pathway, leading to motor and non-motor dysfunctions, such as depression, olfactory dysfunction, and memory impairment. Although levodopa (L-dopa) has been the gold standard PD treatment for decades, it only relieves motor symptoms and has no effect on non-motor symptoms or disease progression. Prior studies have reported that 6-shogaol, the active ingredient in ginger, exerts a protective effect on dopaminergic neurons by suppressing neuroinflammation in PD mice. This study investigated whether cotreatment with 6-shogaol and L-dopa could attenuate both motor and non-motor symptoms and dopaminergic neuronal damage. Both 6-shogaol (20 mg/kg) and L-dopa (80 mg/kg) were orally administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid- induced PD model mice for 26 days. The experimental results showed that L-dopa alleviated motor symptoms, but had no significant effect on non-motor symptoms, loss of dopaminergic neuron, or neuroinflammation. However, when mice were treated with 6-shogaol alone or in combination L-dopa, an amelioration in both motor and non-motor symptoms such as depression-like behavior, olfactory dysfunction and memory impairment was observed. Moreover, 6-shogaol-only or co-treatment with 6-shogaol and L-dopa protected dopaminergic neurons in the striatum and reduced neuroinflammation in the striatum and substantia nigra. Overall, these results suggest that 6-shogaol can effectively complement L-dopa by improving non-motor dysfunction and restoring dopaminergic neurons via suppressing neuroinflammation.

Oncogenic fusion of CD63-BCAR4 contributes cancer stem cell-like properties via ALDH1 activity.

Gene fusions are common somatic alterations in cancers, and fusions with tumorigenic features have been identified as novel drivers of cancer and therapeutic targets. Few studies have determined whether the oncogenic ability of fusion genes is related to the induction of stemness in cells. Cancer stem cells (CSCs) are a subset of cells that contribute to cancer progression, metastasis, and recurrence, and are critical components of the aggressive features of cancer. Here, we investigated the CSC-like properties induced by CD63-BCAR4 fusion gene, previously reported as an oncogenic fusion, and its potential contribution for the enhanced metastasis as a notable characteristic of CD63-BCAR4. CD63-BCAR4 overexpression facilitates sphere formation in immortalized bronchial epithelial cells. The significantly enhanced sphere-forming activity observed in tumor-derived cells from xenografted mice of CD63-BCAR4 overexpressing cells was suppressed by silencing of BCAR4. RNA microarray analysis revealed that ALDH1A1 was upregulated in the BCAR4 fusion-overexpressing cells. Increased activity and expression of ALDH1A1 were observed in the spheres of CD63-BCAR4 overexpressing cells compared with those of the empty vector. CD133 and CD44 levels were also elevated in BCAR4 fusion-overexpressing cells. Increased NANOG, SOX2, and OCT-3/4 protein levels were observed in metastatic tumor cells derived from mice injected with CD63-BCAR4 overexpressing cells. Moreover, DEAB, an ALDH1A1 inhibitor, reduced the migration activity induced by CD63-BCAR4 as well as the sphere-forming activity. Our findings suggest that CD63-BCAR4 fusion induces CSC-like properties by upregulating ALDH1A1, which contributes to its metastatic features.

Effects of neuromuscular block reversal with neostigmine/glycopyrrolate versus sugammadex on bowel motility recovery after laparoscopic colorectal surgery: A randomized controlled trial.

STUDY OBJECTIVE: To compare the effects of neostigmine/glycopyrrolate (a traditional agent) and sugammadex on bowel motility recovery and the occurrence of digestive system complications after colorectal surgery. DESIGN: Prospective, randomized controlled trial. SETTING: A single tertiary center. PATIENTS: 111 patients undergoing laparoscopic colorectal surgery. INTERVENTIONS: Patients were randomized into two groups based on the block reversal agent: 1) a mixture of 50 µg.kg-1 of neostigmine and 10 µg.kg-1 of glycopyrrolate (neostigmine group) and 2) 2 mg.kg-1 of sugammadex (sugammadex group). MEASUREMENTS: The primary outcome was the time from the surgery's completion to the first flatus. The time to the first postoperative defecation, incidences of postoperative nausea or vomiting, ileus, and dry mouth, as well as postoperative length of stay, were also assessed. MAIN RESULTS: The time to the first flatus was significantly shorter in the sugammadex group than in the neostigmine group (59 [42-79] h vs 69 [53-90] h, P = 0.027). The time to the first defecation and the incidences of postoperative nausea or vomiting and ileus did not differ between the groups, nor did the postoperative length of stay. However, the incidence of postoperative dry mouth was significantly lower in the sugammadex group than in the neostigmine group (7 patients [13%] vs 39 patients [71%], P < 0.001). CONCLUSIONS: The time to the first flatus was shorter using 2 mg.kg-1 sugammadex to reverse the neuromuscular block for laparoscopic colorectal surgery compared to reversal with conventional neostigmine/glycopyrrolate.

Functional Impact of the FADS1 rs174546 Single Nucleotide Polymorphism on Serum Lipid Levels: Insights from Molecular Mechanisms and Therapeutic Perspectives in Korean Population.

SCOPE: Single nucleotide polymorphisms (SNP) in the fatty acid desaturase 1 (FADS1) gene is suggested as risk factor of metabolic diseases in genome-wide association studies (GWAS). This study hypothesized that FADS1_rs174546T associates with serum triglycerides (TG) in Korean Genome and Epidemiology Study (KoGES). In addition, functional study of SNP genotypes in cultured cells is performed. METHODS AND RESULTS: FADS1_rs174546T is associated with high level of serum TG (effect size of variant: 6.48 ± 1.84 mg dL-1) in Korean individuals (normotriglyceridemia, n = 5128; hypertriglyceridemia, n = 3714). Functional study in cells with FADS1_rs174546T, shows reduced transcriptional activity, when compared with rs174546C. MiR-6728-3p, which is predicted to bind with rs174546T, decreases transcriptional activity of rs174546T but not in rs174546C, and it is reversed by miR-6728-3p inhibitor. Formononetin is selected as binding molecule to 3'-UTR of FADS1 and increases luciferase activity in both rs174546 (C/T). Moreover, formononetin compensates for the reduced luciferase activity by rs174546T and miR-6728-3p. Formononetin also increases endogenous FADS1 expression and long-chain polyunsaturated fatty acid (LC-PUFA) ratio. CONCLUSION: FADS1_rs174546T is a crucial risk factor for hypertriglyceridemia in the Koreans potentially through the interaction with miR-6728-3p. Formononetin can be a potent dietary intervention to prevent and improve hypertriglyceridemia in both rs174546 (C/T) populations.

Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling.

We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.

Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: twelve months of an ongoing randomized phase 3 trial.

BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol/0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN: This ongoing, 48-month, phase 3 study consists of a 12-month double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The coprimary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy vs placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% vs 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% vs 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was <1% and was attenuated compared with bone loss observed with elagolix monotherapy.

Tricaprylin-based drug crystalline suspension for intramuscular long-acting delivery of entecavir with alleviated local inflammation.

In order to ensure prolonged pharmacokinetic profile along with local tolerability at the injection site, tricaprylin-based drug crystalline suspension (TS) was designed and its local distribution, pharmacokinetics, and inflammatory response, were evaluated with conventional aqueous suspension (AS). As model drug particles, entecavir 3-palmitate (EV-P), an ester lipidic prodrug for entecavir (EV), was employed. The EV-P-loaded TS was prepared by ultra-sonication method. Prepared TS and conventional AS exhibited comparable morphology (rod or rectangular), median diameter (2.7 and 2.6 µm), crystallinity (melting point of 160-165°C), and in vitro dissolution profile. However, in vivo performances of drug microparticles were markedly different, depending on delivery vehicle. At AS-injected site, drug aggregates of up to 500 µm were formed upon intramuscular injection, and were surrounded with inflammatory cells and fibroblastic bands. In contrast, no distinct particle aggregation and adjacent granulation was observed at TS-injected site, with >4 weeks remaining of the oily vehicle in micro-computed tomographic observation. Surprisingly, TS exhibited markedly alleviated local inflammation compared to AS, endowing markedly lessened necrosis, fibrosis thickness, inflammatory area, and macrophage infiltration. The higher initial systemic exposure was observed with TS compared to AS, but TS provided prolonged delivery of EV for 3 weeks. Therefore, we suggest that the novel TS system can be a promising tool in designing parenteral long-acting delivery, with improved local tolerability.

Modified Thoracoabdominal Nerves Block Through Perichondral Approach: A Systematic Review and Meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to investigate the postoperative analgesic efficacy and safety of the modified thoracoabdominal nerve block through the perichondral approach (M-TAPA) in abdominal surgeries. DESIGN: Systematic review and meta-analysis. METHODS: We searched electronic databases to identify relevant studies comparing M-TAPA with conventional analgesic techniques. The primary outcome was the requirement for rescue analgesia at 12 and 24 hours postsurgery. Secondary outcomes included the 11-point numerical rating scale pain scores at 0, 1, 2, 4, 6, 8, 12, and 24 hours following surgery, global quality of recovery scores, and postoperative adverse events. FINDINGS: Five randomized controlled trials involving 308 patients were analyzed. M-TAPA showed no significant difference in the requirement for rescue analgesia at 12 hours (relative risk [RR]: 0.87; 95% confidence interval [CI]: 0.62, 1.22; P = .424; I2 = 40.7%; Ph = .185) and 24 hours (RR: 0.67; 95% CI: 0.22, 1.99; P = .252; I2 = 90.3%; Ph < .001) postsurgery compared to non-M-TAPA. No significant differences in numerical rating scale pain scores or global quality of recovery scores were found between the two groups (all P < .05). However, M-TAPA was associated with a lower occurrence of nausea (RR: 0.37; 95% CI: 0.22, 0.68; P < .001; I2 = 0%; Ph = .834), vomiting (RR: 0.32; 95% CI: 0.17, 0.62; P < .001; I2 = 0%; Ph = .884), and itching (RR: 0.38; 95% CI: 0.21, 0.70; P = .002; I2 = 0%; Ph = .826). CONCLUSIONS: There was no significant difference in analgesic efficacy and safety between M-TAPA and non-M-TAPA techniques.

Locoregional Recurrence in Adenoid Cystic Carcinoma of the Breast: A Retrospective, Multicenter Study (KROG 22-14).

Purpose: This study aims to evaluate the treatment approaches and locoregional patterns for Adenoid cystic carcinoma (ACC) in the breast, which is an uncommon malignant tumor with limited clinical data. Materials and Methods: A total of 93 patients diagnosed with primary ACC in the breast between 1992 and 2022 were collected from multi-institutions. All patients underwent surgical resection, including breast-conserving surgery (BCS) or total mastectomy (TM). The recurrence patterns and locoregional recurrence-free survival (LRFS) were assessed. Results: Seventy-five patients (80.7%) underwent BCS, and 71 of them (94.7%) received post-operative radiation therapy (PORT). Eighteen patients (19.3%) underwent TM, with 5 of them (27.8%) also receiving PORT. With a median follow-up of 50 months, the LRFS rate was 84.2% at 5 years. Local recurrence (LR) was observed in 5 patients (5.4%) and 4 cases (80%) of the LR occurred in the tumor bed. Three of LR (3/75, 4.0%) had a history of BCS and PORT, meanwhile, two of LR (2/18, 11.1%) had a history of mastectomy. Regional recurrence occurred in 2 patients (2.2%), and both cases had a history of PORT with (n=1) and without (n=1) irradiation of the regional lymph nodes. Partial breast irradiation (p=0.35), BCS (p=0.96) and PORT in BCS group (p=0.33) had no significant association with LRFS. Conclusion: BCS followed by PORT was the predominant treatment approach for ACC of the breast and local recurrence mostly occurred in the tumor bed. The findings of this study suggest that partial breast irradiation might be considered for PORT in primary breast ACC.

Rhei Undulati Rhizoma attenuates memory decline and reduces amyloid-ß induced neuritic dystrophy in 5xFAD mouse.

BACKGROUND: Alzheimer's disease (AD) is a common type of dementia characterized by amyloid-ß (Aß) accumulation, lysosomal dysfunction, and tau hyperphosphorylation, leading to neurite dystrophy and memory loss. This study aimed to investigate whether Rhei Undulati Rhizoma (RUR), which has been reported to have anti-neuroinflammatory effect, attenuates Aß-induced memory impairment, neuritic dystrophy, and tau hyperphosphorylation, and to reveal its mode of action. METHODS: Five-month-old 5xFAD mice received RUR (50 mg/kg) orally for 2 months. The Y-maze test was used to assess working memory. After behavioral testing, brain tissue was analyzed using thioflavin S staining, western blotting, and immunofluorescence staining to investigate the mode of action of RUR. To confirm whether RUR directly reduces Aß aggregation, a thioflavin T assay and dot blot were performed after incubating Aß with RUR. RESULTS: RUR administration attenuated the Aß-induced memory impairment in 5xFAD mice. Furthermore, decreased accumulation of Aß was observed in the hippocampus of the RUR-treated 5xFAD group compare to the vehicle-treated 5xFAD group. Moreover, RUR reduced the dystrophic neurites (DNs) that accumulate impaired endolysosomal organelles around Aß. In particular, RUR treatment downregulated the expression of ß-site amyloid precursor protein cleaving enzyme 1 and the hyperphosphorylation of tau within DNs. Additionally, RUR directly suppressed the aggregation of Aß, and eliminated Aß oligomers in vitro. CONCLUSIONS: This study showed that RUR could attenuate Aß-induced pathology and directly regulate the aggregation of Aß. These results suggest that RUR could be an efficient material for AD treatment through Aß regulation.

Traditional Korean diet high in one-carbon nutrients increases global DNA methylation: implication for epigenetic diet.

PURPOSE: DNA methylation is a major epigenetic phenomenon through which diet affects health and disease. This study aimed to determine the epigenetic influence of the traditional Korean diet (K-diet) on global DNA methylation via one-carbon metabolism. METHODS: A crossover study was conducted on 52 women. Two diets, a K-diet, high in plant foods and low in calories and animal fat, and a control diet, similar to the diet currently consumed in Korea, were provided to all subjects alternately for 4 weeks with a 4-week washout period. Clinical parameters were measured before and after each dietary intervention. Nutrient intake was calculated by using a computer-aided nutritional analysis program. One-carbon metabolites in the serum and global DNA methylation in peripheral mononuclear cells were determined using ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: The K-diet group consumed more folate (669.9 ± 6.7 µg vs. 502.7 ± 3.0, p < 0.001), B6, B12, serine, and choline, and less methionine (992.6 ± 63 vs. 1048.3 mg ± 34.1, p < 0.0001) than the control group did. In the K-diet group, the increment of plasma 5-methyltetrahydrofolate (0.08 µg/mL ± 0.11 vs 0.02 ± 0.10, p < 0.009) and decrement of L-homocysteine (- 70.7 ± 85.0 vs - 39.3 ± 69.4, p < 0.0168) were greater than those of the control group. Global DNA methylation was significantly increased in the K-diet group (6.70 ± 3.02% to 9.45 ± 3.69, p < 0.0001) but not in the control group. CONCLUSIONS: A K-diet high in one-carbon nutrients can enhance the global DNA methylation status, suggesting an epigenetic mechanism by which the K-diet conveys health effects. Trial registration Korean Clinical Trial Registry (trial number: KCT0005340, 24/08/2020, retrospectively registered).

Predicting Recurrence-Free Survival After Upfront Surgery in Resectable Pancreatic Ductal Adenocarcinoma: A Preoperative Risk Score Based on CA 19-9, CT, and 18F-FDG PET/CT.

OBJECTIVE: To develop and validate a preoperative risk score incorporating carbohydrate antigen (CA) 19-9, CT, and fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT variables to predict recurrence-free survival (RFS) after upfront surgery in patients with resectable pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: Patients with resectable PDAC who underwent upfront surgery between 2014 and 2017 (development set) or between 2018 and 2019 (test set) were retrospectively evaluated. In the development set, a risk-scoring system was developed using the multivariable Cox proportional hazards model, including variables associated with RFS. In the test set, the performance of the risk score was evaluated using the Harrell C-index and compared with that of the postoperative pathological tumor stage. RESULTS: A total of 529 patients, including 335 (198 male; mean age ± standard deviation, 64 ± 9 years) and 194 (103 male; mean age, 66 ± 9 years) patients in the development and test sets, respectively, were evaluated. The risk score included five variables predicting RFS: tumor size (hazard ratio [HR], 1.29 per 1 cm increment; P < 0.001), maximal standardized uptake values of tumor ≥ 5.2 (HR, 1.29; P = 0.06), suspicious regional lymph nodes (HR, 1.43; P = 0.02), possible distant metastasis on 18F-FDG PET/CT (HR, 2.32; P = 0.03), and CA 19-9 (HR, 1.02 per 100 U/mL increment; P = 0.002). In the test set, the risk score showed good performance in predicting RFS (C-index, 0.61), similar to that of the pathologic tumor stage (C-index, 0.64; P = 0.17). CONCLUSION: The proposed risk score based on preoperative CA 19-9, CT, and 18F-FDG PET/CT variables may have clinical utility in selecting high-risk patients with resectable PDAC.

Comparison of the different versions of NCCN guidelines for predicting margin-negative resection of pancreatic cancer in patients undergoing upfront surgery.

OBJECTIVES: The purpose of this study was to compare the different versions of the National Comprehensive Cancer Network (NCCN) guidelines for defining resectability of pancreatic ductal adenocarcinoma (PDAC) in predicting margin-negative (R0) resection, and to assess inter-reader agreement. METHODS: This retrospective study included 283 patients (mean age, 65.1 years ± 9.4 [SD]; 155 men) who underwent upfront pancreatectomy for PDAC between 2017 and 2019. Two radiologists independently determined the resectability on preoperative CT according to the 2017, 2019, and 2020 NCCN guidelines. The sensitivity and specificity for R0 resection were analyzed using a multivariable logistic regression analysis with generalized estimating equations. Inter-reader agreement was assessed using kappa statistics. RESULTS: R0 resection was accomplished in 239 patients (84.5%). The sensitivity and specificity averaged across two readers were, respectively, 76.6% and 29.5% for the 2020 guidelines, 74.1% and 32.9% for the 2019 guidelines, and 72.6% and 34.1% for the 2017 guidelines. Compared with the 2020 guidelines, both 2019 and 2017 guidelines showed significantly lower sensitivity for R0 resection (p ≤ .009). Specificity was significantly higher with the 2017 guidelines (p = .043) than with the 2020 guidelines. Inter-reader agreements for determining the resectability of PDCA were strong (k ≥ 0.83) with all guidelines, being highest with the 2020 guidelines (k = 0.91). CONCLUSION: The 2020 NCCN guidelines showed significantly higher sensitivity for prediction of R0 resection than the 2017 and 2019 guidelines.

Multiple magnetic transition and magnetocaloric properties in the mixed valence Eu8CuNi2.5Si42.5 type I clathrate compound.

We investigated the magnetocaloric and electrical transport properties of the Eu8CuNi2.5Si42.5 clathrate compound, synthesized by an arc melting and annealing method. X-ray photoemission spectroscopy revealed a mixed valence state of Eu2+ and Eu3+. The low-field and low-temperature magnetic measurements indicated a multiple magnetic transition, from ferromagnetic near 35 K to antiferromagnetic at 25 K. Increasing the magnetic field led to the broadening of antiferromagnetic peaks and a final ferromagnetic state under high magnetic fields, indicative of spin reorientation. The transition from a ferromagnetic to an antiferromagnetic state was further corroborated by specific heat measurements. We noted spontaneous magnetization at low temperatures via magnetic hysteresis and Arrott plot analysis. The coexistence of an antiferromagnetic ground state (attributed to the Eu2+ ions) and ferromagnetic clusters (associated with the Ni2+ ions) was supported by spontaneous magnetization at low temperatures in the antiferromagnetic state. The magnetocaloric analyses revealed a high spin entropy change over a broad temperature range for Eu8CuNi2.5Si42.5, which implies its potential as a robust low-temperature magnetocaloric material, distinguished by its high refrigerant capacity.

Hypertension in an ageing population: Diagnosis, mechanisms, collateral health risks, treatments, and clinical challenges.

Ageing population is considerably increasing worldwide, which is considered to reflect an improved quality of life. However, longevity in the human lifespan has increased the burden of late-life illnesses including cancer, neurodegeneration, and cardiovascular dysfunction. Of these, hypertension is the most common condition with huge health risks, with an increased prevalence among the elderly. In this review, we outline the current guidelines for defining hypertension and examine the detailed mechanisms underlying the relationship between hypertension and ageing-related outcomes, including sodium sensitivity, arterial stiffness, endothelial dysfunction, isolated systolic hypertension, white coat effect, and orthostatic hypertension. As hypertension-related collateral health risk increases among the elderly, the available management strategies are necessary to overcome the clinical treatment challenges faced among elderly population. To improve longevity and reduce adverse health effects, potential approaches producing crucial information into new era of medicine should be considered in the prevention and treatment of hypertension among elderly population. This review provides an overview of mechanisms underlying hypertension and its related collateral health risk in elderly population, along with multiple approaches and management strategies to improve the clinical challenges among elderly population.