Fragmentation patterns of cell-free DNA and somatic mutations in the urine of metastatic breast cancer patients.

BACKGROUND: Urinary cell-free deoxyribonucleic acid (DNA) (ucfDNA) holds promise as a biomarker; however, its potential remains largely unexplored. We examined the fragmentation pattern of ucfDNA and identified somatic mutations within urine samples from metastatic breast cancer (MBC) patients. METHODS: Urine and blood specimens were collected before treatment from 45 MBC patients and posttreatment urine samples from 16 of the 45 patients at the China National Cancer Center. Somatic mutations and tumor mutational burden (TMB) in the urine and plasma of 10 patients were analyzed by next-generation sequencing (NGS). Fragmentation patterns of cfDNA were displayed using electropherograms. Differences in the extracted amount of cfDNA, length of cfDNA fragments, and TMB between urine and plasma were compared using a Wilcoxon test. RESULTS: The fragmentation patterns of ucfDNA were categorized as follows: (1) profile A (n = 26) containing a short peak (100-200 bp) and a long peak (>1500 bp); (2) profile B (n = 8) containing only a long peak; and (3) profile C (n = 11) containing flat pattern. For profile A patients, the short-peaked ucfDNA circulating in the bloodstream was much shorter compared with plasma cfDNA (149 vs. 171 bp, Wilcoxon test, P = 0.023). The fragmentation patterns in lung metastasis patients exhibited a higher propensity toward profile C ( P = 0.002). After treatment, 87.5% of the patients exhibited consistent fragmentation patterns. The concordance rate for somatic mutations in the plasma and urine was 30%, and the median TMB of urine and plasma was not significantly different. CONCLUSIONS: This study established a fragmentation pattern for ucfDNA and detected somatic mutations in the urine of MBC patients. These results suggest the potential application of ucfDNA as a biomarker for MBC.

Effect of comprehensive nursing methods in postoperative ICU of children with CHD.

To explore effect of comprehensive nursing in postoperative ICU of children with CHD. The subjects were 50 cases of children with CHD treated in our hospital: 25 cases in the control group: routine nursing, and 25 cases in the observation group: comprehensive nursing intervention. The effective rate of 92.00% in the observation group was significantly higher. The serum-free calcium value (1.07 ± 0.11) mmol/L of the observation group on the first day after surgery was significantly lower, and the observation group's creatine phosphate, the daily average dosage of creatine phosphate per unit body weight was significantly higher. 96.00% of patients in the observation group were significantly higher in nursing satisfaction. The complication rate of 8.00% in observation group was significantly lower. In order to successfully complete the operation schedule and improve the postoperative recovery effect of children, high requirements are placed on nursing staff. The comprehensive nursing method used in the postoperative ICU of children with CHD can reduce the incidence of postoperative complications and improve nursing satisfaction.

Plastid-localized amino acid metabolism coordinates rice ammonium tolerance and nitrogen use efficiency.

Ammonium toxicity affecting plant metabolism and development is a worldwide problem impeding crop production. Remarkably, rice (Oryza sativa L.) favours ammonium as its major nitrogen source in paddy fields. We set up a forward-genetic screen to decipher the molecular mechanisms conferring rice ammonium tolerance and identified rohan showing root hypersensitivity to ammonium due to a missense mutation in an argininosuccinate lyase (ASL)-encoding gene. ASL localizes to plastids and its expression is induced by ammonium. ASL alleviates ammonium-inhibited root elongation by converting the excessive glutamine to arginine. Consequently, arginine leads to auxin accumulation in the root meristem, thereby stimulating root elongation under high ammonium. Furthermore, we identified natural variation in the ASL allele between japonica and indica subspecies explaining their different root sensitivity towards ammonium. Finally, we show that ASL expression positively correlates with root ammonium tolerance and that nitrogen use efficiency and yield can be improved through a gain-of-function approach.

Normothermic ex vivo heart perfusion with NLRP3 inflammasome inhibitor Mcc950 treatment improves cardiac function of circulatory death hearts after transplantation.

Background: The utilization of donation after circulatory death (DCD) hearts can enlarge the donor pool. However, DCD hearts suffer from serious ischemia/reperfusion injury (IRI). Recent studies found that the activation of NLRP3 inflammasome could play a significant role in organ IRI. Mcc950, which is a novel inhibitor of the NLRP3 inflammasome, can be applied to treat various kinds of cardiovascular diseases. Therefore, we hypothesized that the treatment of mcc950 could protect DCD hearts preserved with normothermic ex vivo heart perfusion (EVHP) against myocardial IRI via inhibiting NLRP3 inflammasome in a rat heart transplantation model of DCD. Methods: Donor-heart rats were randomly divided into four groups: Control group; Vehicle group; MP-mcc950 group; and MP + PO-mcc950 group. Mcc950 was added into the perfusate of normothermic EVHP in the MP-mcc950 and MP + PO-mcc950 groups, and was injected into the left external jugular vein after heart transplantation in the MP + PO-mcc950 group. Cardiac functional assessment was performed. The level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-associated protein of donor hearts were evaluated. Results: The treatment with mcc950 significantly increased the developed pressure (DP), dP/dtmax, and dP/dtmin of the left ventricular of DCD hearts at 90 min after heart transplantation in both MP-mcc950 and MP + PO-mcc950 groups. Furthermore, mcc950 added into perfusate and injected after transplantation in both MP-mcc950 and MP + PO-mcc950 groups significantly attenuated the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome compared with the vehicle group. Conclusions: Normothermic EVHP combined with mcc950 treatment can be a promising and novel DCD heart preservation strategy, which can alleviate myocardial IRI via inhibiting NLRP3 inflammasome.

Effect of curcumin on the formation of polycyclic aromatic hydrocarbons in grilled chicken wings.

Organic macromolecules form carcinogenic and toxic substances such as polycyclic aromatic hydrocarbons (PAHs) under high temperature baking. Thus, this study investigated the effects and inhibition pathways of different curcumin concentrations (0.01, 0.05, 0.25, 0.3 mg/g) on seven PAHs in grilled chicken wings. The results demonstrated that curcumin concentrations displayed positive effects in inhibiting the formation of PAHs (16%-72%), increasing the total phenolic content (397.5-1934.4 mg/g) and free radical scavenging activity, and reducing TBARS values (31.15%-47.76%) and fatty acid content. Additionally, PCA and Pearson correlation analyses indicated that lipid oxidation (r = 0.42) and unsaturated fatty acids (r = 0.55) could promote the production of PAHs, while DPPH, ABTS and TPC could counteract their facilitation of PAHs. In conclusion, the addition of appropriate amounts of curcumin before grilling is a feasible strategy to reduce fat oxidation levels and the number of free radicals for the purpose of limiting PAHs content.

Protective Effects of MicroRNA-200b-3p Encapsulated by Mesenchymal Stem Cells-Secreted Extracellular Vesicles in Myocardial Infarction Via Regulating BCL2L11.

Background Extracellular vesicles (EVs) are a popular treatment candidate for myocardial injury. This work investigated the effects of mesenchymal stem cells (MSCs)-secreted EVs-derived miR-200b-3p on cardiomyocyte apoptosis and inflammatory response after myocardial infarction (MI) through targeting BCL2L11 (Bcl-2-like protein 11) . Methods and Results EVs from MSCs were isolated and identified. EVs from MSCs with transfection of miR-200b-3p for overexpression were injected into MI mice. The effect of miR-200b-3p on cardiac function, infarction area, myocardial fibrosis, cardiomyocyte apoptosis, and inflammatory response was determined in MI mice. The targeting relationship between miR-200b-3p and BCL2L11 was verified, and the interaction between BCL2L11 and NLR family pyrin domain containing 1 (NLRP1) was also verified. MI mice were injected with an overexpressing BCL2L11 lentiviral vector to clarify whether BCL2L11 can regulate the effect of miR-200b-3p on MI mice. EVs from MSCs were successfully extracted. MSCs-EVs improved cardiac function and reduced infarction area, apoptosis of cardiomyocytes, myocardial fibrosis, and inflammation in MI mice. Upregulation of miR-200b-3p further enhanced the effects of MSCs-EVs on the myocardial injury of MI mice. BCL2L11 was targeted by miR-200b-3p and bound to NLRP1. Upregulation of BCL2L11 negated the role of miR-200b-3p-modified MSCs-EVs in MI mice. Conclusions A summary was obtained that miR-200b-3p-encapsulated MSCs-EVs protect against MI-induced apoptosis of cardiomyocytes and inflammation via suppressing BCL2L11.

Real world initial palliative treatment patterns and clinical outcomes in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer: A study of the National Cancer Center, China.

BACKGROUND: To observe whether guideline non-adherence in initial palliative treatment choices for premenopausal hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (MBC) patients result in worse clinical outcomes in the Chinese population. METHODS: The China National Cancer Center database was used to identify 2194 patients diagnosed between 2004 and 2015. A total of 451 premenopausal patients with HR + HER2- MBC were included. Clinicopathological features and survival information were extracted. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using log-rank test. RESULTS: The number of patients receiving initial chemotherapy, endocrine therapy and chemo-endocrine therapy were 222 (49.2%), 80 (17.7%), and 149 (33.0%), respectively. Patients receiving initial chemotherapy were more likely to be luminal B subtype, had more de novo stage IV disease and more liver metastasis, compared with patients receiving initial endocrine therapy. Both PFS and OS were significantly longer for chemo-endocrine therapy group (median PFS 18.9 months and OS 75.0 months), than for endocrine therapy group (median PFS 11.7 months and OS 53.5 months), and chemotherapy group (median PFS 7.1 months and OS 43.9 months). In multivariate analysis, none of the three treatment strategies were independently associated with PFS or OS. CONCLUSION: In real world, a high percentage of premenopausal patients with HR + HER2- disease received chemotherapy as initial palliative treatment in China, which was not associated with worsened survival. Further studies with larger sample size across China are needed to explore the relationship between this guideline non-adherence and clinical outcomes.

Clinicopathological characteristics and survival outcomes in patients with synchronous lung metastases upon initial metastatic breast cancer diagnosis in Han population.

BACKGROUND: We investigated the clinicopathological characteristics and survival of breast cancer lung metastases (BCLM) patients at initial diagnosis of metastatic breast cancer (MBC) in the Han population. METHODS: We attained clinical data of 3155 MBC patients initially diagnosed between April 2000 and September 2019 from the China National Cancer Center and finally included 2263 MBC patients in this study, among which 809 patients presented with lung metastases at first MBC diagnosis. The risk factors for BCLM were determined using multivariate logistic regression analysis and the prognostic factors of BCLM patients were assessed by univariate and multivariate Cox regression analyses. RESULTS: Patients with triple-negative subtype (42.3%) harbored the highest incidence proportions of lung metastases. Age ≥ 50 years, Eastern Cooperative Oncology Group (ECOG) 2, M1, hormone receptor-negative (HR-)/human epidermal growth factor receptor 2-positive (HER2) + subtype, triple-negative subtype and disease-free survival (DFS) > 2 years were remarkably associated with higher incidence of lung metastases, while invasive lobular carcinoma (ILC) and bone metastases were significantly correlated with lower odds of lung metastases at diagnosis. The median survival of BCLM patients was 41.7 months, with triple-negative subtype experiencing the worst prognosis of 26.8 months. ECOG 2, triple-negative subtype, liver metastases, multi-metastatic sites and DFS ≤ 2 years were significantly correlated with poor survival of BCLM patients. CONCLUSIONS: Our study provides essential information on clinicopathological features and survival outcomes of BCLM patients at initial diagnosis of MBC in China.

Normothermic ex vivo Heart Perfusion Combined With Melatonin Enhances Myocardial Protection in Rat Donation After Circulatory Death Hearts via Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.

OBJECTIVE: The adoption of hearts from donation after circulatory death (DCD) is a promising approach for the shortage of suitable organs in heart transplantation. However, DCD hearts suffer from serious ischemia/reperfusion injury (IRI). Recent studies demonstrate that nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis is a novel target to ameliorate myocardial IRI. Melatonin is shown to inhibit NLRP3 inflammasome-mediated pyroptosis. Therefore, this study is designed to verify the hypothesis that melatonin can protect the heart graft preserved with ex vivo heart perfusion (EVHP) against myocardial IRI via inhibiting NLRP3 inflammasome-mediated pyroptosis in a rat model of DCD. METHODS: Donor-heart rats were randomly divided into three groups: (1) Control group: non-DCD hearts were harvested from heart-beating rats and immediately preserved with allogenic blood-based perfusate at constant flow for 105 min in the normothermic EVHP system; (2) DCD-vehicle group; and (3) DCD-melatonin group: rats were subjected to the DCD procedure with 25 min of warm ischemia injury and preserved by the normothermic EVHP system for 105 min. Melatonin (200 µmol/L) or vehicle was perfused in the cardioplegia and throughout the whole EVHP period. Cardiac functional assessment was performed every 30 min during EVHP. The level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis of heart grafts submitted to EVHP were evaluated. RESULTS: Twenty five-minute warm ischemia injury resulted in a significant decrease in the developed pressure (DP), dP/dt max , and dP/dt min of left ventricular of the DCD hearts, while the treatment with melatonin significantly increased the DP, dP/dt max of the left ventricular of DCD hearts compared with DCD-vehicle group. Furthermore, warm ischemia injury led to a significant increase in the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis in the hearts preserved with EVHP. However, melatonin added in the cardioplegia and throughout the EVHP period significantly attenuated the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis compared with DCD-vehicle group. CONCLUSION: EVHP combined with melatonin post-conditioning attenuates myocardial IRI in DCD hearts by inhibiting NLRP3 inflammasome-mediated pyroptosis, which might expand the donor pool by the adoption of transplantable DCD hearts.

A Novel Rat Model of Cardiac Donation After Circulatory Death Combined With Normothermic ex situ Heart Perfusion.

Background: In heart transplantation, the adoption of hearts from donation after circulatory death (DCD) is considered to be a promising approach to expanding the donor pool. Normothermic ex situ heart perfusion (ESHP) is emerging as a novel preservation strategy for DCD hearts. Therefore, pre-clinical animal models of ESHP are essential to address some key issues before efficient clinical translation. We aim to develop a novel, reproducible, and economical rat model of DCD protocol combined with normothermic ESHP. Methods: Circulatory death of the anesthetized rats in the DCD group was declared when systolic blood pressure below 30 mmHg or asystole was observed after asphyxiation. Additional 15 min of standoff period was allowed to elapse. After perfusion of cold cardioplegia, the DCD hearts were excised and perfused with allogenic blood-based perfusate at constant flow for 90 min in the normothermic ESHP system. Functional assessment and blood gas analysis were performed every 30 min during ESHP. The alteration of DCD hearts submitted to different durations of ESHP (30, 60, and 90 min) in oxidative stress, apoptosis, tissue energy state, inflammatory response, histopathology, cell swelling, and myocardial infarction during ESHP was evaluated. Rats in the non-DCD group were treated similarly but not exposed to warm ischemia and preserved by the normothermic ESHP system for 90 min. Results: The DCD hearts showed compromised function at the beginning of ESHP and recovered over time, while non-DCD hearts presented better cardiac function during ESHP. The alteration of DCD hearts in oxidative stress, apoptosis, tissue energy state, histopathological changes, cell swelling, and inflammatory response didn't differ among different durations of ESHP. At the end of 90-min ESHP, DCD, and non-DCD hearts presented similarly in apoptosis, oxidative stress, inflammatory response, myocardial infarction, and histopathological changes. Moreover, the DCD hearts had lower energy storage and more evident cell swelling compared to the non-DCD hearts. Conclusion: We established a reproducible, clinically relevant, and economical rat model of DCD protocol combined with normothermic ESHP, where the DCD hearts can maintain a stable state during 90-min ESHP.

Risk Factors and Survival of Patients With Liver Metastases at Initial Metastatic Breast Cancer Diagnosis in Han Population.

The risk factors for morbidity and mortality in patients with breast cancer liver metastases (BCLM) upon initial metastatic breast cancer (MBC) diagnosis have not been adequately identified in Han population. Data of 3,161 female patients who were initially diagnosed with MBC from December 1991 to September 2019 and treated in the China National Cancer Center were extracted and a total of 2,263 MBC patients were included in our study, among which 550 patients had liver metastases. Multivariable logistic regression was performed to identify risk factors for the presence of liver metastases at initial MBC diagnosis. Univariable and multivariable Cox proportional hazards regression analyses were conducted to determine prognostic factors for the survival of BCLM patients. Patients with hormone receptor (HR)-negative, human epidermal growth factor receptor 2 (HER2)-positive (35.0% of the entire population) subtype had the highest incidence of liver metastases. De novo stage IV breast cancer, HR-/HER2+ and HR+/HER2+ subtypes were associated with higher odds of liver metastases and patients with lung metastases had lower risk of liver metastases at initial MBC diagnosis. The median overall survival of BCLM patients was 31.4 months and BCLM patients with HR+/HER2- subtype had the longest survival of 38.2 months. Older age, worse performance status, later stage of initial breast cancer, triple-negative subtype and lung metastases were significantly associated with a poorer prognosis in BCLM patients. Our study offers insights into the incidence and prognosis of BCLM patients at initial MBC diagnosis in Han population.

Effects of Solvents on the Glycerolysis Performance of the SBA-15 Supported Lipases.

In this study, Candida antarctica lipase B (CALB), Rhizomucor miehei lipase (RML) and Lecitase® Ultra (LU) were immobilized onto the mesoporous silica SBA-15. The glycerolysis performance of the obtained supported lipases (lipase@SBA-15) in solvent systems was carefully investigated. LU@SBA-15 exhibited good glycerolysis performance in solvent-free system, with diacylglycerols (DAG) content and triacylglycerols (TAG) conversion at 52.4 and 98.6% respectively obtained after 12 h reaction at 60°C. CALB@SBA-15 showed good glycerolysis activity in tert-pentanol and tert-butanol systems, with TAG conversion over 90% obtained. In addition, the present CALB@SBA-15 exhibited selectivity for monoacylglycerols (MAG) production, with glycerol to TAG molar ratio increased to 3:1, MAG content over 80% and TAG conversion over 99% could be obtained from both tert-pentanol and tert-butanol systems. However, RML@SBA-15 showed low glycerolysis activity neither in solvent nor in solvent-free systems. The present results favor the practical enzymatic design for MAG and DAG production.

In Real Life, Low-Level HER2 Expression May Be Associated With Better Outcome in HER2-Negative Breast Cancer: A Study of the National Cancer Center, China.

BACKGROUND: To characterize the clinical and pathological features and survival of patients with human epidermal growth factor receptor 2 (HER2)-low breast cancer in China. METHODS: The China National Cancer Center database was used to identify 1,433 metastatic breast cancer patients with HER2-negative disease diagnosed between 2005 and 2015. Clinicopathological features, survival, and prognosis information were extracted. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors associated with OS were analyzed using Cox regression model with 95% confidence interval (95% CI). RESULTS: There were 618 (43.1%) and 815 (56.9%) HER2-low and HER2-zero tumors out of 1,433 tumors, respectively. The proportion of hormone receptor (HR)-positive tumors was significantly higher in HER2-low tumors than in those with HER2-zero tumors (77.8% vs. 69.2%, p < 0.001). Patients with HER2-low tumors survived significantly longer than those with HER2-zero tumors in the overall population (48.5 months vs. 43.0 months, p = 0.004) and HR-positive subgroup (54.9 months vs. 48.1 months, p = 0.011), but not in the HR-negative subgroup (29.5 months vs. 29.9 months, p = 0.718). Multivariate regression analysis revealed that HER2-low tumors were independently associated with increased OS in HER2-negative population (HR: 0.85, 95% CI: 0.73-0.98, p = 0.026). CONCLUSION: Our findings demonstrate that HER2-low tumors could be identified as a more distinct clinical entity from HER2-zero tumors, especially for the HR-positive subgroup. A more complex molecular landscape of HER2-low breast cancer might exist, and more precise diagnostic algorithms for HER2 testing could be investigated, thus offering new therapeutic targets for breast cancer treatment.

Incidence, risk factors and survival of patients with brain metastases at initial metastatic breast cancer diagnosis in China.

PURPOSE: To characterize the incidence, risk factors and survival of patients with brain metastases at initial diagnosis of metastatic breast cancer (MBC) in China. METHODS: The China National Cancer Center database was used to identify 2087 MBC patients diagnosed between 2003 and 2015. Clinicopathological features, treatment and survival information were extracted. Multivariable logistic and Cox regression were performed to determine factors predictive of brain metastases at MBC diagnosis and survival, respectively. RESULTS: Brain metastases occurred in ninety patients (4.3%) at MBC diagnosis, and in 27 patients (2.5%), 42 patients (7.2%) and 21 patients (5.2%) with hormone receptor positive, human epidermal growth factor receptor 2 negative (HR + HER2-), HER2-positive and triple negative breast cancer (TNBC), respectively. HER2-positive subtype (OR = 2.38; 95% CI 1.40-4.04; p < 0.0001), TNBC subtype (OR = 1.89; 95% CI 1.02-3.51; p = 0.005), and metastases to all three sites of bone, liver and lungs (OR = 3.23; 95% CI 1.52-6.87; p = 0.002) were shown to increase the risk of BM at MBC diagnosis. Median survival after BM was 23.7 months. First-line tyrosine kinase inhibitors (TKI) improved survival compared to trastuzumab-based regimen (44.9 vs 35.4 months, p = 0.09). Factors that independently decreased BM death risk were ECOG<2, brain metastases only and multidisciplinary treatment. CONCLUSION: HER2-positive and TNBC subtypes have a higher incidence of BM at initial MBC diagnosis. Brain screening might be considered in patients with HER2-positive disease at MBC diagnosis, and further prospective randomized study is warranted.

Transcriptome analysis of strawberry fruit in response to exogenous arginine.

MAIN CONCLUSION: Transcriptome and physiological analysis showed that exogenous arginine can delay the ripening process of postharvest strawberry fruit. Arginine (Arg) plays an important role in the growth and development of plants, but its growth and development regulatory mechanisms in strawberry fruit are unknown. In this study, we found that the content of Arg decreased after the onset of fruit coloration and exogenous Arg inhibited fruit coloration. We comprehensively analyzed the transcriptome of 'Sweet Charlie' strawberry fruit with or without Arg treatment and identified a large number of differential genes and metabolites. Based on the transcriptome data, we also found that Arg inhibited ripening, which coincided with changes in several physiological parameters and their corresponding gene transcripts, including firmness, anthocyanin content, sugar content, Arg content, indole-acetic acid (IAA) content, abscisic acid (ABA) content, and ethylene emissions. We also found that Arg induced the expression of heat-shock proteins (HSPs) and antioxidant enzyme genes, which improved strawberry stress resistance. This study elucidated the molecular mechanism by which exogenous Arg delays strawberry fruit ripening, providing some genetic information to help guide the future improvement and cultivation of strawberry.

Development and validation of a nomogram for predicting survival of advanced breast cancer patients in China.

BACKGROUND: There is a lack of prognostic models predicting the overall survival (OS) of advanced breast cancer (ABC) patients in China. METHODS: Data from the China National Cancer Center database that recorded 4039 patients diagnosed with breast cancer between 1987 and 2019 were extracted and a total of 2263 ABC participants were enrolled in this study, which were further randomized 3:1 and divided into training (n = 1706) and validation (n = 557) groups. The nomogram was built based on independent predictors identified by univariate and multivariate cox regression analyses. The discriminatory and predictive capacities of the nomogram were assessed by Harrell's concordance index (C-index) and calibration plots. RESULTS: Univariate and multivariate analyses found that age, Eastern Cooperative Oncology Group (ECOG) score, T-stage, N-stage, tumor subtype, the presence of distant lymph node (DLN)/liver/brain metastasis, local therapy, efficacy of first-line therapy and metastatic-free interval (MFI) were significantly related to OS (all P < 0.05). These variables were incorporated into a nomogram to predict the 2-year and 3-year OS of ABC patients. The C-indexes of the nomogram were 0.700 (95% confidence interval [CI]: 0.683-0.717) for the training set and 0.686 (95% CI: 0.652-0.719) for the validation set. The calibration curves revealed satisfactory consistency between actual survival and nomogram prediction in both the internal and external validations. The nomogram was capable of stratifying patients into different risk cohorts. CONCLUSIONS: We constructed and validated a nomogram that might serve as an efficient tool to provide prognostic prediction for ABC patients and guide the physicians to make personalized treatment decisions.

ZJ01, a Small Molecule Inhibitor of the Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1-Nrf2) Protein-Protein Interaction, Reduces Hyperoxic Acute Lung Injury in a Mouse Model.

BACKGROUND Hyperoxic acute lung injury (ALI) is a complication of ventilation in patients with respiratory failure. Nuclear factor erythroid-2-related factor 2 (Nrf2) has an important role in ALI. Kelch-like ECH-associated protein 1 (Keap1) binds to Nrf2. ZJ01 is a small molecule inhibitor of Keap1-Nrf2 protein-protein interaction (PPI) that can reduce Keap1-induced inhibition of Nrf2. This study aimed to investigate the effects of ZJ01 and the heme oxygenase-1 (HO-1) inhibitor, zinc protoporphyrin IX (ZnPP IX), in a mouse model of hyperoxic ALI. MATERIAL AND METHODS C57BL/6J mice included five study groups: the room air+vehicle-treated group; the room air+ZJ01 group; the hyperoxia+vehicle-treated group; the hyperoxia+ZJ01 group; and the hyperoxia+ZJ01+ZnPP IX group. ZJ01, ZnPP IX, or vehicle were given 1 h after the hyperoxia challenge. The lungs from the mice were harvested at 72 h following the hyperoxia challenge. RESULTS Hyperoxia exposure for 72 h increased the activity of myeloperoxidase, the lung water content, the levels of tumor necrosis factor-alpha (TNF-alpha), and matrix metalloprotease-9 (MMP-9) in the vehicle-treated mice. ZJ01 treatment reduced hyperoxia-induced inflammation and increased the activation of Nrf2 and HO-1 compared with the vehicle-treated mice. Histology of the lungs showed that ZJ01 treatment reduced the changes of hyperoxia-induced ALI. Pretreatment with ZnPP IX reversed the beneficial effect of ZJ01. CONCLUSIONS ZJ01, a Keap1-Nrf2 PPI inhibitor, reduced hyperoxic ALI in a mouse model through the Nrf2/HO-1 pathway.

Polymorphisms of MTHFR and TYMS predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer.

BACKGROUND: Breast cancer is a global problem, and a large number of new cases are diagnosed every year. Capecitabine is effective in patients with metastatic breast cancer (MBC). Hand-foot syndrome (HFS) is a common adverse effect of capecitabine. In this study, we investigated the association between single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic biomarkers. METHODS: We selected 3 genes involved in capecitabine metabolism and screened genetic variants in these target genes. We genotyped a total of 22 SNPs in the thymidylate synthase gene (TYMS), the methylene tetrahydrofolate reductase gene (MTHFR), and the ribonucleotide reductase M1 gene (RRM1) in 342 MBC patients treated with capecitabine-based chemotherapy. The genotype distributions of each SNP in patients with and without HFS were assessed using Pearson's χ2 test, and the relationship between HFS and genotypes of SNPs was determined using logistic regression analysis. The association between SNPs and their corresponding gene expression was analyzed using the Blood expression quantitative trait loci (eQTL) browser online tools. RESULTS: We found 4 positive sites for HFS in the TYMS and MTHFR genes: TYMS rs2606241 (P = 0.022), TYMS rs2853741 (P = 0.019), MTHFR rs3737964 (P = 0.029), and MTHFR rs4846048 (P = 0.030). Logistic regression analyses showed that the genotype AG of MTHFR rs3737964 [odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.31-0.97, P = 0.038] and MTHFR rs4846048 (OR = 0.54, 95% CI 0.30-0.98, P = 0.042) were protective factors of HFS, whereas the genotype CT of TYMS rs2853741 (OR = 2.25, 95% CI 1.31-3.87, P = 0.012) increased the risk of HFS. The association between the genotype GT of TYMS rs2606241 (OR = 1.27, 95% CI 0.73-2.23, P = 0.012) and HFS was uncertain. Further eQTL analyses confirmed that the alleles of rs3737964 and rs4846048 affected the gene expression levels of MTHFR in cis. CONCLUSIONS: We have identified four potentially useful pharmacogenetic markers, TYMS rs2606241, TYMS rs2853741, MTHFR rs3737964, and MTHFR rs4846048 to predict capecitabine-induced HFS in MBC patients.

Immobilization of Candida antarctica Lipase B onto organically-modified SBA-15 for efficient production of soybean-based mono and diacylglycerols.

In this study, SBA-15 was modified by a series of silane coupling reagents and later used to immobilize Candida antartica lipase B (CALB). The enzymatic properties of the immobilized CALB samples were studied. In addition, the catalytic performance in glycerolysis of soybean oil for diacylglycerols (DAG) production was also investigated. The highest enzymatic activity up to 6100.00 ±â€¯246.41 U/g was observed from the propyl methacrylate group modified SBA-15 supported CALB. No loss of activity was observed from the propyl methacrylate group modified SBA-15 supported CALB, but a higher-than-initial activity was notably found from 3-aminopropyl group and n-octyl group modified SBA-15 supported CALB after a 4-h incubation in air at 70 °C. 1-isocyanatopropane group modified SBA-15 supported CALB exhibited selectivity for DAG production. DAG content up to 61.90 ±â€¯2.38 wt% and a DAG/MAG ratio at 3.11 ±â€¯0.08 was obtained after a 24-h reaction at 60 °C in a solvent-free system.

Berberine Attenuates NLRP3 Inflammasome Activation in Macrophages to Reduce the Secretion of Interleukin-1ß.

OBJECTIVES: The purpose of this study is to evaluate whether Berberine can suppress the inflammatory response in atherosclerosis lesions and its potential associated signaling pathways and mechanism of action. METHODS: We isolated human peripheral blood mononuclear cells. After co-culturing them with ox-LDL stimulated cells, ROS was measured by its fluorescence intensity and NADPH oxidase activity was detected by the OD value from the spectrophotometer. Human peripheral blood mononuclear cells were then pretreated with different concentrations of berberine after treatment with NLRP3 activator ATP. Western blot was used to measure the releas of IL-1ß. We also used confocal microscopy to detect the nuclear import of NF-kB in macrophages. RESULTS: In this study we observed that berberine suppressed IL-1ß secretion that was induced by the activation of the NLRP3 inflammasome in macrophages. In addition, we demonstrated that berberine may possibly reduce reactive oxygen species (ROS)-dependent NLRP3 inflammasome activation. Moreover, Berberine inhibited the expression of pro-IL-1ß through inhibition of the nuclear factor κb (NF-κB) pathway, which prevented the priming IL-1ß secretion. CONCLUSION: Our results suggest that berberine alleviates NLRP3 inflammation activation by reducing IL-1ß secretion from macrophages, which could be an important therapeutic target in atherosclerosis.