Cytokine Storm Related to CD4+ T Cells in Influenza Virus-Associated Acute Necrotizing Encephalopathy.

Acute necrotizing encephalopathy (ANE) is a rare but deadly complication with an unclear pathogenesis. We aimed to elucidate the immune characteristics of H1N1 influenza virus-associated ANE (IANE) and provide a potential therapeutic approach for IANE. Seven pediatric cases from a concentrated outbreak of H1N1 influenza were included in this study. The patients' CD4+ T cells from peripheral blood decreased sharply in number but highly expressed Eomesodermin (Eomes), CD69 and PD-1, companied with extremely high levels of IL-6, IL-8 in the cerebrospinal fluid and plasma. Patient 2, who showed high fever and seizures and was admitted to the hospital very early in the disease course, received intravenous tocilizumab and subsequently showed a reduction in temperature and a stable conscious state 24 h later. In conclusion, a proinflammatory cytokine storm associated with activated CD4+ T cells may cause severe brain pathology in IANE. Tocilizumab may be helpful in treating IANE.

Safety and efficacy of anlotinib combined with taxane and lobaplatin in neoadjuvant treatment of clinical stage II/III triple-negative breast cancer in China (the neoALTAL trial): a single-arm, phase 2 trial.

Background: Anlotinib is a new type of tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 1/2/3, platelet-derived growth factor receptors α/ß, and fibroblast growth factor receptors 1-4 and c-Kit, with a broad spectrum of inhibitory effects on tumor angiogenesis and growth. It has been proven effective in HER2-negative metastatic breast cancer, but its efficacy in early-stage triple-negative breast cancer (TNBC) is unknown. This phase 2 study aims to evaluate the efficacy and safety of adding anlotinib to neoadjuvant chemotherapy in patients with TNBC. Methods: Patients with clinical stage II/III TNBC were treated with 5 cycles of anlotinib (12 mg, d1-14, q3w) plus 6 cycles of taxanes (docetaxel 75 mg/m2 ,d1, q3w or nab-paclitaxel 125 mg/m2, d1 and d8, q3w) and lobaplatin (30 mg/m2, d1, q3w), followed by surgery. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0) and the secondary endpoints include breast pCR (bpCR), axillary pCR (apCR), residual cancer burden (RCB), objective response rate (ORR), survival, and safety. Exploratory endpoints were efficacy biomarkers based on Fudan University Shanghai Cancer Center Immunohistochemical (FUSCC IHC) classification for TNBC and next-generation sequencing (NGS) of DNA from tumor tissue and blood samples of patients with 425-gene panel. This trial is registered with www.chictr.org.cn (ChiCTR2100043027). Findings: From Jan 2021 to Aug 2022, 48 patients were assessed and 45 were enrolled. All patients received at least one dose of study treatment and underwent surgery. The median age was 48.5 years (SD: 8.7), 71% were nodal involved, and 20% had stage III. In the intention-to-treat population, 26 out of 45 patients achieved pCR (57.8%; 90% CI, 44.5%-70.3%), and 39 achieved residual cancer burden class 0-I (86.7%; 95% CI, 73.2%-94.9%). The bpCR and apCR rate were 64.4% (29/45) and 71.9% (23/32), respectively. No recurrence or metastasis occurred during the short-term follow-up. Based on the FUSCC IHC-based subtypes, the pCR rates were 68.8% (11/16) for immunomodulatory subtype, 58.3% (7/12) for basal-like immune-suppressed subtype and 33.3% (4/12) for luminal androgen receptor subtype, respectively. NGS revealed that the pCR were 77% (10/13) and 50% (14/28) in MYC-amplified and wild-type patients, respectively, and 78% (7/9) and 53% (17/32) in gBRCA1/2-mutated and wild-type patients, respectively. The median follow-up time of the study was 14.9 months (95% CI: 13.5-16.3 months). There was no disease progression or death during neoadjuvant therapy. No deaths occurred during postoperative follow-up. In the safety population (N = 45), Grade 3 or 4 treatment emergent adverse events occurred in 29 patients (64%), and the most common events were neutropenia (38%), leukopenia (27%), thrombocytopenia (25%), anemia (13%), and hypertension (13%), respectively. Interpretation: The addition of anlotinib to neoadjuvant chemotherapy showed manageable toxicity and encouraging antitumor activity for patients with clinical stage II/III TNBC. Funding: Chongqing Talents Project, Chongqing Key Project of Technology Innovation and Application Development and Chongqing Outstanding Youth Natural Science Foundation.

Screening for immune-related biomarkers associated with myasthenia gravis and dilated cardiomyopathy based on bioinformatics analysis and machine learning.

Background: We aim to investigate genes associated with myasthenia gravis (MG), specifically those potentially implicated in the pathogenesis of dilated cardiomyopathy (DCM). Additionally, we seek to identify potential biomarkers for diagnosing myasthenia gravis co-occurring with DCM. Methods: We obtained two expression profiling datasets related to DCM and MG from the Gene Expression Omnibus (GEO). Subsequently, we conducted differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) on these datasets. The genes exhibiting differential expression common to both DCM and MG were employed for protein-protein interaction (PPI), Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Additionally, machine learning techniques were employed to identify potential biomarkers and develop a diagnostic nomogram for predicting MG-associated DCM. Subsequently, the machine learning results underwent validation using an external dataset. Finally, gene set enrichment analysis (GSEA) and machine algorithm analysis were conducted on pivotal model genes to further elucidate their potential mechanisms in MG-associated DCM. Results: In our analysis of both DCM and MG datasets, we identified 2641 critical module genes and 11 differentially expressed genes shared between the two conditions. Enrichment analysis disclosed that these 11 genes primarily pertain to inflammation and immune regulation. Connectivity map (CMAP) analysis pinpointed SB-216763 as a potential drug for DCM treatment. The results from machine learning indicated the substantial diagnostic value of midline 1 interacting protein1 (MID1IP1) and PI3K-interacting protein 1 (PIK3IP1) in MG-associated DCM. These two hub genes were chosen as candidate biomarkers and employed to formulate a diagnostic nomogram with optimal diagnostic performance through machine learning. Simultaneously, single-gene GSEA results and immune cell infiltration analysis unveiled immune dysregulation in both DCM and MG, with MID1IP1 and PIK3IP1 showing significant associations with invasive immune cells. Conclusion: We have elucidated the inflammatory and immune pathways associated with MG-related DCM and formulated a diagnostic nomogram for DCM utilizing MID1IP1/PIK3IP1. This contribution offers novel insights for prospective diagnostic approaches and therapeutic interventions in the context of MG coexisting with DCM.

Streamlined enzymatic synthesis of human milk fat substitutes.

The positional distribution of palmitic acid (PA) in human milk fat substitutes (HMFSs) plays a pivotal role in mimicking the nutritional profile of human milk fat for nourishing non-breastfed infants. This study innovatively introduced a streamlined enzymatic process for preparing HMFSs rich in sn-2 PA using palm stearin, a PA-rich source without the necessity for positional distribution of PA. The initial step involved enhancing the sn-2 PA concentration through enzymatic interesterification using Lipase UM1, which exhibited superior catalytic efficiency than Novozym 435. This process increased the sn-2 PA level from 40.98 % to 64.51 %. Subsequently, acidolysis was employed to reduce PA levels by replacing PA at sn-1,3 positions using sn-1,3-regioselective lipases. The PA content decreased from 60.64 % to 26.73 %, simultaneously raising the relative sn-2 PA concentration to 71.57 %, meeting the benchmarks for HMFSs. This study establishes a robust conceptual framework for the prospective industrial synthesis of HMFSs.

Branched-chain amino acid catabolic defect promotes α-cell proliferation via activating mTOR signaling.

Elevated circulating level of branched-chain amino acids (BCAAs) is closely related to the development of type 2 diabetes. However, the role of BCAA catabolism in various tissues in maintaining glucose homeostasis remains largely unknown. Pancreatic α-cells have been regarded as amino acid sensors in recent years. Therefore, we generated α-cell specific branched-chain alpha-ketoacid dehydrogenase E1α subunit (BCKDHA) knockout (BCKDHA-αKO) mice to decipher the effects of BCAA catabolism in α-cells on whole-body energy metabolism. BCKDHA-αKO mice showed normal body weight, body fat, and energy expenditure. Plasma glucagon level and glucose metabolism also remained unchanged in BCKDHA-αKO mice. Whereas, the deletion of BCKDHA led to increased α-cell number due to elevated cell proliferation in neonatal mice. In vitro, only leucine among BCAAs promoted aTC1-6 cell proliferation, which was blocked by the agonist of BCAA catabolism BT2 and the inhibitor of mTOR Rapamycin. Like Rapamycin, BT2 attenuated leucine-stimulated phosphorylation of S6 in αTC1-6 cells. Elevated phosphorylation level of S6 protein in pancreatic α-cells was also observed in BCKDHA-αKO mice. These results suggest that local accumulated leucine due to defective BCAA catabolism promotes α-cell proliferation through mTOR signaling, which is insufficient to affect glucagon secretion and whole-body glucose homeostasis.

A multicenter single-arm trial of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

The objective of this multicenter, single-arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib (ECPy-THPy) in the treatment of patients with stage II-III HER2-positive breast cancer. The present study enrolled patients with stage II-III HER2-positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21-day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention-to-treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7-75.8%), while the objective response rate was 89.1%. In the post-hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy-THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II-III HER2-positive breast cancer.

Construction of a ferroptosis-based prognostic model for breast cancer helps to discriminate high/low risk groups and treatment priority.

Introduction: Breast cancer is a common malignant tumor associated with high morbidity and mortality. The role of ferroptosis, a regulated form of cell death, in breast cancer development and prognosis remains unclear. This study aims to investigate the relationship between ferroptosis-related genes and breast cancer and develop a prognostic model. Methods: RNA-seq expression datasets and clinical samples of breast cancer patients were obtained from public databases. Immunity- and drug resistance-related data were integrated. A preliminary screening was performed, resulting in the identification of 73 candidate ferroptosis factors. Univariate Cox regression analysis was conducted to select 12 genes, followed by LASSO Cox regression analysis to construct a prognostic risk prediction model consisting of 10 ferroptosis-related genes. The model was further characterized by immune cell infiltration. The expression levels of ferroptosis-related genes were validated in human breast cancer cell lines, and immunohistochemical (IHC) analysis was conducted on cancer specimens to assess ferroptosis-related protein expression. Results: The study identified 10 ferroptosis-related genes that were significantly associated with breast cancer prognosis. The constructed prognostic risk prediction model showed potential for predicting the prognostic value of these genes. In addition, the infiltration of immune cells was observed to be a characteristic of the model. The expression levels of ferroptosis-related genes were confirmed in human breast cancer cell lines, and IHC analysis provided evidence of ferroptosis-related protein expression in cancer specimens. Discussion: This study provides a novel prognostic model for breast cancer, incorporating 10 ferroptosis-related genes. The model demonstrates the potential for predicting breast cancer prognosis and highlights the involvement of immune cell infiltration. The expression levels of ferroptosis-related genes and proteins further support the association between ferroptosis and breast cancer development.

The value of hematocrit for predicting bronchopulmonary dysplasia in very low birth weight preterm infants.

To determine hematocrit (HCT) and to identify independent risk factors for predicting bronchopulmonary dysplasia (BPD) in preterm infants with very low birth weight (VLBW) infants. This retrospective study included 296 premature infants with VLBW in the neonatal intensive care unit of the First Affiliated Hospital of the University of Science and Technology of China between January 2015 and December 2019. Maternal pregnant information and clinical information as well as hematological parameters of preterm babies were collected and compared. Then the maximum area under the curve of receiver operating characteristic curve was developed to estimate the predictive indicator in the blood. Finally, differential variables together with the predictive index were screened for multiple logistic regression analysis to determine independent prognostic factors for BPD. Infants were divided into a BPD group (134 cases) and a non-BPD group (162 cases). The area under the curve of HCT at postnatal 1 week was 0.737 with the sensitivity of 52.30 % and the specificity of 86.00%. Birth weight (BW) <1.12 kg, gestational age <28.4 weeks, newborn respiratory distress syndrome, mechanical ventilation ≥ 7 days, ventilation associated pneumonia, patent arterial duct, PaO2/FiO2 <300 mm Hg and HCT <0.455 at postnatal 1 week were risk factors for BPD of VLBW infants. HCT levels below 0.455 at 1 week after birth serve as a valuable indicator for the potential development of BPD.

Study on the synthesis of pine sterol esters in solvent-free systems catalyzed by Candida rugosa lipase immobilized on hydrophobic macroporous resin.

BACKGROUND: Pine sterol ester is a type of novel food source nutrient with great advantages in lowering blood cholesterol levels, inhibiting tumors, preventing prostate enlargement, and regulating immunity. Macroporous resins with large specific surface area, stable structures, and various functional groups (epoxy, amino, and octadecyl groups) have been selected for immobilization of Candida rugosa lipase (CRL) to improve its stability and efficiency in the synthesis of pine sterol esters. A solvent-free strategy using oleic acid (substrate) as an esterification reaction medium is an important alternative for avoiding the use of organic solvents. RESULTS: The immobilization conditions of CRL immobilized on several types of commercial macroporous resins were optimized. Fortunately, by adsorption (hydrophobic interaction), a high immobilization efficiency of CRL was obtained using macroporous resins with hydrophobic octadecyl groups with an immobilization efficiency of 86.5%, enzyme loading of 138.5 mg g-1 and enzyme activity of 34.7 U g-1 . The results showed that a 95.1% yield could be obtained with a molar ratio of oleic acid to pine sterol of 5:1, an enzyme amount of 6.0 U g-1 (relative to pine sterol mass) at 50 °C for 48 h. CONCLUSION: The hydrophobic macroporous resin (ECR8806M) with a large specific surface area and abundant functional groups was used to achieve efficient immobilization of CRL. CRL@ECR8806M is an efficient catalyst for the synthesis of phytosterol esters and has the potential for further large-scale applications. Therefore, this simple, green, and low-cost strategy for lipase immobilization provides new possibilities for the high-efficiency production of pine sterol esters and other food source nutrients. © 2023 Society of Chemical Industry.

Role of serum- and glucocorticoid-inducible kinase 1 in the regulation of hepatic gluconeogenesis.

Excessive hepatic gluconeogenesis partially accounts for the occurrence of type 2 diabetes mellitus. Serum- and glucocorticoid inducible-kinase 1 (SGK1) is linked to the development of metabolic syndrome, such as obesity, hypertension, and hyperglycemia. However, the regulatory role of SGK1 in glucose metabolism of liver remains uncertain. Our microarray analysis showed that SGK1 expression was strongly induced by 8-Br-cAMP and suppressed by metformin in primary mouse hepatocytes. Hepatic SGK1 expression was markedly increased in obese and diabetic mice. Metformin treatment decreased hepatic SGK1 expression levels in db/db mice. Inhibition or knockdown of SGK1 suppressed gluconeogenesis in primary mouse hepatocytes, with decreased expressions of key gluconeogenic genes. Furthermore, SGK1 silencing in liver decreased hepatic glucose production in C57BL/6 mice. Knockdown of SGK1 had no impact on CREB phosphorylation level but increased AKT and FoxO1 phosphorylation levels with decreased expressions of transcription factors including FoxO1 and hepatocyte nuclear factors. Adenovirus-mediated expression of dominant-negative AMPK antagonized metformin-suppressed SGK1 expression induced by 8-Br-cAMP. These findings demonstrate that hepatic specific silence of SGK1 might be a potential therapeutic strategy for type 2 diabetes.

Punicalagin attenuates ventricular remodeling after acute myocardial infarction via regulating the NLRP3/caspase-1 pathway.

CONTEXT: Punicalagin has myocardial protection; the mechanism of punicalagin on ventricular remodeling (VR) after acute myocardial infarction (AMI) remains unclear. OBJECTIVE: These studies explore the role and mechanism of punicalagin in preventing and treating VR after AMI. MATERIALS AND METHODS: Molecular docking was used to predict the targets of punicalagin. After 2 weeks of AMI model, the SD rats were randomly divided into model, and punicalagin (200, 400 mg/kg, gavage) groups for 4 weeks. Thoracotomy with perforation but no ligature was performed on rats in control group. The protein expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis speck-like protein (ASC), caspase-1, gasdermin D (GSDMD), and GSDMD-N, the mRNA expression of NLRP3, caspase-1, GSDMD, interleukin-1ß (IL-1ß) and IL-18 were evaluated. RESULTS: Punicalagin had binding activities with NLRP3 (Vina score, -5.8), caspase-1 (Vina score, -6.7), and GSDMD (Vina score, -6.7). Punicalagin could improve cardiac function, alleviate cardiac pathological changes, minimize the excessive accumulation of collagen in the left ventricular myocardium (p < 0.01), and inhibit cardiomyocyte apoptosis (p < 0.01). Furthermore, punicalagin could inhibit the overexpression of NLRP3, caspase-1, and GSDMD via immunohistochemistry (p < 0.01). Punicalagin inhibited the protein levels of NLRP3, caspase-1, ASC, GSDMD, and GSDMD-N (p < 0.05, p < 0.01). Punicalagin reduced the mRNA expression of NLRP3, caspase-1, GSDMD, IL-1ß and IL-18 (p < 0.05, p < 0.01). CONCLUSIONS: Punicalagin may provide a useful treatment for the future myocardial protection.

Selective and Efficient Synthesis of Pine Sterol Esters Catalyzed by Deep Eutectic Solvent.

Phytosterol esters have attracted widespread academic and industrial interests due to their advantages in lowering cholesterol, as antioxidants, and in preventing or treating cancer. However, the generation of by-products limits the application of phytosterol esters in food fields. In this study, deep eutectic solvents (DESs), a series of green, nontoxic, low-cost and biodegradable solvents, were adopted as the catalyst for the synthesis of pine sterol esters. The results showed that the acidic DES which was prepared with choline chloride (ChCl) and p-toluene sulfonic acid monohydrate (PTSA) with a molar ratio of 1:3 performed best in the prescreening experiments. To further improve the efficiency of the pine sterol ester, the molar ratio of substrates, the amount of catalyst, the reaction temperature and the reaction time were optimized, and its yield was improved to 94.1%. Moreover, the by-products of the dehydration side reactions of the sterol can be efficiently inhibited. To make this strategy more universal, other fatty acids were also used as the substrate for the synthesis of pine sterol esters, and a yield of above 92.0% was obtained. In addition, the reusability of DES was also investigated in this study, and the efficiency of DES was well maintained within five recycled uses. Finally, DFT calculations suggested that the suitable H-bonds between ChCl and PTSA decreased the nucleophilic capacity and increased the steric hindrance of the latter, and further prevented the attack on ßH and reduced the generation of by-products. This study developed a reliable and eco-friendly strategy for the preparation of high-quality phytosterol esters with low-dosage catalyst usage and high selectivity.

Magnetic Polyethyleneimine Nanoparticles Fabricated via Ionic Liquid as Bridging Agents for Laccase Immobilization and Its Application in Phenolic Pollutants Removal.

In this study, polyethyleneimine was combined with magnetic Fe3O4 nanoparticles through the bridging of carboxyl-functionalized ionic liquid, and laccase was loaded onto the carrier by Cu2+ chelation to achieve laccase immobilization (MCIL-PEI-Cu-lac). The carrier was characterized by Fourier transform infrared spectroscopy, scanning electron microscope, thermogravimetric analysis, X-ray diffraction analysis, magnetic hysteresis loop and so on. MCIL-PEI-Cu-lac has good immobilization ability; its loading and activity retention could reach 52.19 mg/g and 91.65%, respectively. Compared with free laccase, its thermal stability and storage stability have been significantly improved, as well. After 6 h of storage at 60 °C, 51.45% of the laccase activity could still be retained, and 81.13% of the laccase activity remained after 1 month of storage at 3 °C. In the pollutants removal test, the removal rate of 2,4-dichlorophenol (10 mg/L) by MCIL-PEI-Cu-lac could reach 100% within 10 h, and the removal efficiency could still be maintained 60.21% after repeated use for 8 times. In addition, MCIL-PEI-Cu-lac also has a good removal effect on other phenolic pollutants (such as bisphenol A, phenol, 4-chlorophenol, etc.). Research results indicated that an efficient strategy for laccase immobilization to biodegrade phenolic pollutants was developed.

Association of Long-term Oncologic Prognosis With Minimal Access Breast Surgery vs Conventional Breast Surgery.

Importance: Minimal access breast surgery (MABS) has been used in breast cancer management. However, long-term prognostic data associated with MABS vs conventional breast surgery (CBS) are lacking. Objective: To investigate long-term therapeutic outcomes associated with MABS vs CBS for breast cancer management. Design, Setting, and Participants: In this single-center retrospective cohort study, 9184 individuals were assessed for inclusion. After exclusions, 2412 adult female individuals were included who were diagnosed with stage 0 to III breast cancer, underwent unilateral breast surgery between January 2004 and December 2017, and had no distant metastasis or history of severe underlying disease. Propensity score matching was performed to minimize selection bias. Data were analyzed from January 1, 2004, to December 31, 2019. Exposures: MABS or CBS. Main Outcomes and Measures: Data on demographic and tumor characteristics and long-term outcomes were collected and analyzed. Results: This study included 2412 patients (100% female; median [IQR] age, 44 [40-49] years). Of these, 603 patients underwent MABS (endoscopic, endoscopy-assisted, or robot-assisted procedures in 289, 302, and 12 patients, respectively) and 1809 patients underwent CBS. The median follow-up time was 84 months (93 in the MABS group and 80 months in the CBS group). Intergroup differences were not significant for the following parameters: 10-year local recurrence-free survival (93.3% vs 96.3%; hazard ratio [HR], 1.39; 95% CI, 0.86-2.27; P = .18), regional recurrence-free survival (95.5% vs 96.7%; HR, 1.38; 95% CI, 0.81-2.36; P = .23), and distant metastasis-free survival (81.0% vs 82.0%; HR, 0.95; 95% CI, 0.74-1.23; P = .72). The 5-, 10-, and 15-year disease-free survival rates in the MABS group were 85.9%, 72.6%, and 69.1%, respectively. The corresponding rates in the CBS group were 85.0%, 76.6%, and 70.7%. The intergroup differences were not significant (HR, 1.07; 95% CI, 0.86-1.31; P = .55). The 5-, 10-, and 15-year overall survival rates in the MABS group were 92.0%, 83.7%, and 83.0%, respectively. The corresponding rates in the CBS group were 93.6%, 88.7%, and 81.0%. The intergroup differences were not significant (HR, 1.29; 95% CI, 0.97-1.72; P = .09). Post hoc subgroup analysis showed no significant intergroup differences in disease-free survival. Conclusions and Relevance: In this cohort study, long-term outcomes following MABS were not significantly different from those following CBS in patients with early-stage breast cancer. MABS may be a safe and feasible alternative in this patient population.

Cytomegalovirus-specific neutralizing antibodies effectively prevent uncontrolled infection after allogeneic hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) infection remains one of the most frequent and life-threatening infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Herein, we comprehensively compared the immune cells of patients with uncontrolled and controlled CMV infection post-allo-HSCT and found that B-cells were extraordinarily insufficient because of impaired B-cells reconstitution in the uncontrolled infection group. Furthermore, in the controlled infection group, reconstructed B-cells showed signatures of mature B-cells, high expression of CXCR4 and IFITM1, and enrichment of CMV-associated B-cell receptors, which were lacking in the uncontrolled infection group. Consistently, sera from the uncontrolled infection group failed to inhibit CMV infection via neutralizing virus in vitro because of its lower content of anti-CMV-specific immunoglobulin G (IgG) than the controlled infection group. Overall, these results highlighted the contribution of B cells and anti-CMV-specific neutralizing IgGs to the restraint of CMV infection post-allo-HSCT, suggesting their potential as a supplementary treatment to improve outcomes.

Internationalization, cultural appreciation and institutional governmentality for quality control in transnational higher education cooperation: An empirical assessment.

This article examines the dynamic mechanism of cultural appreciation and institutional governmentality to ensure successful quality control in a transnational higher education collaboration context. Adopting participatory action research and a case study approach, this paper investigates the quality control system in a Chinese tourism university. The present study finds that mutual cultural appreciation, responsible government guidance and institutional governmentality are essential quality control measures for transnational higher education cooperation. The quality control system is suggested to be established to enrich and improve the quality standards of joint international higher education collaboration. This study proposes to expand the international influence and recognition of China-foreign education collaboration through quality international exchange and cooperation.

Immobilization of Interfacial Activated Candida rugosa Lipase Onto Magnetic Chitosan Using Dialdehyde Cellulose as Cross-Linking Agent.

Candida rugosa lipase (CRL) was activated with surfactants (sodium dodecyl sulfate [SDS]) and covalently immobilized onto a nanocomposite (Fe3O4-CS-DAC) fabricated by combining magnetic nanoparticles Fe3O4 with chitosan (CS) using polysaccharide macromolecule dialdehyde cellulose (DAC) as the cross-linking agent. Fourier transform infrared spectroscopy, transmission electron microscope, thermogravimetric analysis, and X-ray diffraction characterizations confirmed that the organic-inorganic nanocomposite support modified by DAC was successfully prepared. Enzymology experiments confirmed that high enzyme loading (60.9 mg/g) and 1.7 times specific enzyme activity could be obtained under the optimal immobilization conditions. The stability and reusability of immobilized CRL (Fe3O4-CS-DAC-SDS-CRL) were significantly improved simultaneously. Circular dichroism analysis revealed that the active conformation of immobilized CRL was maintained well. Results demonstrated that the inorganic-organic nanocomposite modified by carbohydrate polymer derivatives could be used as an ideal support for enzyme immobilization.

Virtual screening analysis of natural flavonoids as trimethylamine (TMA)-lyase inhibitors for coronary heart disease.

Coronary heart disease (CHD) is defined by atherosclerosis, which can result in stenosis or blockage of the arterial cavity, leading to ischemic cardiac diseases such as angina and myocardial infarction. Accumulating evidence indicates that the gut microbiota plays a vital role in the beginning and progression of CHD. The gut microbial metabolite, trimethylamine-N-oxide (TMAO), is intimately linked to the pathophysiology of CHD. TMAO is formed when trimethylamine (TMA) is converted by flavin-containing monooxygenases in the hepatocytes. Therefore, inhibition of TMA production is essential to reduce TMAO levels. Flavonoids may reduce the risk of death from cardiovascular disease. In this article, we reviewed and evaluated twenty-two flavonoids for the therapy of CHD based on their inhibition of TMA-lyase by molecular docking. Docking results revealed that baicalein, fisetin, acacetin, and myricetin in flavonoid aglycones, and baicalin, naringin, and hesperidin in flavonoid glycosides had a good binding effect with TMA-lyase. This indicates that these chemicals were the most active and could be used as lead compounds for structural modification in the future. PRACTICAL APPLICATIONS: Flavonoids are a large class of polyphenolic compounds found in fruits, vegetables, flowers, tea, and herbal medicines, which are inexorably metabolized and transformed into bioactive metabolites by α-rhamnosidase, ß-glucuronidase, ß-glucosidase, and nitroreductase produced by the gut microbiota, which plays a beneficial role in the prevention and treatment of cardiovascular diseases. Because flavonoids protect the cardiovascular system and regulate the gut microbiota, and the gut microbiota is directly connected to TMAO, thus, reducing TMAO levels involves blocking the transition of TMA to TMAO, which may be performed by reducing TMA synthesis. Molecular docking results found that baicalein, fisetin, acacetin, and myricetin in flavonoid aglycones, and baicalin, naringin, and hesperidin in flavonoid glycosides had good binding effects on TMA-lyase, which were the most active and could be used as lead compounds for structural modification.

Lobaplatin-based neoadjuvant chemotherapy for triple-negative breast cancer: a 5-year follow-up of a randomized, open-label, phase II trial.

Purpose: We report the 5-year follow-up findings of a randomized, open-label, phase II trial of lobaplatin-based neoadjuvant chemotherapy plus adjuvant therapy for triple-negative breast cancer (TNBC). Patients and methods: This study included patients aged ⩾18 years with untreated, operable stage I-III TNBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. One group of patients (TE group, n = 99) received four cycles of docetaxel (T, 75 mg/m²) plus epirubicin (E, 80 mg/m²) every 3 weeks, and another group (TEL group, n = 101) received the same treatment with the addition of lobaplatin (L, 30 mg/m2). Two cycles of the corresponding treatments were administered after surgery in both groups. The primary endpoints were total pathological complete response (tpCR) rate and overall response rate (ORR), and the secondary endpoints were disease-free survival, overall survival, and long-term safety. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-14005019). Results: The median follow-up was 48.2 months (interquartile range: 31.1-60.0). The tpCR rate was 41.4% and 17.8% in the TEL group and TE group, respectively (p < 0.001). The HR for comparison of DFS between the TEL group and TE group was 0.44 (95% CI: 0.21-0.90, P p = 0.028). The addition of lobaplatin resulted in an HR of 0.44 (95% CI: 0.18-1.02, P = 0.061) for the difference in OS between the two groups. The ORR, which included complete response and partial response, was 92.9% in the TEL group and 74.3% in the TE group (p = 0.001). The TEL group patients were more likely to develop grade III-IV anemia and thrombocytopenia. No lobaplatin-related deaths or increased risk of long-term toxicity was observed. Conclusion: Neoadjuvant lobaplatin therapy can improve the tpCR and ORR rates of TNBC with tolerable side effects and have a tendency to improve the long-term survival.

Pyrotinib-Containing Neoadjuvant Therapy in Patients With HER2-Positive Breast Cancer: A Multicenter Retrospective Analysis.

Background: Pyrotinib, a small-molecule tyrosine kinase inhibitor, has been investigated as a component of neoadjuvant therapy in phase 2 trials of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This study aimed to evaluate the effectiveness and safety of pyrotinib-containing neoadjuvant therapy for patients with HER2-positive early or locally advanced breast cancer in the real-world setting. Methods: Data of 97 patients with HER2-positive breast cancer from 21 centers across China treated with pyrotinib-containing neoadjuvant therapy were reviewed. Neoadjuvant therapy consisted of taxane/carboplatin/trastuzumab plus pyrotinib (TCbH+Py, 30 [30.9%]), anthracycline/cyclophosphamide followed by taxane/trastuzumab plus pyrotinib (AC-TH+Py) or taxane followed by anthracycline/cyclophosphamide/trastuzumab plus pyrotinib (T-ACH+Py, 29 [29.9%]), taxane/trastuzumab plus pyrotinib (TH+Py, 23 [23.7%]), and other pyrotinib-containing neoadjuvant treatment (15 [15.5%]). The primary outcome was breast pathological complete response (bpCR, ypT0/is) rate. Secondary outcomes included total pathological complete response (tpCR, ypT0/is ypN0) rate, objective response rate (ORR), and the incidence of preoperative adverse events. Results: The ORR of pyrotinib-containing neoadjuvant therapy was 87.6% (85/97). The bpCR and tpCR rates were 54.6% (95% confidence interval [CI], 44.2%-64.7%) and 48.5% [95% CI, 38.2%-58.8%], respectively. The most common grade 3 or 4 treatment-related adverse events included diarrhea (15 [15.5%]), decreased hemoglobin (nine [9.3%]), and decreased neutrophil count (eight [8.2%]). No treatment-related deaths occurred. Conclusion: Pyrotinib-containing neoadjuvant therapy for patients with HER2-positive early or locally advanced breast cancer shows favorable effectiveness with manageable toxicity in the real-world setting. Trastuzumab plus pyrotinib may be a novel option of dual HER2-targeted blockade.