Analysis of influencing factors and construction of prediction model for postoperative nausea and vomiting in patients undergoing laparoscopic sleeve gastrectomy: a single-center retrospective cohort study.

BACKGROUND: With the increasing number of bariatric surgeries, the high incidence of postoperative nausea and vomiting (PONV) associated with this surgery has also gradually attracted attention. Among the common bariatric surgery methods, patients undergoing sleeve gastrectomy (SG) have the highest incidence of nausea and vomiting. The mechanism of occurrence of PONV is very complex. This study aims to explore the influencing factors of PONV in patients undergoing laparoscopic sleeve gastrectomy (LSG) and construct a nomogram prediction model based on these factors. METHODS: With the approval of the Ethics Committee, the electronic medical records of patients who underwent LSG from July 2022 to May 2023 were collected retrospectively. RESULTS: A total of 114 patients with complete medical records who underwent LSG from July 2022 to May 2023 were included in this study. Among them, 46 patients developed PONV, resulting in a PONV incidence rate of 40.4%. Multivariate logistic regression analysis revealed that female gender, the use of inhalation anesthesia, and operation time ≥ 120 min were risk factors for PONV in LSG. Additionally, the use of more than two kinds of antiemetic drugs was identified as a protective factor. Based on these factors, a nomogram model was constructed. CONCLUSION: PONV in patients undergoing LSG is related to gender, type of anesthesia, duration of surgery, and combination therapy with antiemetic drugs. The nomogram prediction model constructed in this study demonstrates high accuracy and discrimination in predicting the occurrence of PONV in patients undergoing LSG.

Effect of ultrasound-guided lung recruitment to reduce pulmonary atelectasis after non-cardiac surgery under general anesthesia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: At present, the application of bedside lung ultrasound is increasing gradually, but there is no relevant expert consensus or guidance for its evaluation in the field of perioperative anesthesia. Through this meta-analysis, we tried to determine the impact of ultrasound-guided lung recruitment maneuvers (LRM) on perioperative patients. METHODS: We searched PubMed, Cochrane Library database, Embase, and Clinical Trials gov for the randomized controlled trials (RCTs) published up to December 31, 2022. The primary outcome was the incidence of postoperative atelectasis. Secondary outcomes included lung ultrasound score (LUS) and LUS of each part. A total of 443 patients were examined in nine randomized controlled trials. RESULTS: The incidence of atelectasis after surgery in patients with ultrasound-guided LRM was less (RR 0.31; 95% CI 0.25-0.40; p < 0.05). The LUS (WMD - 6.24; 95% CI - 6.90-5.59; p < 0.05) and the LUS of each part (LUS in front lung region (WMD - 2.00; 95% CI - 2.49 to - 1.51; p < 0.05); LUS in lateral lung region (WMD - 2.50; 95% CI - 3.20 to - 1.80; p < 0.05); LUS in posterior lung region (WMD - 3.24; 95% CI - 4.23 to - 2.24; p < 0.05)) in patients with ultrasound-guided LRM were lower. CONCLUSION: Ultrasound-guided lung recruitment maneuvers have been shown to be a promising approach for improving perioperative lung ventilation by increasing aeration while mitigating the development of atelectasis. In comparison to non-ultrasound-guided methods, this technique has exhibited superior effects.

Nickel-Catalyzed C(sp3)-Sb Coupling of Chlorostibines with Unactivated Alkyl Chlorides and In Vitro Anticancer Activity of Products.

In this study, we present a nickel-catalyzed reductive C(sp3)-Sb coupling of unactivated alkyl chlorides with chlorostibines. This approach is highly versatile, tolerating various functional groups such as acetal, alkene, nitrile, amine, ester, silyl ether, thioether, and various heterocyclic compounds. Notably, the late-stage modification of bioactive molecules and the satisfactory anticancer activity against cancerous MDA-MB-231 also demonstrate the potential application.

A real-world study of recombinant human endostatin combined with PD-1/PD-L1 blockade and chemotherapy for patients with advanced non-small cell lung cancer negative for actionable molecular biomarkers.

The ongoing ENPOWER study exploring the efficacy and safety of the recombinant human endostatin (endostar) combined with programmed cell death 1 antibody sintilimab and chemotherapy showed encouraging efficacy and safety in advanced non-squamous non-small cell lung cancer. To evaluate the real-world efficacy and safety of endostar combined with immune checkpoint inhibitor and chemotherapy (EIC) for advanced non-squamous non-small cell lung cancer patients negative for actionable molecular biomarkers (NSCLCnm), patients with advanced NSCLCnm hospitalized to Zhejiang Provincial People's Hospital from January 2020 to December 2022 were screened for eligibility. The included patients were analyzed for the objective response rate (ORR) and disease control rate (DCR). The pre- and posttreatment expression levels of serum tumor associated biomarkers, chemokines and subpopulations of immune cells in peripheral blood were compared. For the 31 patients with advanced NSCLCnm treated with EIC, the median follow-up and treatment cycles were 18.0 months and 4, respectively. The ORR and DCR were 38.7% and 90.3%, respectively. For those who received EIC as first-line treatment, the ORR and DCR were 63.2% and 94.7%, respectively. EIC significantly decreased expression levels of carcinoma antigen 125, carcinoma embryonic antigen and cytokeratin 19 (P<0.05) in patients who were partial remission or stable disease. Among the 31 patients, 27 (87.1%) experienced at least 1 treatment-related adverse events, and 13 (41.9%) had the treatment-related adverse events of grade 3 or higher. No antiangiogenesis-related adverse events were observed. The current study showed that EIC was potentially effective for patients with NSCLCnm, especially when used as first-line therapy, and well tolerated.

Case Report: Life-threatening pancytopenia with tislelizumab followed by cerebral infarction in a patient with lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) are an integral antitumor therapy for many malignancies. Most patients show very good tolerability to ICIs; however, serious immune-related adverse events (irAEs) with ICIs have been well documented and prevent some patients from continuing ICIs or even become the direct cause of patient death. Cytopenia is a rare irAE but can be life-threatening. Here, we present the case of a 66-year-old male patient with metastatic lung adenocarcinoma who received two doses of chemotherapy + PD-1 antibody tislelizumab and developed pancytopenia after each dose. Although the first episode of pancytopenia resolved with a treatment regimen of granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), and red blood cell and platelet transfusion, the second episode showed extreme resistance to these treatments and improved only after the administration of steroids. His second pancytopenia episode resolved after a long course of treatment with methylprednisolone, G-CSF, TPO, hetrombopag and multiple red blood cell and platelet transfusions. However, he suffered a cerebral infarction when his platelet count was in the normal range and gradually recovered 1 week later. This case highlights the importance of the early recognition and management of hematological irAEs.

Efficacy and safety of acupoint application in the treatment of ulcerative colitis: A systematic review and meta-analysis.

BACKGROUND: The efficacy of acupoint application in the treatment of ulcerative colitis (UC) is still controversial. The purpose of this study is to systematically evaluate the clinical efficacy and safety of acupoint application in the treatment of ulcerative colitis. METHODS: The databases of China National Knowledge Infrastructure (CNKI), Chinese Biology Medicine (CBM), VIP, Wanfang, Embase, PubMed, the Cochrane Library and Web of Science were searched. The time limit was from the establishment of the database to July 2022. The published randomized controlled trials of acupoint application in the treatment of UC were analyzed by meta-analysis and trial sequential analysis. RESULTS: A total of 13 studies were included, with a total sample size of 878 cases. Compared with conventional western medicine, acupoint application can effectively improve the effective rates of clinical comprehensive (risk ratio [RR] 1.13, 95% confidence interval [CI] 1.06-1.20, P = .0003), syndrome (RR 1.13, 95% CI 1.03-1.24, P = .009), and interleukin-4 (IL-4) (mean differences 2.62, 95% CI 1.96-3.28, P < .00001) in the treatment of UC, and reduce interferon-γ (mean differences -5.38, 95% CI -6.81 to -3.94, P < .00001). The effective rates of colonoscopy (RR 0.94, 95% CI 0.84-1.05, P = .25), pathological examination (RR 1.04, 95% CI 0.90-1.20, P = .60) and rate of adverse reaction (RR 0.55, 95% CI 0.25-1.21, P = .14) were the same. Trial sequential analysis indicated that the benefits of effective rates of clinical comprehensive and syndrome, IL-4, and interferon-γ were conclusive. Harbord regression showed no publication bias (P = .98). The evaluation of evidence quality suggested that the evidence quality of effective rates of clinical comprehensive and syndrome was moderate and the evidence quality of other indicators was low or very low. CONCLUSION: Acupoint application is a safe and effective method for the treatment of UC, and has the prospect of clinical application.

Introducing Bidirectional Axial Coordination into BiVO4 @Metal Phthalocyanine Core-Shell Photoanodes for Efficient Water Oxidation.

Core-shell photoanodes have shown great potential for photoelectrochemical (PEC) water oxidation. However, the construction of a high-quality interface between the core and shell, as well as a highly catalytic surface, remains a challenge. Herein, guided by computation, we present a BiVO4 photoanode coated with ZnCoFe polyphthalocyanine using pyrazine as a coordination agent. The bidirectional axial coordination of pyrazine plays a dual role by facilitating intimate interfacial contact between BiVO4 and ZnCoFe polyphthalocyanine, as well as regulating the electron density and spin configuration of metal sites in ZnCoFe phthalocyanine, thereby promoting the potential-limiting step of *OOH desorption. The resulting photoanode displayed a high photocurrent density of 5.7±0.1 mA cm-2 at 1.23 VRHE . This study introduces a new approach for constructing core-shell photoanodes, and uncovers the key role of pyrazine axial coordination in modulating the catalytic activity of metal phthalocyanine.

Mixing Characteristic and High-Throughput Synthesis of Cadmium Sulfide Nanoparticles with Cubic Hexagonal Phase Junctions in a Chaotic Millireactor.

A four-stage oscillating feedback millireactor with splitters (S-OFM) was designed to improve the mixing performance based on chaotic advection. Three-dimensional CFD simulations were used to investigate its flow characteristics and mixing performance, and the generation mechanisms of secondary flows were examined. The results show that the mixing index (MIcup) increased with the increase in the Reynolds number (Re), and MIcup could reach 99.8% at Re = 663. Poincaré mapping and Kolmogorov entropy were adopted to characterize the chaotic advection intensity, which indicates that there is a intensity increase with the increase in Re. In addition, the results of Villermaux-Dushman experiments demonstrate that S-OFM performs excellently, and the mixing time could reach 1.04 ms at Re = 2764. Finally, S-OFM was successfully used to synthesize CdS nanoparticles with cubic hexagonal phase junctions. At a flow rate of 180 mL/min, the average particle size was 10.5 nm and the particle size distribution was narrow (with a coefficient of variation of 0.14).

Copper-Catalyzed Regioselective Iodoformylation of Terminal Alkynes to Access Versatile Electrophiles (E)-ß-Iodo-α,ß-Unsaturated Aldehydes.

Herein, we describe a method for synthesizing (E)-ß-iodo-α,ß-unsaturated aldehydes via the iodoformylation of terminal alkynes with TMSCF3 and NaI. This synthetic method uses inexpensive and easy-to-handle chemical feedstocks and employs a commercially available CuI catalyst. It can transform a broad range of terminal alkynes into bis-electrophile (E)-ß-iodo-α,ß-unsaturated aldehydes with excellent chemoselectivity, regioselectivity, and stereoselectivity. Moreover, it was demonstrated that this protocol has abundant organic reactivity.

Optimal dose of tirzepatide for type 2 diabetes mellitus: A meta-analysis and trial sequential analysis.

Objective: The purpose of this study is to evaluate the optimal dose of tirzepatide (TZP) for the treatment of type 2 diabetes mellitus (T2DM) by meta-analysis and trial sequential analysis (TSA). Methods: Clinical trials of TZP for T2DM were obtained by searching 8 databases with a time limit from database creation to May 2022. Mean differences (MD) and 95% confidence intervals (95%CI) were used for continuous variables, and relative risk (RR) and 95%CI were used for dichotomous variables. Results: Compared with TZP 5 mg, meta-analysis showed that TZP 10 mg significantly reduced glycosylated hemoglobin type A1c (HbA1c) (MD -0.24, 95%CI -0.31~-0.17, P < 0.00001), fasting serum glucose (FSG) (MD -5.82, 95%CI -8.35~-3.28, P < 0.00001) and weight (MD -2.47, 95%CI -2.95~-1.98, P < 0.00001), and TZP 15 mg significantly reduced HbA1c (MD -0.37, 95%CI -0.44~-0.29, P < 0.00001), FSG (MD -8.52, 95%CI -11.07~-5.98, P < 0.00001) and weight (MD -4.63, 95%CI -5.45~-3.81, P < 0.00001). Compared with TZP 10 mg, TZP 15 mg dramatically reduced HbA1c (MD -0.12, 95%CI -0.19~-0.05, P = 0.001), FSG (MD -2.73, 95%CI -5.29~-0.17, P = 0.04) and weight (MD -2.18, 95%CI -2.67~-1.70, P < 0.00001). The TSA indicated that the benefits observed in the current information set were conclusive, except for the FSG of "TZP 15 mg vs. TZP 10 mg". In terms of safety endpoints, meta-analysis revealed that there was no significant difference in the serious adverse events (AEs), major adverse cardiovascular events-4 (MACE-4), cardiovascular death, hypertension, cancer and hypoglycemic of the three dose groups of TZP. Compared with TZP 5 mg, TZP 10 mg increased total adverse events (RR 1.06, 95%CI 1.01~1.11, P = 0.03) and gastrointestinal (GI) AEs (RR 1.17, 95%CI 1.03~1.33, P = 0.02), and TZP 15 mg increased total AEs (RR 1.10, 95%CI 1.05~1.15, P = 0.0001). There were no significant differences in total AEs and GI AEs for TZP 15 mg compared to TZP 10 mg. The TSA demonstrated that the total AEs of "TZP 15 mg vs. TZP 5 mg" were conclusive. Conclusions: TZP 15 mg >TZP 10 mg > TZP 5 mg in terms of lowering glycemia and reducing weight. TZP 5 mg > TZP 10 mg = TZP 15 mg in terms of safety. On this basis, we recommend TZP 5 mg as the first-choice dose for patients with T2DM to minimize AEs while reducing glycemia and weight. If patients cannot effectively control their glycemia after taking TZP 5 mg, it is recommended to take TZP 15 mg directly to achieve the best effect of glycemic reduction. However, most of the included studies have the background of basic medication, the independent efficacy and safety of different doses of TZP still need to be tested. Systematic review registration: Unique Identifier: CRD42022341966.

Macrophage-derived exosomal aminopeptidase N aggravates sepsis-induced acute lung injury by regulating necroptosis of lung epithelial cell.

Sepsis-induced acute lung injury (ALI) is a serious sepsis complication and the prevailing cause of death. Circulating plasma exosomes might exert a key role in regulating intercellular communication between immunological and structural cells, as well as contributing to sepsis-related organ damage. However, the molecular mechanisms by which exosome-mediated intercellular signaling exacerbate ALI in septic infection remains undefined. Therefore, we investigated the effect of macrophage-derived exosomal APN/CD13 on the induction of epithelial cell necrosis. Exosomal APN/CD13 levels in the plasma of septic mice and patients with septic ALI were found to be higher. Furthermore, increased plasma exosomal APN/CD13 levels were associated with the severity of ALI and fatality in sepsis patients. We found remarkably high expression of APN/CD13 in exosomes secreted by LPS-stimulated macrophages. Moreover, c-Myc directly induced APN/CD13 expression and was packed into exosomes. Finally, exosomal APN/CD13 from macrophages regulated necroptosis of lung epithelial cells by binding to the cell surface receptor TLR4 to induce ROS generation, mitochondrial dysfunction and NF-κB activation. These results demonstrate that macrophage-secreted exosomal APN/CD13 can trigger epithelial cell necroptosis in an APN/CD13-dependent manner, which provides insight into the mechanism of epithelial cell functional disorder in sepsis-induced ALI.

A pH-Dependent rhodamine fluorophore with antiproliferative activity of bladder cancer in Vitro/Vivo and apoptosis mechanism.

Herein, 26 rhodamine fluorophores were synthesized from readily available Rh-6G and relative amines at room temperature with good selectivity, functional groups compatibility and high yields. We found that one of them 3f showed pH-dependent anticancer bioactivity, with cell viability of 68.4% under pH 6.5 and 83.2% under pH 7.5, LDH fold change of 42.8% under pH 6.5 and 26.4% under pH 7.5 in 22.35 µM in human bladder cancer cell line EJ. Besides, 3f showed anticancer bioactivity in vivo towards human bladder cancer, by triggering apoptosis through mitochondrial pathway.

Clinical efficacy of moluodan in the treatment of chronic atrophic gastritis: A protocol for systematic review and meta-analysis.

BACKGROUND: Chronic atrophic gastritis (CAG) is an important stage of precancerous lesions of gastric cancer, and also a key period of drug intervention. However, there is still a lack of drugs to maintain the treatment of CAG until the advent of moluodan. OBJECTIVE: This study was conducted to assess the clinical efficacy of moluodan in the treatment of CAG by meta-analysis and trial sequential analysis. METHODS: China National Knowledge Infrastructure, China Biology Medicine, VIP, Wanfang, Embase, PubMed, the Cochrane Library, and Web of Science databases were searched, all with the time limit from database establishment to July 2022. The published randomized controlled trials of moluodan for CAG were conducted for meta-analysis and trial sequential analysis. RESULTS: 7 studies with a total sample size of 1143 cases were included. Compared to folic acid/vitamins, moluodan alone significantly increased the effective rate of pathological detection (relative risk [RR] = 1.73, 95% confidence interval [95%CI] = [1.48,2.02], P < .00001), and moluodan in combination with folic acid/vitamins significantly increased the effective rates of pathological detection (RR = 1.37, 95%CI = [1.23,1.52], P < .00001), gastroscopy (RR = 1.37, 95%CI = [1.18,1.60], P < .0001) and symptoms (RR = 1.25, 95%CI = [1.13,1.38], P < .0001). Harbord regression showed no publication bias (P = .22). Quality of evidence evaluation demonstrated moderate quality of evidence for all indicators. CONCLUSIONS: Moluodan can improve the effective rates of pathological examination, gastroscopy and symptoms in patients with CAG, and play a role in slowing down the disease progression and reducing clinical symptoms. It may be a potential drug for the treatment of CAG and has the value of further exploration.

Mechanism Study of Thermally Induced Anti-Tumor Drug Loading to Engineered Human Heavy-Chain Ferritin Nanocages Aided by Computational Analysis.

Diverse drug loading approaches for human heavy-chain ferritin (HFn), a promising drug nanocarrier, have been established. However, anti-tumor drug loading ratio and protein carrier recovery yield are bottlenecks for future clinical application. Mechanisms behind drug loading have not been elaborated. In this work, a thermally induced drug loading approach was introduced to load anti-tumor drug doxorubicin hydrochloride (DOX) into HFn, and 2 functionalized HFns, HFn-PAS-RGDK, and HFn-PAS. Optimal conditions were obtained through orthogonal tests. All 3 HFn-based proteins achieved high protein recovery yield and drug loading ratio. Size exclusion chromatography (SEC) and transmission electron microscopy (TEM) results showed the majority of DOX loaded protein (protein/DOX) remained its nanocage conformation. Computational analysis, molecular docking followed by molecular dynamic (MD) simulation, revealed mechanisms of DOX loading and formation of by-product by investigating non-covalent interactions between DOX with HFn subunit and possible binding modes of DOX and HFn after drug loading. In in vitro tests, DOX in protein/DOX entered tumor cell nucleus and inhibited tumor cell growth.

Development of purification process for dual-function recombinant human heavy-chain ferritin by the investigation of genetic modification impact on conformation.

Ferritin is a promising drug delivery platform and has been functionalized through genetic modifications. This work has designed and expressed a dual-functional engineered human heavy-chain ferritin (HFn) with the inserted functional peptide PAS and RGDK to extend half-life and improve tumor targeted drug delivery. A facile and cost-effective two-step purification pathway for recombinant HFn was developed. The genetic modification was found to affect HFn conformation, and therefore varied the purification performance. Heat-acid precipitation followed by butyl fast flow hydrophobic interaction chromatography (HIC) has been developed to purify HFn and modified HFns. Nucleic acid removal reached above 99.8% for HFn and modified HFns. However, HFn purity reached above 95% and recovery yield (overall) above 90%, compared with modified HFns purity above 82% and recovery yield (overall) above 58%. It is interesting to find that the inserted functional peptides significantly changed the molecule conformation, where a putative turnover of the E-helix with the inserted functional peptides formed a "flop" conformation, in contrast with the "flip" conformation of HFn. It could be the cause of fragile stability of modified HFns, and therefore less tolerant to heat and acid condition, observed by the lower recovery yield in heat-acid precipitation.

CCAR2 promotes a malignant phenotype of osteosarcoma through Wnt/ß-catenin-dependent transcriptional activation of SPARC.

CCAR2 plays a pivotal role in the regulation of the DNA damage response and cancer progression. Although aberrant expression of CCAR2 has been reported in several types of cancer, its biological function and molecular mechanism in osteosarcoma (OS) have not yet been fully elucidated. Here, we show that silence of CCAR2 prevented the malignant phenotype of OS cell in vitro and decreased tumor growth in nude mice. By analyzing the transcriptomic profile of CCAR2 knockdown U2OS cells, we identified secreted protein acidic and rich in cysteine (SPARC) is tightly regulated by CCAR2. Mechanically, we found that SPARC is transcriptionally regulated by Wnt/ß-catenin signaling, and CCAR2 acts as a co-activator of Wnt/ß-catenin signaling to regulate the expression of SPARC in OS cells. Additionally, SPARC knockdown largely eliminated the malignant phenotype induced by CCAR2 overexpression and forced expression of SPARC promoted the malignant phenotype of CCAR2-depleted cells. In conclusion, our results suggest that CCAR2 exerted oncogenic roles in OS cells mainly via up-regulating SPARC expression and targeting the CCAR2-SPARC axis might have promising application prospect for the treatment of osteosarcoma.

Prognostic Nomogram for Liver Metastatic Colon Cancer Based on Histological Type, Tumor Differentiation, and Tumor Deposit: A TRIPOD Compliant Large-Scale Survival Study.

OBJECTIVE: A proportional hazard model was applied to develop a large-scale prognostic model and nomogram incorporating clinicopathological characteristics, histological type, tumor differentiation grade, and tumor deposit count to provide clinicians and patients diagnosed with colon cancer liver metastases (CLM) a more comprehensive and practical outcome measure. METHODS: Using the Transparent Reporting of multivariable prediction models for individual Prognosis or Diagnosis (TRIPOD) guidelines, this study identified 14,697 patients diagnosed with CLM from 1975 to 2017 in the Surveillance, Epidemiology, and End Results (SEER) 21 registry database. Patients were divided into a modeling group (n=9800), an internal validation group (n=4897) using computerized randomization. An independent external validation cohort (n=60) was obtained. Univariable and multivariate Cox analyses were performed to identify prognostic predictors for overall survival (OS). Subsequently, the nomogram was constructed, and the verification was undertaken by receiver operating curves (AUC) and calibration curves. RESULTS: Histological type, tumor differentiation grade, and tumor deposit count were independent prognostic predictors for CLM. The nomogram consisted of age, sex, primary site, T category, N category, metastasis of bone, brain or lung, surgery, and chemotherapy. The model achieved excellent prediction power on both internal (mean AUC=0.811) and external validation (mean AUC=0.727), respectively, which were significantly higher than the American Joint Committee on Cancer (AJCC) TNM system. CONCLUSION: This study proposes a prognostic nomogram for predicting 1- and 2-year survival based on histopathological and population-based data of CLM patients developed using TRIPOD guidelines. Compared with the TNM stage, our nomogram has better consistency and calibration for predicting the OS of CLM patients.

Immunogenicity study of engineered ferritins with C- and N-terminus insertion of Epstein-Barr nuclear antigen 1 epitope.

Human ferritin heavy chain, an example of a protein nanoparticle, has recently been used as a vaccine delivery platform. Human ferritin has advantages of uniform architecture, robust thermal and chemical stabilities, and good biocompatibility and biodegradation. There is however a lack of understanding about the relationship between insertion sites in ferritin (N-terminus and C-terminus) and the corresponding humoral and cell-mediated immune responses. To bridge this gap, we utilized an Epstein-Barr Nuclear Antigen 1 (EBNA1) epitope as a model to produce engineered ferritin-based vaccines E1F1 (N-terminus insertion) and F1E1 (C-terminus insertion) for the prevention of Epstein-Barr virus (EBV) infections. X-ray crystallography confirmed the relative positions of the N-terminus insertion and C-terminus insertion. For N-terminus insertion, the epitopes were located on the exterior surface of ferritin, while for C-terminus insertion, the epitopes were inside the ferritin cage. Based on the results of antigen-specific antibody titers from in-vivo tests, we found that there was no obvious difference on humoral immune responses between N-terminus and C-terminus insertion. We also evaluated splenocyte proliferation and memory lymphocyte T cell differentiation. Both results suggested C-terminus insertion produced a stronger proliferative response and cell-mediated immune response than N-terminus insertion. C-terminus insertion of EBNA1 epitope was also processed more efficiently by dendritic cells (DCs) than N-terminus insertion. This provides new insight into the relationship between the insertion site and immunogenicity of ferritin nanoparticle vaccines.

Engineered Human Heavy-Chain Ferritin with Half-Life Extension and Tumor Targeting by PAS and RGDK Peptide Functionalization.

Ferritin, one of the most investigated protein nanocages, is considered as a promising drug carrier because of its advantageous stability and safety. However, its short half-life and undesirable tumor targeting ability has limited its usage in tumor treatment. In this work, two types of functional peptides, half-life extension peptide PAS, and tumor targeting peptide RGDK (Arg-Gly-Asp-Lys), are inserted to human heavy-chain ferritin (HFn) at C-terminal through flexible linkers with two distinct enzyme cleavable sites. Structural characterizations show both HFn and engineered HFns can assemble into nanoparticles but with different apparent hydrodynamic volumes and molecular weights. RGDK peptide enhanced the internalization efficiency of HFn and showed a significant increase of growth inhibition against 4T1 cell line in vitro. Pharmacokinetic study in vivo demonstrates PAS peptides extended ferritin half-life about 4.9 times in Sprague Dawley rats. RGDK peptides greatly enhanced drug accumulation in the tumor site rather than in other organs in biodistribution analysis. Drug loaded PAS-RGDK functionalized HFns curbed tumor growth with significantly greater efficacies in comparison with drug loaded HFn.

Nickel-Catalyzed N,N-Diarylation of 8-Aminoquinoline with Large Steric Aryl Bromides and Fluorescence of Products.

A simple and efficient methodology for the synthesis of large sterically hindered triarylamines in a single step was developed. A direct N,N-diarylation of 8-aminoquinoline with sterically hindered bromides, making use of inexpensive nickel as a catalyst and simple sodium salt as a base, gives the products in good to excellent yields. Various bromides and substituted 8-aminoquinolines are tolerated. Preliminary fluorescence results indicate that these sterically hindered and conjugated triarylamines may have some potential in material chemistry.