Triple-Mechanism Enhanced Flexible SiO2 Nanofiber Composite Hydrogel with High Stiffness and Toughness for Cartilaginous Ligaments.

Hydrogels are widely used in tissue engineering, soft robotics and wearable electronics. However, it is difficult to achieve both the required toughness and stiffness, which severely hampers their application as load-bearing materials. This study presents a strategy to develop a hard and tough composite hydrogel. Herein, flexible SiO2 nanofibers (SNF) are dispersed homogeneously in a polyvinyl alcohol (PVA) matrix using the synergistic effect of freeze-drying and annealing through the phase separation, the modulation of macromolecular chain movement and the promotion of macromolecular crystallization. When the stress is applied, the strong molecular interaction between PVA and SNF effectively disperses the load damage to the substrate. Freeze-dried and annealed-flexible SiO2 nanofibers/polyvinyl alcohol (FDA-SNF/PVA) reaches a preferred balance between enhanced stiffness (13.71 ± 0.28 MPa) and toughness (9.9 ± 0.4 MJ m-3). Besides, FDA-SNF/PVA hydrogel has a high tensile strength of 7.84 ± 0.10 MPa, super elasticity (no plastic deformation under 100 cycles of stretching), fast deformation recovery ability and excellent mechanical properties that are superior to the other tough PVA hydrogels, providing an effective way to optimize the mechanical properties of hydrogels for potential applications in artificial tendons and ligaments.

Identification and Validation of the Diagnostic Markers for Inflammatory Bowel Disease by Bioinformatics Analysis and Machine Learning.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract which is mediated by the inappropriate immune responses. This study was aimed to identify novel diagnostic biomarkers for diagnosis of IBD and explore the relationship between the diagnostic biomarkers and infiltrated immune cells. GSE38713, GSE53306, and GSE75214 downloaded from the Gene Expression Omnibus (GEO) database were split into training and testing sets. Differentially expressed genes (DEGs) were screened using the "limma" package. Gene Ontology (GO) and KEGG pathway enrichment analysis of DEGs were performed by clusterProfiler package. The LASSO regression and support vector machine recursive feature elimination (SVM-RFE) algorithms were conducted to identify novel diagnostic biomarkers. The receiver operating characteristic (ROC) curve was applied to evaluate the diagnostic value of the candidate biomarkers. The relationship of the candidate biomarkers and infiltrating immune cells in IBD were evaluated by CIBERSOTR. Quantitative Real-Time PCR (qRT-PCR) was applied to measure the expression level of the biomarkers in IBD. A total of 289 dysregulated genes were identified as DEGs in IBD. These DEGs were significantly enriched in chemokine signaling pathway and cytokine-cytokine receptor interaction. RHOU was identified as a critical diagnostic gene in IBD, which was confirmed using ROC curve and qRT-PCR assays. Immune cell infiltration analysis showed that RHOU was correlated with macrophages M2, dendritic cells resting, mast cells resting, T cells CD4 memory resting, macrophages M0, and mast cells activated. Our results imply that RHOU may be a potential diagnostic biomarker for IBD.

Comparative Study of Application of Computed Tomography/Ultrasound and Computed Tomography Imaging Guidance Methods in the Microwave Ablation of Liver Cancer.

PURPOSE: The aim of the study is to assess the clinical value of the combined computed tomography (CT)/ultrasound (US) guidance in microwave ablation (MWA) for hepatocellular carcinoma (HCC). METHODS: From July 16, 2016, to June 20, 2021, medical records of 150 HCC patients treated with MWA were retrospectively analyzed. Ninety-two patients with 115 liver tumors underwent MWA under combined CT/US guidance, and 58 patients with 73 liver tumors received MWA under CT guidance alone. The clinical efficacy of combined CT/US-guided MWA was analyzed. We compared the complications, procedure time, and CT scan times between the 2 groups. RESULTS: The total complete ablation rate and complete ablation rate of high-risk location tumors were significantly higher in the group treated with combined CT/US guidance ( P = 0.0471 and P = 0.0347, respectively), the imaging guidance modality (odds ratio, 0.303; 95% confidence interval [CI], 0.095-0.970; P = 0.044) was an independent factor for ablation efficacy. These 2 groups also had significant differences in the procedure time ( P = 0.0171), the incidence rate of pneumothorax ( P = 0.0209), abdominal pain ( P = 0.0196), nausea or vomiting ( P = 0.0026), and intraoperative CT scan times ( P < 0.001). The overall complication rates ( P = 0.4023) and recurrence rates ( P = 0.5063) between the 2 groups were not statistically significant. However, CT/US group has a better short-term progressive free survival (log-rank P = 0.103, Breslow P = 0.030). In multivariate analysis, guidance modality (hazard ratio, 0.586; 95% CI, 0.368-0.934; P = 0.025) and Barcelona Clinic Liver Cancer stage (hazard ratio, 2.933; 95% CI, 1.678-5.127; P < 0.001) were risk factor for progressive free survival. CONCLUSIONS: Percutaneous MWA under the combined CT/US guidance for HCC can improve clinical benefits.

Prognostic value of Mortalin correlates with roles in epithelial-mesenchymal transition and angiogenesis in lung adenocarcinoma.

Mortalin is involved in the malignant phenotype of many cancers. However, the specific molecular mechanisms involving Mortalin in lung adenocarcinoma remain unclear. In this study, we showed that both Mortalin mRNA and protein are overexpressed in lung adenocarcinoma. In addition, Mortalin overexpression was positively correlated with poor overall survival. In vitro experiments showed that Mortalin silencing inhibited the proliferation, colony formation and migration abilities of A549 and H1299 cells. Mortalin promotes EMT progression, angiogenesis and tumor progression by activating the Wnt/ß-catenin signaling pathway. In vivo experiments further confirmed that Mortalin promoted malignant progression of lung adenocarcinoma. Taken together, our data suggest that Mortalin represents an attractive prognostic marker and therapeutic target in lung adenocarcinoma patients.

Mortalin promotes breast cancer malignancy.

Mortalin is a member of the heat shock protein 70 (HSP70) family that promotes the development of many cancers. It is reportedly a tumor promoter, but the mechanism of Mortalin in breast cancer is unclear. We designed a series of experiments to explore the correlation between Mortalin and the malignancy of breast cancer, and to assess the potential of Mortalin as a novel therapeutic target in breast cancer. The expression level of Mortalin in breast cancer tissues was detected. Then, we did a series of functional experiment. The findings indicated that Mortalin facilitates the proliferation, metastasis, and endothelial-to-mesenchymal transition (EMT) process of breast cancer. In our research, Mortalin is regulated EMT process and malignant progression of breast cancer through Wnt/ß-Catenin signaling pathway. The findings imply that Mortalin significantly promotes the progression of breast cancer malignancy and reduces patient survival, suggesting that Mortalin as a biomarker and prognostic factor in breast cancer.

Bioinspired Special Wettability Surfaces: From Fundamental Research to Water Harvesting Applications.

Nowadays, the pollution of water has become worse in many parts of the world, which causes a severe shortage of clean water and attracts widespread attention worldwide. Bioinspired from nature, i.e. spider silk, cactus, Namib desert beetle, Nepenthes alata, special wettability surfaces have attracted great interest from fundamental research to water-harvesting applications. Here, recently published literature about creatures possessing water-harvesting ability are reviewed, with a focus on the corresponding water-harvesting mechanisms of creatures in dry or arid regions, consisting of the theory of wetting and transporting. Then a detailed account of the innovative fabrication technologies and bionic water-harvesting materials with special wetting are summarized, i.e. bio-inspired artificial spider silk, bio-inspired artificial cactus-like structures, and bio-inspired artificial Namib desert beetle-like surfaces. Special attentions are paid to the discussion of the advantages and disadvantages of the technologies, as well as factors that affect the amount of water-harvesting. Finally, conclusions, future outlooks and the current challenges for future development of the water-harvesting technology are presented and discussed.

Bioinspired Surfaces with Superwettability for Anti-Icing and Ice-Phobic Application: Concept, Mechanism, and Design.

Ice accumulation poses a series of severe issues in daily life. Inspired by the nature, superwettability surfaces have attracted great interests from fundamental research to anti-icing and ice-phobic applications. Here, recently published literature about the mechanism of ice prevention is reviewed, with a focus on the anti-icing and ice-phobic mechanisms, encompassing the behavior of condensate microdrops on the surface, wetting, ice nucleation, and freezing. Then, a detailed account of the innovative fabrication and fundamental research of anti-icing materials with special wettability is summarized with a focus on recent progresses including low-surface energy coatings and liquid-infused layered coatings. Finally, special attention is paid to a discussion about advantages and disadvantages of the technologies, as well as factors that affect the anti-icing and ice-phobic efficiency. Outlooks and the challenges for future development of the anti-icing and ice-phobic technology are presented and discussed.

Understanding the Role of Dynamic Wettability for Condensate Microdrop Self-Propelling Based on Designed Superhydrophobic TiO2 Nanostructures.

The ability to release the adhered drops on superhydrophobic surfaces is very important for self-cleaning, antifrosting/icing, microfluidic device, and heat transfer applications. In this paper, three types of in situ electrochemical anodizing TiO2 nanostructure films are rationally designed and fabricated on titanium substrates with special superwettability, viz., TiO2 nanotube arrays, irregular TiO2 nanotube arrays, and hierarchical TiO2 particle arrays (HTPA), and their corresponding behavior in condensate microdrop self-propelling (CMDSP) is investigated. Compared to the flat titanium counterpart, all three types of rough TiO2 samples demonstrate a uniform distribution of smaller microscale droplets. Among the treated surfaces, the HTPA possesses the highest condensate density, and more than 80% of the droplets possess a diameter below 10 µm. Theoretical analysis indicates that the feature is mainly due to the morphology and structure induced extremely low droplet adhesion on super-antiwetting TiO2 hierarchical surfaces, where the excess surface energy released from the migration leads to the self-propelling of merged microdrop. This work offers a way to rationally construct CMDSP surfaces with excellent self-cleaning, antifrosting/icing ability, and enhanced condensation heat transfer efficiency.

Accessing Both Retention and Inversion Pathways in Stereospecific, Nickel-Catalyzed Miyaura Borylations of Allylic Pivalates.

We have developed a stereospecific, nickel-catalyzed Miyaura borylation of allylic pivalates, which delivers highly enantioenriched α-stereogenic γ-aryl allylboronates with good yields and regioselectivities. Our complementary sets of conditions enable access to either enantiomer of allylboronate product from a single enantiomer of readily prepared allylic pivalate substrate. Excellent functional group tolerance, yields, regioselectivities, and stereochemical fidelities are observed. The stereochemical switch from stereoretention to stereoinversion largely depends upon solvent and can be explained by competitive pathways for the oxidative addition step. Our mechanistic investigations support a stereoretentive pathway stemming from a directed oxidative addition and a stereoinvertive pathway that is dominant when MeCN blocks coordination of the directing group by binding the nickel catalyst.

Correlation between HER-2/neu(erbB-2) expression level and therapeutic effect of combination treatment with HERCEPTIN and chemotherapeutic agents in gastric cancer cell lines.

INTRODUCTION: Although advanced gastric cancer has many limitations and response rate is marginal in chemotherapy. Overexpression of human epidermal growth factor receptor 2(HER-2/neu) gene and its protein are associated with increased cell division and a high rate of tumor growth and have been reported in several malignancies. Especially, approximately 30% of breast cancer patients have overexpression of HER-2/neu protein and the overexpression metastasize faster, induces resistance of the chemotherapy and down-regulate function of estrogen receptor. Recombinant humanized anti-HER2 antibody (Herceptin) inhibits proliferation of HER-2/neu overexpressing tumor cells and the use of that in combination in metastatic breast cancer have increased cytotoxicity of chemotherapeutic agents. METHODS: We evaluated the expression of HER-2/neu protein in gastric cell lines by FACS and then comparing the cytotoxicity in chemotherapeutics (doxorubicin, cisplatin, paclitaxel, 5-FU) alone and in combination with Herceptin according to the expression of HER-2/neu protein by MTT assay. RESULTS: 1. NCI-N87 (88%) gastric cancer cell line and SK-BR-3 (89%) breast cancer cell line with strong positivity of HER-2/neu expression. YBC-2 (55%) and YBC-3 (48%) gastric cancer cell line with intermediated, weak positivity respectively. Negative control U-87 MG (6%) brain cancer cell line were showed low expression of HER-2/neu. 2. Cell growth was dose-dependently inhibited in HER-2/neu positive, control cell line SK-BR-3 by Herceptin treatment but not observed in HER-2/neu negative control cell line U-87 MG. Effective growth inhibition was not observed in gastric cancer cell lines with single treatment of Herceptin, all cell lines observed the dose-dependent growth inhibition to chemotherapeutic agents (doxorubicin, cisplatin, paclitaxel and 5-FU). 3. Combination of Herceptin with doxorubicin observed synergistic effects in all cancer cell lines except YBC-3, combination of Herceptin with cisplatin observed NCI-N87 and SK-BR-3 and combination of Herceptin with paclitaxel observed synergistic effects in YBC-2. Combination of Herceptin with 5-FU observed antagonistic effects in all cancer cell lines. CONCLUSIONS: According to HER-2/neu expression level, effect of anti-cancer agents was observed differently in combination of Herceptin with chemotherapeutic agents. This suggests that HER-2/neu expression level can be applied standard of combination drug selection in combination of Herceptin With chemotherapeutic agents in gastric cancer.

Prognostic implications of ezrin and phosphorylated ezrin expression in non-small cell lung cancer.

BACKGROUND: The cytoskeletal organizer ezrin is a member of the ezrin-radixin-moesin (ERM) family and plays important roles in not only cell motility, cell adhesion, and apoptosis, but also in various cell signaling pathways. Phosphorylation at Thr-567 and Tyr-353 are key regulatory events in the transition of the dormant to active form of ezrin. This study investigated the prognostic implications of ezrin and phosphorylated ezrin (p-ezrin) expression in non-small cell lung carcinoma (NSCLC). METHODS: Ezrin and p-ezrin protein expressions were examined by immunohistochemistry in 150 NSCLC and adjacent non-tumor tissues and 14 normal lung tissues. qRT-PCR was used to determine ezrin mRNA expression levels in fresh tissues. The correlations between overexpression of ezrin and p-ezrin and the clinicopathological features of NSCLC were analyzed. The survival rates were calculated by the Kaplan-Meier method for 108 NSCLC cases. RESULTS: Ezrin and ezrinThr-567 proteins showed cytosolic and membranous staining patterns; however, ezrinTyr-353 protein only showed cytosolic staining. Ezrin and p-ezrin were significantly upregulated in NSCLC compared with the normal counterparts. Increased ezrin, ezrinThr-567, and ezrinTyr-353 levels were correlated with the late stage and poor differentiation of NSCLC. However, only ezrinThr-567 was correlated with the presence of lymph node metastasis. In regard to survival, only ezrinThr-567 was related with the overall survival time of patients with NSCLC, and both ezrin and ezrinThr-567 were associated with shortened survival time for patients with early stage NSCLC. CONCLUSIONS: Ezrin and p-ezrin, especially ezrinThr-567, may prove to be useful as a novel prognostic biomarker of NSCLC.

Significance of NQO1 overexpression for prognostic evaluation of gastric adenocarcinoma.

NQO1 (NAD(P)H: quinone oxidoreductase, also known as DT-diaphorase) plays a prominent role in maintaining cellular homeostasis. NQO1 is abnormally elevated in many solid cancer types, including those of the adrenal gland, breast, colon, lung, ovary, and thyroid. However, little is known about the status of NQO1 in gastric adenocarcinoma (GAC). To investigate the clinicopathological significance of NQO1 expression in GAC, and thus evaluate its role as a potential prognostic marker, 203 cases of primary GAC, 31 of gastric dysplasia, and 53 of adjacent non-tumor tissues were selected for immunohistochemical staining of NQO1 protein. Correlations between NQO1 overexpression and clinicopathological characteristics were evaluated by χ(2) test and Fisher's exact test, while survival rates were calculated by Kaplan-Meier method. The relationship between prognostic factors and patient survival was analyzed by Cox proportional hazards model. Through these analyses it was found that the strongly positive rate of NQO1 protein in GAC was significantly higher than that in gastric dysplasia and adjacent non-tumor tissues. Analysis by qRT-PCR also confirmed that NQO1 mRNA levels were increased in GAC compared with those detected in either adjacent non-tumor tissues or normal gastric mucosa. Additionally, the NQO1 expression rate was positively correlated with tumor size, serosal invasion, tumor stage, and both disease-free survival and 5-year survival rates. Further analysis showed that although NQO1 was not an independent predictor of GAC, elevated expression of NQO1 could predict lower disease-free survival and 5-year survival times in late-stage patients. In conclusion, NQO1 plays an important role in the progression of GAC, and might be a potential, but not an independent, poor prognostic biomarker and therapeutic target of GAC.

Evaluation of the efficacy of transarterial chemoembolization combined with microwave ablation followed by adjuvant therapy in patients with hepatocellular carcinoma.

Objective: This study aimed to explore the efficacy of transarterial chemoembolization (TACE) combined with microwave ablation (MWA) adjuvant to lenvatinib and anti-PD-1 antibodies for patients with hepatocellular carcinoma (HCC). Methods: A retrospective analysis of 67 patients with HCC treated at our hospital between October 2018 and May 2022 was conducted. All patients underwent a combination of TACE and MWA. Among them, 29 received postoperative treatment with molecular-targeted agents, like lenvatinib, along with anti-PD-1 antibodies such as sindilizumab, karelizumab, or tirilizumab. The remaining 38 patients did not receive postoperative systemic therapies, like targeted or immunotherapy. The survival and prognosis of all patients were analyzed. Results: Nine patients in the observation group and 29 patients in the control group experienced recurrence, and the median progression-free survival 1 (PFS1) was not reached 'Not Applicable'(NA) and 17.05 months (P=0.035), respectively. Failure to combine adjuvant therapy was identified as an independent risk factor for tumor recurrence, and the observation group had a 0.245 times lower risk of recurrence compared to that in the control group (P=0.005). Multivariable Cox regression analysis confirmed that the maximum tumor size, and tumor number were risk factors for tumor recurrence. Patients with a large maximum tumor size had a 1.519 times higher risk of recurrence compared to those with a small maximum tumor size (P=0.006), and patients with a large number of tumors had a 5.978 times higher risk of recurrence compared to those with a small number of tumors (P=0.02). The median PFS2 of the two groups was 11.795 and 21.257 months, respectively, though not statistically significant (P=0.955). However, there was a disparity in the percentage of BCLC stages associated with recurrence between the two groups. In the observation group approximately 22.22% of patients progressed to stage C, while in the control group, this proportion was 34.48%. The observation group exhibited a lower risk of distant metastasis compared to the control group. Conclusion: Adjuvant treatment of HCC following TACE combined with MWA improved PFS and achieved better clinical outcomes compared to that with TACE combined with MWA alone.

Novel multifunctional environmentally friendly degradable zeolitic imidazolate frameworks@poly (γ-glutamic acid) hydrogel with efficient dye adsorption function.

Recently, metal-organic frameworks (MOFs) have been widely developed due to the rich porosity, excellent framework structure and multifunctional nature. Meanwhile, a series of MOFs crystals and MOF-based composites have been emerged. However, the widespread applications of MOFs are hindered by challenges such as rigidity, fragility, solution instability, and processing difficulties. In this study, we addressed these limitations by employing an in-situ green growth approach to prepare a zeolitic imidazolate frameworks-8@poly (γ-glutamic acid) hydrogel (ZIF-8@γ-PGA) with hierarchical structures. This innovative method effectively resolves the inherent issues associated with MOFs. Furthermore, the ZIF-8@γ-PGA hydrogel is utilized for dye adsorption, demonstrating an impressive maximum adsorption capacity of 1130 ± 1 mg/g for methylene blue (MB). The adsorption behavior exhibits an excellent agreement with both the kinetic model and isotherm. Meanwhile, because the adsorbent raw materials are all green non-toxic materials, multiple applications of materials can also be realized. Significantly, the results of antibacterial experiments showed that the ZIF-8@γ-PGA hydrogel after in-situ growth of ZIF-8 had better antibacterial properties. Thus, the ZIF-8@γ-PGA hydrogel has great potential for development in wound dressings, sustained drug owing to its biocompatibility and antibacterial activity.

Finotonlimab with chemotherapy in recurrent or metastatic head and neck cancer: a randomized phase 3 trial.

Immunotherapy combined with chemotherapy regimen has been shown to be effective in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, due to the small number of patients, its efficacy remains controversial in Asian populations, particularly in mainland China. Here a randomized, double-blind phase 3 trial evaluated the efficacy and safety of finotonlimab (SCT-I10A), a programmed cell death 1 (PD-1) monoclonal antibody, combined with cisplatin plus 5-fluorouracil (C5F) for the first-line treatment of R/M HNSCC. Eligible patients (n = 370) were randomly 2:1 assigned to receive finotonlimab plus C5F (n = 247) or placebo plus C5F (n = 123). The primary endpoint was overall survival (OS). In the finotonlimab plus C5F group, OS was 14.1 months (95% confidence interval (CI) 11.1-16.4), compared with 10.5 months (95% CI 8.1-11.8) in the placebo plus C5F group. The hazard ratio was 0.73 (95% CI 0.57-0.95, P = 0.0165), meeting the predefined superiority criteria for the primary endpoint. Finotonlimab plus C5F showed significant OS superiority compared with C5F alone and acceptable safety profile with R/M HNSCC, supporting its use as a first-line treatment option for R/M HNSCC. These results validate the efficacy and safety of the combination of finotonlimab and C5F in Asian patients with R/M HNSCC. ClinicalTrials.gov identifier: NCT04146402 .

Silver-mediated trifluoromethylation of aryldiazonium salts: conversion of amino group into trifluoromethyl group.

A novel strategy for aromatic trifluoromethylation by converting aromatic amino group into CF3 group is reported herein. This method, which can be considered as trifluoromethylation variation of the classic Sandmeyer reaction, uses readily available aromatic amines as starting materials and is performed under mild conditions.

Novel exosome-related risk signature as prognostic biomarkers in glioblastoma.

Exosomes are progressively being detected as an indicator for the diagnosis and prognosis of cancer in clinical settings. Many clinical trials have confirmed the impact of exosomes on tumor growth, particularly in anti-tumor immunity and immunosuppression of exosomes. Therefore, we developed a risk score based on genes found in glioblastoma-derived exosomes. In this study, we used the TCGA dataset as the training queue and GSE13041, GSE43378, GSE4412, and CGGA datasets as the external validation queue. Based on machine algorithms and bioinformatics methods, an exosome-generalized risk score was established. We found that the risk score could independently predict the prognosis of patients with glioma, and there were significant differences in the outcomes of patients in the high- and low-risk groups. Univariate and multivariate analyses showed that risk score is a valid predictive biomarker for gliomas. Two immunotherapy datasets, IMvigor210 and GSE78220, were obtained from previous studies. A high-risk score showed a significant association with multiple immunomodulators that could act on cancer immune evasion. The exosome-related risk score could predict the effectiveness of anti-PD-1 immunotherapy. Moreover, we compared the sensitivity of patients with high- and low-risk scores to various anti-cancer drugs and found that patients with high-risk scores had better responses to a variety of anti-cancer drugs. The risk-scoring model established in this study provides a useful tool to predict the total survival time of patients with glioma and guide immunotherapy.

One-Step Construction of the Positively/Negatively Charged Ultrathin Janus Nanofiltration Membrane for the Separation of Li+ and Mg2.

To coordinate the trade-off between the separation and permeation of the nanofiltration membrane for the separation of Mg2+/Li+, we regulated poly(ethyleneimine)/piperazine interface polymerization parameters to construct a positively/negatively charged ultrathin Janus nanofiltration membrane at a free aqueous-organic interface. At the optimized interfacial polymerization parameters, 0.03 wt % of piperazine reacted with trimethylbenzene chloride prior to poly(ethyleneimine), forming a primary polyamide layer with fewer defects or limiting large-scale defects of the polyamide layer. The controlled subsequent reaction of poly(ethyleneimine) and trimethylbenzene chloride results in a Janus nanofiltration membrane, with one side enriched with the carboxyl groups, the other side enriched with the amine groups, and a dense polyamide structure in the middle. Under the optimum conditions, the positive potential of the rear surface of the prepared membrane was 14.57 mV, and the water contact angle reached 71.31°, while the negative potential of the front surface was -25.48 mV, and the water contact angle was 12.93°, confirming a Janus membrane with opposite charges and large hydrophilicity differences in the front and rear surfaces. With a high cross-linking degree, a 40 nm thick polyamide layer is 29.09% more thinner than the traditional polyamide membrane. The ultrathin Janus nanofiltration membrane showed an excellent separation factor (SLi,Mg of 18.26), stability, and water permeability flux (10.6 L·m-2·h-1·bar-1). The rejections to MgCl2, CaCl2, MgSO4, and Na2SO4 are measured above 90% at a nearly constant permeability of 10.6 L·m-2·h-1·bar-1, particularly stable rejections to MgCl2 and Na2SO4.

A Randomized Phase III Study of Anlotinib Versus Bevacizumab in Combination With CAPEOX as First-Line Therapy for RAS/BRAF Wild-Type Metastatic Colorectal Cancer: A Clinical Trial Protocol.

Background: Chemotherapy combined with antivascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor monoclonal antibodies is the most promising approach to prolong survival and improve the quality of life of patients with unresectable metastatic colorectal cancer (mCRC). Anlotinib is an oral antiangiogenic tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, fibroblast growth factor receptors 1-4, and platelet-derived growth factor receptors a/ß. Since anlotinib combined with oxaliplatin and capecitabine (CAPEOX) as a first-line treatment was previously shown to be effective and safe for patients with RAS/BRAF wild-type (WT) mCRC, we designed this randomized, open-label, parallel-group, non-inferiority, phase III study to evaluate the efficacy and safety of anlotinib plus CAPEOX versus bevacizumab plus CAPEOX in patients with RAS/BRAF WT mCRC. Methods/design: The primary inclusion criteria are Eastern Cooperative Oncology Group performance status 0/1, confirmed RAS/BRAF WT colorectal adenocarcinoma, and unresectable metastases assessed by a multidisciplinary team. The main exclusion criteria are as follows: high microsatellite instability or deficient mismatch repair status, resectable or potentially resectable metastases, and previous systemic therapy for mCRC. A total of 698 patients will be randomized into the anlotinib and bevacizumab groups in a 1:1 ratio. Patients will receive 4 to 8 cycles of induction therapy (CAPEOX plus anlotinib or bevacizumab), followed by maintenance treatment (capecitabine plus anlotinib or bevacizumab) until disease progression or unacceptable toxicity. Progression-free survival (PFS) assessed by an independent review committee is the primary endpoint, whereas investigator-assessed PFS, overall survival, objective response rate, disease control rate, duration of response, resection rate of liver metastases, quality of life, and safety are the secondary endpoints. Enrollment commenced in May 2021. Discussion: A prospective, randomized, phase III trial will provide a meaningful comparison of the efficacy and safety of anlotinib plus CAPEOX with standard treatment for patients with unresectable RAS/BRAF WT mCRC.

Optimizing DC vaccination by combination with oncolytic adenovirus coexpressing IL-12 and GM-CSF.

Dendritic cell (DC)-based vaccination is a promising strategy for cancer immunotherapy. However, clinical trials have indicated that immunosuppressive microenvironments induced by tumors profoundly suppress antitumor immunity and inhibit vaccine efficacy, resulting in insufficient reduction of tumor burdens. To overcome these obstacles and enhance the efficiency of DC vaccination, we generated interleukin (IL)-12- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-coexpressing oncolytic adenovirus (Ad-ΔB7/IL12/GMCSF) as suitable therapeutic adjuvant to eliminate immune suppression and promote DC function. By treating tumors with Ad-ΔB7/IL12/GMCSF prior to DC vaccination, DCs elicited greater antitumor effects than in response to either treatment alone. DC migration to draining lymph nodes (DLNs) dramatically increased in mice treated with the combination therapy. This result was associated with upregulation of CC-chemokine ligand 21 (CCL21(+)) lymphatics in tumors treated with Ad-ΔB7/IL12/GMCSF. Moreover, the proportion of CD4(+)CD25(+) T-cells and vascular endothelial growth factor (VEGF) expression was decreased in mice treated with the combination therapy. Furthermore, combination therapy using immature DCs also showed effective antitumor effects when combined with Ad-ΔB7/IL12/GMCSF. The combination therapy had a remarkable therapeutic efficacy on large tumors. Taken together, oncolytic adenovirus coexpressing IL-12 and GM-CSF in combination with DC vaccination has synergistic antitumor effects and can act as a potent adjuvant for promoting and optimizing DC vaccination.