Novel In Situ Growth of ZIF-8 in Porous Epoxy Matrix for Mechanically Robust Composite Electrolyte of High-Performance, Long-Life Lithium Metal Batteries.

Polymer electrolytes (PEs) with high flexibility, low cost, and excellent interface compatibility have been considered as an ideal substitute for traditional liquid electrolytes for high safety lithium metal batteries (LMBs). Nevertheless, the mechanical strength of PEs is generally poor to prevent the growth of lithium dendrites during the charge/discharge process, which seriously restricts their wide practical applications. Herein, a mechanical robust ZIF-8/epoxy composite electrolyte with unique pore structure was prepared, which effectively inhibited the growth of lithium dendrites. Meanwhile, the in situ growth of ZIF-8 in porous epoxy matrix can promote the uniform flux and fast transport of lithium ions. Ultimately, the optimal electrolyte shows high ionic conductivity (2.2 × 10-3 S cm-1), wide electrochemical window (5 V), and a large Li+ transference number (0.70) at room temperature. The Li||NCM811 cell using the optimal electrolyte exhibits high capacity and excellent cycling performance (83.2% capacity retention with 172.1 mA h g-1 capacity retained after 200 cycles at 0.2 C). These results indicate that the ZIF-8/epoxy composite electrolyte is of great promise for the application in LMBs.

Primary Pulmonary Lymphoepithelioma-like Carcinoma: A Case Report Utilizing Camrelizumab and Anlotinib for Prolonged Survival.

BACKGROUND: Primary Pulmonary Lymphoepithelioma-like Carcinoma (PPLELC) is a rare form of cancer for which no standard treatment has been established to date. Patients with advanced-stage PPLELC generally have a poor prognosis with overall survival of 22.7 months. CASE PRESENTATION: Here, we report a case of advanced primary pulmonary lymphoepithelioma-like carcinoma. Initially, the patient underwent a first-line (GP) and a second-line (DP) of chemotherapy, which provided temporary relief but resulted in varying degrees of myelosuppression. When the disease progressed again, we administered a third-line treatment consisting of camrelizumab combined with anlotinib. RESULT: This resulted in a progression-free survival of over 26 months without significant toxic side effects. CONCLUSION: Our findings suggest that combining camrelizumab and anlotinib could lead to a long progressionfree survival in patients with advanced PPLELC.

A phase Ib study evaluating the safety and efficacy of IBI310 plus sintilimab in patients with advanced non-small-cell lung cancer who have progressed after anti-PD-1/L1 therapy.

BACKGROUND: The development of immune checkpoint inhibitors has made a significant breakthrough in the treatment of non-small-cell lung cancer (NSCLC). However, there remains a huge unmet clinical need for patients with acquired resistance after initial treatment response. METHODS: This study evaluated the combination of IBI310 (an anti-cytotoxic T lymphocyte-associated antigen-4 [CTLA-4] antibody) and sintilimab (an anti-programmed death 1 [PD-1]) antibody) in NSCLC patients who have previously been treated with anti-PD-1/ligand (L)1 and acquired resistance. The patients were randomly assigned to receive either a lower dose of IBI310 (1 mg/kg Q3W, cohort A) or a higher dose of IBI310 (3 mg/kg Q3W, cohort B) in combination with sintilimab (200 mg Q3W). The primary endpoints of the study were objective response rate (ORR) assessed by RECISTv1.1 and safety, while secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: As of November 2, 2023, the study had enrolled 30 patients, with 15 patients in each cohort. The ORR was 13.3% (2/15, 95% confidence interval [CI], 1.7-40.5) in cohort B. DCR were 46.7% (95% CI, 21.3-73.4) and 66.7% (95% CI, 38.4-88.2) in cohorts A and B, respectively. In cohorts A and B of this trial, the median follow-up times were 4.2 and 5.6 months, respectively. Median PFS was 1.45 (95% CI, 1.35-2.73) versus 2.73 (95% CI, 1.41-4.90) months for cohort A versus B; the median OS was 7.03 (95% CI, 3.09-not calculable [NC]) months in cohort A and 8.90 (95% CI, 5.13-NC) months in cohort B. Of the 30 patients, 86.7% in both cohorts experienced treatment-related adverse events (TRAEs) with Grade ≥3 TRAEs occurring in 40% and 53.3% of patients in cohorts A and B, respectively. CONCLUSION: IBI310 3 mg/kg Q3W plus sintilimab was effective in a small number of previously treated anti-PD-1/L1-resistant NSCLC patients.

Application and Research Progress of Covalent Organic Frameworks for Solid-State Electrolytes in Lithium Metal Batteries.

Covalent organic frameworks (COFs) are a class of crystalline porous organic polymers with periodic networks that are constructed from small molecular units via covalent bonds, which have low densities, high porosity, large specific surface area, and ease of functionalization. The one-dimension nanochannels in COFs offer an effective means of transporting lithium ions while maintaining a stable structure over a wide range of temperatures. As a new category of ionic conductors, COFs exhibit unparalleled application potential in solid-state electrolytes. Here, we provide a comprehensive summary of recent applications and research progress for COFs in solid-state electrolytes of lithium metal batteries and discuss the possible development directions in the future. This review is expected to provide theoretical guidance for the design of high-performance solid-state electrolytes.

Efficacy and safety of original EGFR-TKI combined with bevacizumab in advanced lung adenocarcinoma patients harboring EGFR-mutation experiencing gradual progression after EGFR-TKI treatment: a single-arm study.

Background: Keeping on original epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment is the standard treatment for gradual progression EGFR-positive metastatic non-small cell lung cancer (NSCLC). Angiogenic pathway can lead to EGFR-TKI resistance, but the effectiveness of combination strategies in this group is still controversial. This study aimed to assess the efficacy and safety of the original EGFR-TKI combined with bevacizumab in advanced and metastatic lung adenocarcinoma patients harboring EGFR-mutation who experience gradual progression in a real-world setting. Methods: From June 2019 to December 2021, a total of 35 metastatic EGFR positive NSCLC patients experienced gradual progression after EGFR-TKI treatments and received original TKI combined with bevacizumab were identified at Chongqing University Cancer Hospital, China. All patients were confirmed EGFR positive by rebiopsy before treatment. Patients were treated with EGFR-TKI and bevacizumab (15 mg/kg Q3W) after gradual progression until rapid progression or intolerable toxicity. The overall survival (OS), progression-free survival 1 (PFS1, period from the beginning of EGFR-TKI treatment to the rapid progression of the disease), PFS2 (period from the beginning of EGFR-TKI combined with bevacizumab treatment to the rapid progression of the disease), disease control rate (DCR), and adverse events of the combined treatment were collected and analyzed. Results: A total of 33 patients could participate the efficacy evaluation. Median PFS1 and PFS2 were 20.5 and 8 months, respectively; DCR was 93.94%; median OS was immature. Multivariate Cox proportional hazards model showed that smoking status [hazard ratio (HR) =3.692, 95% confidence interval (CI): 1.450-9.404, P=0.006], combined EGFR T790M mutation or rare mutation (HR =2.480, 95% CI: 1.073-5.729, P=0.034), and malignant pleural effusion (HR =3.707, 95% CI: 1.460-9.414, P=0.006) were independent risk factors for PFS2. The most common treatment-related adverse events greater than grade 3 included hypertension (23.7%), proteinuria (8.3%), and increased alanine aminotransferase (ALT; 4.1%) and aspartate aminotransferase (AST; 2.9%). Conclusions: Continuous original TKI combined with bevacizumab showed partly favorable efficacy and safety and may represent a therapeutic option for metastatic EGFR-mutation NSCLC patients experiencing gradual progression after EGFR-TKI treatment.

Targeted Nanotherapeutics Using LACTB Gene Therapy Against Melanoma.

INTRODUCTION: ß-lactamase (LACTB) is a tumor suppressor gene in various tumors including melanoma. However, it remains challenging to efficiently deliver the LACTB gene into melanoma. Recently, we designed a nonviral nanocarrier iRGD/DOTAP/MPEG-PDLLA (iDPP) that could deliver gene targetedly to melanoma efficiently without obvious adverse effects. METHODS: In this study, the tumor-targeted nanoparticle iDPP was prepared to deliver LACTB gene to treat melanoma in vitro and in vivo. First, the expression level of LACTB in 6 clinical specimens of melanoma patients was evaluated. Subsequently, the characteristics of iDPP/LACTB nanocomplexes were studied. Afterwards, the in vitro and in vivo anti-tumor efficacy of the iDPP/LACTB nanocomplexes were explored utilizing the B16-F10 mouse melanoma cell line and the B16-F10 subcutaneous melanoma model. RESULTS: Compared with the normal epithelium, the expression level of LACTB in melanoma tissues was significantly downregulated. In vitro B16-F10 cell tests showed iDPP/LACTB nanocomplexes could increase the mRNA levels of P21, Bid, Bax, Pidd1, and Sival genes and up-regulate the p53 signaling pathway of melanoma cells, thus promoting cell apoptosis and blocking the cell cycle. Injected intravenously, iDPP nanoparticles could deliver DNA to the subcutaneous melanoma targetedly. Based on in vivo mouse xenograft model, iDPP/LACTB nanocomplexes could effectively inhibit tumor proliferation and induce tumor apoptosis, thus significantly inhibiting melanoma growth (tumor inhibition rate is about 68%) in the subcutaneous B16-F10 melanoma model. CONCLUSION: The downregulated LACTB might be a potential target for melanoma therapy. The iDPP/LACTB nanocomplexes could inhibit the growth of the mouse melanoma without obvious side effects, which provide a new option for melanoma gene therapy research.

Circular RNA MYLK Promotes Glycolysis and Proliferation of Non-Small Cell Lung Cancer Cells by Sponging miR-195-5p and Increasing Glucose Transporter Member 3 Expression.

INTRODUCTION: Circular RNAs (circRNAs) are deregulated in many types of human cancers, including non-small cell lung cancer (NSCLC). In this study, we aimed to explore the functional role of circMYLK in NSCLC. MATERIALS AND METHODS: The expression levels of circMYLK and miR-195-5p in NSCLC tissues and cell lines were detected by RT-qPCR analysis. MTT assay, colony formation assay and transwell assay were performed to investigate the effects of circMYLK and miR-195-5p on the malignant phenotypes of NSCLC cells. The glucose consumption and lactate production of NSCLC cells were detected using commercial kits. The direct binding relation between circMYLK and miR-195-5p in NSCLC was predicted by bioinformatics analysis and validated by dual-luciferase reporter assay. RESULTS: The results showed that circMYLK was significantly up-regulated in NSCLC tissues and cell lines, and its high expression was closely associated with deleterious clinicopathological characteristics and poor prognosis of NSCLC patients. Knockdown of circMYLK remarkably inhibited the malignant phenotypes of NSCLC cells, including proliferation, migration, invasion, glucose consumption and lactate production. Moreover, circMYLK was identified as a molecule sponge for miR-195-5p, and glucose transporter member 3 (GLUT3) was shown to be a target gene of miR-195-5p in NSCLC. Further rescue experiments revealed that the oncogenic effects of circMYLK on NSCLC cells could be largely abrogated by co-transfection with miR-195-5p mimic. CONCLUSION: In summary, our study provides convincing evidence that circMYLK serves as a tumor promoter in NSCLC and can be used as a potential therapeutic target for NSCLC patients.

A Vesicular Stomatitis Virus-Inspired DNA Nanocomplex for Ovarian Cancer Therapy.

Gene therapy provides a novel method for cancer therapy. This study shows a DNA nanocomplex that is inspired from vesicular stomatitis virus (VSV) for ovarian cancer therapy. This DNA nanocomplex consists of a cationized monomethoxy poly (ethylene glycol)-poly (d,l-lactide) (MPEG-PLA) nanoparticle and a plasmid encoding the matrix protein of vesicular stomatitis virus (VSVMP) that plays a critical role in the VSV-induced apoptosis of cancer cells. The cationized MPEG-PLA nanoparticle that is self-assembled by MPEG-PLA copolymer and N -[1-(2,3-dioleoyloxy) propyl]-N,N,N-trimethylammonium chloride (DOTAP) has low cytotoxicity and high transfection efficiency (>80%). Intraperitoneal administration of the p VSVMP nanocomplex remarkably inhibits the intraperitoneal metastasis of ovarian cancer and does not cause significant systemic toxicity. The apoptosis induction and anti-angiogenesis are involved in the anticancer mechanism. This work demonstrates a VSV-inspired DNA nanocomplex that has potential application for the treatment of intraperitoneal metastasis of ovarian cancer.

Differential diagnosis of acute miliary pulmonary tuberculosis from widespread-metastatic cancer for postoperative lung cancer patients: two cases.

Pulmonary infections and lung cancer can resemble each other on radiographic images, which makes it difficult to diagnosis accurately and apply an appropriate therapy. Here we report two cases that two postoperative patients with lung adenocarcinoma developed diffuse nodules in bilateral lungs in a month which needed to be distinguished between metastatic malignancies and infectious diseases. Although there are much similarities in disease characteristics of two cases, patient in case one was diagnosed as acute miliary pulmonary tuberculosis (TB) while patient in case two was diagnosed as metastatic disease. The symptoms and pulmonary foci on CT scan of patient in case one improved distinctly after the immediate anti-TB treatment, but the disease of patient in case two progressed after chemotherapy. These findings caution us that differential diagnosis is crucial and have significance in guiding clinical work.

Ovarian Cancer Therapy by VSVMP Gene Mediated by a Paclitaxel-Enhanced Nanoparticle.

Nanoparticles have great promise for gene delivery. However, the transfection efficiency of nanoparticle-based gene delivery systems is always unsatisfied to meet the requirement of effective gene therapy. Herein, we used low-dosage paclitaxel to enhance a nanoscaled gene delivery system that was self-assembled from N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammoniummethyl sulfate and monomethoxy poly(ethylene glycol)-poly(d,l-lactide) (DPP), creating a paclitaxel-encapsulated DPP (P-DPP) nanoparticle. The encapsulated low-dosage paclitaxel significantly improved the gene delivery efficiency of the DPP nanoparticles against multiple cancer cells, in some of which the transfection efficiency is as high as 92%. By the P-DPP nanoparticle, vesicular stomatitis virus matrix protein (VSVMP) that could induce cell apoptosis was delivered to treat ovarian cancer. The encapsulation of paclitaxel in DPP nanoparticles increased the expression of VSVMP, enhancing VSVMP to induce antiproliferation and apoptosis in SKOV3 ovarian cancer cells. Intraperitoneal administration of P-DPP-delivered VSVMP effectively inhibited the intraperitoneal metastasis of SKOV3 ovarian cancer, which was more efficient than DPP-delivered VSVMP. Moreover, it was found that the tumor cell apoptosis induction, tumor cell proliferation inhibition, and tumor angiogenesis suppression were involved in the anticancer mechanism of this nanocomplex. Our data suggest that the encapsulation of low-dosage paclitaxel can enhance the gene delivery efficiency of the DPP nanoparticles against multiple cancer cells and exert a synergistic anticancer effect with VSVMP gene in ovarian cancer treatment. The VSVMP gene therapy delivered by the paclitaxel-enhanced nanoparticle has potential application in ovarian cancer therapy.

The accumulation of macrophages attenuates the effect of recombinant human endostatin on lung cancer.

BACKGROUND: Although anti-angiogenic therapy is widely applied clinically, its efficacy has been less than expected. Screening for regulatory factors and sensitive indicators to define the effectiveness of these drugs is required. Through a retrospective study of clinical data, we found that patients with a higher peripheral monocyte-to-lymphocyte ratio (MLR) obtained less benefit from recombinant human endostatin (rhES, Endostar®), an anti-angiogenic drug, in lung cancer. Because MLR is positively correlated with macrophage count in tumors, this result suggests that macrophages may influence the effectiveness of rhES therapy in lung cancer. METHODS: Clinical data from 72 lung cancer patients treated with rhES were collected. Animal study, flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, Western blot analysis, and transwell migration assays were carried on Lewis lung carcinoma (LLC) cells, bone marrow-derived macrophages, macrophage cell line RAW264.7, and ANA-1 cells. RESULTS: Clinical data showed that compared with the baseline MLR before rhES treatment, patients with progressive disease had higher MLRs than those of patients with partial response. Experimental results showed that more macrophages were recruited in the LLC tumors after rhES treatment and the majority of them displayed an M2-like phenotype. rhES aggravated hypoxia and the inflammatory response in the tumor microenvironment. Hypoxia promoted the expression of CCL2 by endothelial and fibroblast cells, which could induce macrophages recruitment, and increased levels of inflammatory cytokines (interleukin-4 [IL-4], IL-6, and IL-10) skewed macrophage polarization toward the M2-like phenotype. Hypoxia or inflammation cytokine-treated macrophages enhanced the progression of LLC in vitro and in vivo. CONCLUSION: We found rhES could aggravate hypoxia and the inflammatory response in the tumor microenvironment. These changes were favorable for macrophage accumulation, and skewed their polarization toward the M2-like phenotype which could help LLC to escape from the anti-angiogenic therapy. Thus, these data indicate the accumulation of macrophages in the tumor microenvironment may adversely affect the efficacy of rhES on lung cancer.

Salvage treatment with erlotinib after gefitinib failure in advanced non-small-cell lung cancer patients with poor performance status: A matched-pair case-control study.

PURPOSE: Gefitinib plays an important role in non-small-cell lung cancer (NSCLC) treatment; however, progression of the disease occurs in most patients even after an initial response. The role of erlotinib after gefitinib failure has been investigated but continues to be debated, especially in heavily treated patients with poor performance status (PS). Therefore, a retrospective matched-pair case-control study was carried out to evaluate the role of erlotinib after gefitinib failure in advanced NSCLC patients. METHODS: A total of 58 patients were identified. The two groups were balanced with demographic and baseline clinical characteristics. All patients had PS ≥2 and most of them (89.7%) had received more than two systemic therapies before erlotinib or best supportive care (BSC). The epidermal growth factor receptor (EGFR) and KRAS genotypes were analyzed in 36 (62.1%) patients, 19 of them were in the erlotinib group. RESULTS: Median overall survival (OS) for all patients was 6 months. Median OS for patients who received erlotinib and BSC was 10 and 3 months, respectively (P= 0.001). Disease control rate (DCR) and objective response rate (ORR) were 51.7% and 10.3% in patients receiving erlotinib, respectively, while median time to progression (TTP) was 3 months. Among the 19 patients in the erlotinib group with biomarker results available, those with EGFR mutation achieved longer median TTP (P= 0.016) and better DCR (P= 0.177) than those with wild-type EGFR. CONCLUSIONS: A switch to erlotinib after gefitinib failure may represent a better therapeutic option for advanced NSCLC patients with poor PS, and an EGFR mutation seemed to be associated with better survival rate.

Curcumin-loaded biodegradable polymeric micelles for colon cancer therapy in vitro and in vivo.

Curcumin is an effective and safe anticancer agent, but its hydrophobicity inhibits its clinical application. Nanotechnology provides an effective method to improve the water solubility of hydrophobic drug. In this work, curcumin was encapsulated into monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles through a single-step nano-precipitation method, creating curcumin-loaded MPEG-PCL (Cur/MPEG-PCL) micelles. These Cur/MPEG-PCL micelles were monodisperse (PDI = 0.097 ± 0.011) with a mean particle size of 27.3 ± 1.3 nm, good re-solubility after freeze-drying, an encapsulation efficiency of 99.16 ± 1.02%, and drug loading of 12.95 ± 0.15%. Moreover, these micelles were prepared by a simple and reproducible procedure, making them potentially suitable for scale-up. Curcumin was molecularly dispersed in the PCL core of MPEG-PCL micelles, and could be slow-released in vitro. Encapsulation of curcumin in MPEG-PCL micelles improved the t(1/2) and AUC of curcumin in vivo. As well as free curcumin, Cur/MPEG-PCL micelles efficiently inhibited the angiogenesis on transgenic zebrafish model. In an alginate-encapsulated cancer cell assay, intravenous application of Cur/MPEG-PCL micelles more efficiently inhibited the tumor cell-induced angiogenesis in vivo than that of free curcumin. MPEG-PCL micelle-encapsulated curcumin maintained the cytotoxicity of curcumin on C-26 colon carcinoma cells in vitro. Intravenous application of Cur/MPEG-PCL micelle (25 mg kg(-1) curcumin) inhibited the growth of subcutaneous C-26 colon carcinoma in vivo (p < 0.01), and induced a stronger anticancer effect than that of free curcumin (p < 0.05). In conclusion, Cur/MPEG-PCL micelles are an excellent intravenously injectable aqueous formulation of curcumin; this formulation can inhibit the growth of colon carcinoma through inhibiting angiogenesis and directly killing cancer cells.