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Cyclophosphamide (CTX) is an anticancer medication that suppresses host immunity as well as adversely affects mucosal inflammation and gut microflora dysbiosis. The gut microflora is recognized as a substantial factor in host metabolism and immunological homeostasis. To improve immunity and inhibit cytotoxic and homeostatic imbalances triggered by CTX, it is essential to monitor immunoregulators. In this research, we assessed the impact of Octopus peptide hydrolysate (OPH) on immune modulation, intestinal integrity, and gut microbial composition in CTX-induced immune-deficient mice. The results revealed that OPH increased body weight, and immunological organ indices, and improved the histological changes in the colon, thymus, and spleen. The OPH stimulated the secretion of cytokines (IL-1β, IL-6, and TNF-α) and antibodies (IgM and IgA) while reducing the ratio of lipopolysaccharide (LPS) and diamine oxidase (DAO) in the serum. OPH further enhanced goblet cell and mucus production, upregulated the expression of gut tight-junction proteins (Occludin, Zonula Occludin-1, Mucin-2, and Claudin-1), and activated the TLR4/NF-κB cascade (p-IκBα, P65/p-p65). In addition, OPH treatment declined the Bacteroidetes/Firmicutes ratio, enhanced the relative ratio of Alistipes/Lachnospiraceae, and reversed the ecological equilibrium of the gut microflora. The findings revealed that OPH serves as a prebiotic to prevent CTX-mediated disruption in the intestinal barrier and boosts gut mucosal immunity by attenuating gut microflora imbalance, implying that OPH could be used as an immunological ingredient in nutritious foods to regulate the immune system and protect the gut from inflammatory diseases.

Postoperative pulmonary complications (PPCs) are associated with high mortality rates after lung cancer surgery. Although some studies have discussed the different risk factors for PPCs, the relationship between these factors and their impact on PPCs remains unclear. Hence, this study aimed to systematically summarize the incidence and determine the risk factors for PPCs.We conducted a systematic search of five English and four Chinese databases from their inception to April 1, 2023. A total of 34 articles (8 cohort studies and 26 case-control studies) (n = 31696, 5833 with PPCs) were included in the analysis. The primary outcome was the incidence of PPC. The secondary outcome was the odds ratio (OR) of PPCs based on the identified risk factors calculated by RevMan 5.4. A narrative descriptive summary of the study results was presented when pooling the results or conducting a meta-analysis was not possible.The pooled incidence of PPCs was 18.4 %. This meta-analysis demonstrated that TNM staging (OR 4.29, 95 % CI 2.59–7.13), chronic obstructive pulmonary disease (COPD) (OR 2.47, 95 % CI 1.80–3.40), smoking history (OR 2.37, 95 % CI 1.33–4.21), poor compliance with respiratory rehabilitation (OR 1.64, 95 % CI 1.17–2.30), male sex (OR 1.62, 95 % CI 1.28–2.04), diabetes (OR 1.56, 95 % CI 1.07–2.27), intraoperative bleeding volume (OR 1.44, 95 % CI 1.02–2.04), Eastern Cooperative Oncology Group score (ECOG) > 1 (OR 1.37, 95 % CI 1.04–1.80), history of chemotherapy and/or radiotherapy (OR 1.32, 95 % CI 1.03–1.70), older age (OR 1.18, 95 % CI 1.11–1.24), and duration of surgery (OR 1.07, 95 % CI 1.04–1.10) were significantly associated with a higher risk of PPCs. In contrast, the peak expiratory flow rate (PEF) (OR 0.99, 95 % CI 0.98–0.99) was a protective factor. Clinicians should implement targeted and effective interventions to prevent the occurrence of PPCs.

In bilingual word recognition, cross-language activation has been found in unimodal bilinguals (e.g., Chinese-English bilinguals) and bimodal bilinguals (e.g., American Sign language-English bilinguals). However, it remains unclear how signs' phonological parameters, spoken words' orthographic and phonological representation, and language proficiency affect cross-language activation in bimodal bilinguals. To resolve the issues, we recruited deaf Chinese sign language (CSL)-Chinese bimodal bilinguals as participants. We conducted two experiments with the implicit priming paradigm and the semantic relatedness decision task. Experiment 1 first showed cross-language activation from Chinese to CSL, and the CSL words' phonological parameter affected the cross-language activation. Experiment 2 further revealed inverse cross-language activation from CSL to Chinese. The Chinese words' orthographic and phonological representation played a similar role in the cross-language activation. Moreover, a comparison between Experiments 1 and 2 indicated that language proficiency influenced cross-language activation. The findings were further discussed with the Bilingual Interactive Activation Plus (BIA+) model, the deaf BIA+ model, and the Bilingual Language Interaction Network for Comprehension of Speech (BLINCS) model.

In this study, Er2-xYbxZr2O7 (x = 0–2.0) transparent ceramics were successfully prepared by vacuum sintering at 1850 °C for 6 h. The phase composition, microstructure evolution and optical properties of the as-prepared ceramics were investigated. The powders and ceramics demonstrate a single-phase defective fluorite structure. All the ceramics exhibit excellent optical performance and the highest in-line transmittance can reach to 76% at 1100 nm when x = 1.0. The upconversion and infrared emission under 980 nm exciting were measured and discussed as well. The Er2-xYbxZr2O7 transparent ceramics exhibit efficient upconversion photoluminescence emission in the visible wavelength region at 524 nm, 541 nm, 650 nm and downconversion emission at 1530 nm, 1565 nm, 1646 nm.

Exosomes, membranous nanovesicles, naturally carry proteins, mRNAs, and microRNAs (miRNAs) and play important roles in tumor pathogenesis. Here we showed that gastric cancer (GC) cell-derived exosomes can function as vehicles to deliver miR-155 to promote angiogenesis in GC. In this study, we first detected that the expression of miR-155 and c-MYB was negatively correlated in GC and that c-MYB was a direct target of miR-155. We next characterized the promotional effect of exosome-delivered miR-155 on angiogenesis and tumor growth in GC. We found that miR-155 could inhibit c-MYB but increase vascular endothelial growth factor (VEGF) expression and promote growth, metastasis, and tube formation of vascular cells, causing the occurrence and development of tumors. We also used a tumor implantation mouse model to show that exosomes containing miR-155 significantly augment the growth rate of the vasculature and tumors in vivo. Our results illustrate the potential mechanism between miR-155 and angiogenesis in GC. These findings contribute to our understanding of the function of miR-155 and exosomes for GC therapy. Keywords: exosomes, miR-155, c-MYB, angiogenesis, VEGF

Background: Chronic oxaliplatin-induced peripheral neurotoxicity (OIPN) is the most troublesome and dose-limiting side effect of oxaliplatin. There is no effective treatment for chronic OIPN. We conducted a randomised controlled trial to investigate the efficacy of monosialotetrahexosylganglioside (GM1) in treating chronic OIPN. Methods: In this single-centre, double-blind, phase Ⅲ trial, gastrointestinal cancer patients with persistent chronic OIPN were randomised in 1:1 ratio to receive either GM1 or placebo at Tianjin Medical University Cancer Institute and Hospital, China. GM1 was dosed at 60 mg daily for every 3 weeks or 40 mg daily for every 2 weeks. Seven- and fourteen- day infusions were administered to concurrent oxaliplatin users and oxaliplatin discontinuation patients, respectively. The primary endpoint was the relief of neurotoxicity (≥30% improvement), measured by a newly developed patient reported outcome measure (MCIPN) based on prior questionnaires including the European Organization for Research and Treatment of Cancer Quality of Life Chemotherapy Induced Peripheral Neuropathy Questionnaire twenty-item scale. Visual analogue score (VAS) was used as another instrument for patients to evaluate the total Chronic OIPN treatment effect. VAS responders (≥30% improvement), double responders (≥30% improvement in both MCIPN and VAS), and high responders (≥50% improvement in the MCIPN total score) were also calculated. The secondary endpoints were safety and quality of life. The additional endpoints are progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), and tumour response. (Trial registration number: NCT02486198 at ClinicalTrials.gov). Findings: Between May 2015 to December 2017, 145 patients were randomly assigned to receive either GM1 (n=73) and placebo (n=72). Majority of the patients in both arms (90% in GM1 and 83% in placebo) continued receiving oxaliplatin on the trial. More patients responded in the GM1 group than in the placebo group (MCIPN responders: 53% vs 14%, VAS responders: 49% vs 22%, double responders: 41% vs 7%, and high responders: 32% vs 13%, all P < ·01). Analyses were also performed in concurrent oxaliplatin users. The results were consistent with those of the whole group. No deleterious effects of GM1 on survival or tumour response were found. There were no ≥G3 GM1-related adverse events. Interpretation: In patients with chronic OIPN, the use of GM1 reduces the severity of chronic OIPN compared with placebo. Funding: This work was supported by clinical trial development fund of Tianjin Medical University Cancer Institute and Hospital (No.C1706).

Gastric cancer (GC) has a poor prognosis due to its relentless proliferation and metastasis. One of the reasons for this plight is the formidable angiogenesis ability of GC. Considering the important role of cancer exosomes as carriers and communicators in the tumor microenvironment, we explored the role of exosome-microRNA (miRNA) in regulating angiogenesis. Western blotting and quantitative real-time PCR were used to measure the protein and mRNA levels of the miRNA target gene. To detect changes in cellular biological functions, we pretreated human umbilical vein endothelial cells (HUVECs) that were severally cocultured with GC-derived exosomes and transfected them with different miRNAs directly. Also, we used the mouse xenograft model to verify the effect of miR-155 on angiogenesis of GC tissues in vivo. Our study confirmed that miR-155, as a driver of angiogenesis, encapsulated by exosomes from GC can enhance the generation of new vessels for GC in vitro through inhibiting the expression of Forkhead box O3 (FOXO3a) protein, which led to the progression of GC. Therefore, miR-155 is probable to become a potential biomarker for the detection of migration and angiogenesis of GC, and serves as a novel target for anti-angiogenesis therapy. Keywords: gastric cancer, GC, exosomes, miR-155, FOXO3a, angiogenesis

Summary: 2D metal organic frameworks (MOFs) with layered structure and much exposed atoms on the surface are expected to be promising electrode materials for hybrid supercapacitors. However, the insulating character strongly hinders their further applications. Herein, we propose a novel MOF//MOF strategy to enhance 2D MOF's conductivity, by which two kinds of 2D MOFs with specific functions are concurrently incorporated into one homogeneous layered MOF with enhanced conductivity and electrochemical performance. The synthesized Ni//Cu MOF shows a triple high capacitance of 1,424 Fg−1 and excellent rate capability compared with the pristine Ni MOF. A hybrid supercapacitor is thereof fabricated, which can provide a maximum energy density of 57 Wh kg−1 and a maximum power density of 48,000 W kg−1. These results not only demonstrate that our strategy can effectively boost the conductivity and redox activity but also pave new routes to synthesize new MOFs for various applications.

Objective: Anti-angiogenic therapy and immune checkpoint blockade therapy are currently important treatments for non-small cell lung cancer. However, the combined use of the two therapies is controversial, and few studies have investigated the effects of different time sequences of the two therapies on treatment outcomes. Methods: The tumor-bearing mouse model was established and the mice were divided into four groups, including AA-ICB sequence group, ICB-AA sequence group, synchronization group and the control group. Immunohistochemistry was used to assess tumor microvessels and PD-L1 expression. Selected immune cell populations were evaluated using flow cytometry. Meta-analysis and clinical information were used to elucidate the clinical effects of administration sequence. Results: We found that anti-PD-L1 treatment followed by anti-VEGFR2 therapy exerts the best inhibitory effect on tumor growth. Different sequences of anti-angiogenic therapy and immune checkpoint blockade therapy resulted in different proportions of tumor microvessels and immune cell populations in the tumor microenvironment. We further revealed that the administration of anti-PD-L1 before anti-VEGFR brought more normalized tumor blood vessels and CD8+T cell infiltration and reduced immunosuppressive cells in the tumor microenvironment. Subsequent re-transplantation experiments confirmed the long-term benefits of this treatment strategy. The meta-analysis reinforced that immunotherapy prior to anti-angiogenic therapy or combination therapy have better therapeutic effects in advanced non-small cell lung cancer. Conclusion: Our study demonstrated that the therapeutic effect of anti-angiogenic treatment after immune checkpoint therapy was superior to that of concurrent therapy, whereas anti-angiogenic therapy followed by immunotherapy did not bring more significant clinical benefits than independent monotherapy.

Background/Purpose: Oral submucous fibrosis (OSF) is a premalignant condition caused by the chewing of areca nut (AN). Transforming growth factor β (TGFβ) plays a central role in the pathogenesis of OSF. Connective tissue growth factor (CTGF or CCN2) and early growth response-1 (Egr-1) are important mediators in the fibrotic response to TGFβ in several fibrotic disorders including OSF. Arecoline, a major AN alkaloid, induced the synthesis of CCN2 and Egr-1 in human buccal mucosal fibroblast (BMFs). The aims of this study were to investigate whether arecoline-induced CCN2 and Egr-1 syntheses are mediated through TGFβ1 signaling and to inspect the detailed mechanisms involved. Methods: Western blot and TGFβ1 Emax® ImmunoAssay were used to measure the effect of arecoline on the TGFβ signaling pathways. 2′,7′-dichlorodihydrofluorescein diacetate and MitoSOX™ Red were used to measure the effect of arecoline on the cellular and mitochondrial reactive oxygen species (ROS). Results: Arecoline induced latent TGFβ1 activation, Smad2 phosphorylation, and mitochondrial and total cellular ROS in BMFs. TGFβ-neutralizing antibody completely inhibited the arecoline-induced synthesis of CCN2 and Egr-1. Mito-TEMPO, a mitochondria-targeted antioxidant, completely suppressed arecoline-induced latent TGFβ1 activation and mitochondrial and total cellular ROS. Epigallocatechin-3-gallate (EGCG) dose-dependently inhibited arecoline-induced TGFβ1 activation and mitochondrial ROS in BMFs. Conclusion: Our results indicated that arecoline-induced mitochondrial ROS plays pivotal roles in the activation of latent TGFβ1 leading to the initiation of TGFβ1 signaling and subsequent increase in the synthesis of CCN2 and Egr-1. EGCG can be a useful agent in the chemoprevention and treatment of OSF. Keywords: Areca nut chewing, EGCG, Fibroblast, TGFβ, Oral submucous fibrosis

Deregulation of metabolic pathways is one of the hallmarks of cancer progression. Connective tissue growth factor (CTGF/CCN2) acts as a tumor suppressor in oral squamous cell carcinoma (OSCC). However, the role of CTGF in modulating cancer metabolism is still unclear. Methods: OSCC cells stably overexpressing CTGF (SAS/CTGF) and shRNA against CTGF (TW2.6/shCTGF) were established. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were examined by the Seahorse XF24 analyzer. The expression of CTGF and mitochondrial biogenesis related genes was measured by real-time polymerase chain reaction or Western blot analysis. Results: CTGF decreased OCR, ECAR, adenosine triphosphate (ATP) generation, mitochondrial DNA (mtDNA), and mitochondrial transcription factor A (mtTFA) protein expression in OSCC cells. Overexpression of mtTFA restored CTGF-decreased OCR, ECAR, mtDNA copy number, migration and invasion of SAS/CTGF cells. Immunoprecipitation assay showed a higher level of ubiquitinated mtTFA protein after CTGF treatment. MG132, an inhibitor of proteasomal degradation, reversed the effect of CTGF on mtTFA protein expression in SAS cells. Conclusion: CTGF can decrease glycolysis, mitochondrial oxidative phosphorylation, ATP generation, and mtDNA copy number by increasing mtTFA protein degradation through ubiquitin proteasome pathway and in turn reduces migration and invasion of OSCC cells. Therefore, CTGF may be developed as a potential additive therapeutic drug for oral cancer in the near future.

Connective tissue growth factor (CCN2) has been associated with the pathogenesis of various fibrotic diseases, including oral submucous fibrosis (OSF). The chemical constituents of areca nut along with the mechanical trauma cause OSF. The coarse fibers of areca nut injure the mucosa and hence sphingosine-1-phosphate (S1P) is released at the wounded sites. Recent studies have shown that S1P is involved in wound healing and the development of fibrosis. The aims of this study were to investigate the effects of S1P on CCN2 expression in human buccal fibroblasts (HBFs) and identify the potential targets for drug intervention or chemoprevention of OSF. Methods: Western blot analyses were used to study the effects of S1P on CCN2 expression and its signaling pathways in HBFs and whether epigallocatechin-3-gallate (EGCG), the main and most significant polyphenol in green tea, could inhibit this pathway. Results: S1P significantly enhanced CCN2 synthesis in HBFs. This effect can be inhibited by c-Jun NH2-terminal kinase (JNK) inhibitor and extracellular signal-regulated kinase inhibitor but not by P38 mitogen-activated protein kinase inhibitor. Interestingly, EGCG completely blocked S1P-induced CCN2 expression via suppressing S1P-induced JNK phosphorylation. Conclusion: S1P released by repetitive mechanical trauma during AN chewing may contribute to the pathogenesis of OSF through upregulating CCN2 expression in HBFs. EGCG could be an adjuvant to the current offered therapy options or the prevention of OSF through suppression of JNK activation.

Transforming growth factor-β (TGF-β) plays an important role in the pathogenesis of cyclosporine A (CsA)-induced gingival overgrowth (GO). Connective tissue growth factor (CTGF/CCN2) acts as a cofactor with TGF-β to induce the maximal profibrotic effects of TGF-β. We investigated the effects of CsA on CCN2 expression in human gingival fibroblasts (HGFs) and the potential chemopreventive agent for CsA-induced GO. Methods: Western blot analyses were used to examine the signaling pathways of CsA-induced CCN2 expression in HGFs and whether epigallocatechin-3-gallate (EGCG), curcumin, or lovastatin can inhibit CsA-induced CCN2 expression. Results: CsA significantly stimulated CCN2 synthesis in HGFs. This effect can be inhibited by c-Jun NH2-terminal kinase (JNK) and Smad3 inhibitors but not by TGF-β neutralizing antibody and TGF-β type I receptor inhibitor. Furthermore, EGCG completely blocked CsA-induced CCN2 expression. Conclusion: CsA-induced CCN2 protein expression is mediated through JNK and Smad signaling. CsA may contribute to the pathogenesis of GO through upregulation of CCN2 expression in HGFs. EGCG could be an adjuvant for the prevention of CsA-induced GO.