CO2-Responsive Wormlike Micelles Based on Pseudo-Tetrameric Surfactant.

Wormlike micelles, which are linear aggregates created by the self-assembly of surfactants, may entangle to form dynamic three-dimensional network-like structures, endowing solutions with considerable macroscopic viscoelasticity. Recently, a pressing need has arisen to research a novel stimuli-responsive worm-like micelle that is efficient and environmentally friendly. CO2 is an inexpensive, abundant, non-toxic, biocompatible, and non-combustible gas, and it is anticipated that CO2 may serve as the trigger for stimuli-responsive worm-like micelles. In this paper, the formation of CO2-switchable pseudo-tetrameric surfactants, which subsequently self-assemble into CO2-switched wormlike micelles, is accomplished using a simple mixing of two commercial reagents, such as stearic acids and cyclen. The rheological characteristics switched by the use of CO2 are cycled between that of a low-viscosity (1.2 mPa·s) fluid and a viscoelastic fluid (worm-like micelles, 3000 mPa·s). This article expands the field of study on stimuli-responsive worm-like micelles.

Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) have influenced the treatment paradigm for multiple solid tumors, increasing evidence suggests that primary and adaptive resistance may limit the long-term efficacy of ICIs. New therapeutic strategies with other drug combinations are hence warranted to enhance the antitumor efficacy of ICIs. As a novel tumor suppressor, histone deacetylase (HDAC) inhibitor tucidinostat has been successfully confirmed to act against hematological malignancies. However, the underlying mechanisms of action for tucidinostat and whether it can manipulate the tumor microenvironment (TME) in solid tumors remain unclear. METHODS: Three murine tumor models (4T1, LLC, and CT26) were developed to define the significant role of different doses of tucidinostat in TME. The immunotherapeutic effect of tucidinostat combined with anti-programmed cell death ligand 1 antibody (aPD-L1) was demonstrated. Furthermore, the effect of tucidinostat on phenotypic characteristics of peripheral blood mononuclear cells (PBMCs) from lung cancer patients was investigated. RESULTS: With an optimized dose, tucidinostat could alter TME and promote the migration and infiltration of CD8+ T cells into tumors, partially by increasing the activity of C-C motif chemokine ligand 5 (CCL5) via NF-κB signaling. Moreover, tucidinostat significantly promoted M1 polarization of macrophages and increased the in vivo antitumor efficacy of aPD-L1. Tucidinostat also enhanced the expression of the costimulatory molecules on human monocytes, suggesting a novel and improved antigen-presenting function. CONCLUSIONS: A combination regimen of tucidinostat and aPD-L1 may work synergistically to reduce tumor burden in patients with cancer by enhancing the immune function and provided a promising treatment strategy to overcome ICI treatment resistance.

Peptidic microarchitecture-trapped tumor vaccine combined with immune checkpoint inhibitor or PI3Kγ inhibitor can enhance immunogenicity and eradicate tumors.

BACKGROUND: With the rapid development of immune checkpoint inhibitors and neoantigen (NeoV)-based personalized tumor vaccines, tumor immunotherapy has shown promising therapeutic results. However, the limited efficacy of available tumor vaccines impedes the development of personalized tumor immunotherapy. In this study, we developed a novel tumor vaccine system and proposed combined therapeutic strategies for improving treatment effects. METHODS: We developed a novel tumor vaccine system comprising a newly synthesized peptidic microarchitecture (PMA) with high assembly efficacy. The PMA-trapped neoantigen vaccine was developed to codeliver tumor neoantigen and the Toll-like receptor 9 agonist CpG (NeoV), abbreviated as PMA-NeoV. A microfluidic chip was used to produce PMA particles in a uniform and precise manner. Vaccine effectiveness was investigated both in vitro and in vivo. The combined immunotherapeutic effect of PMA-NeoV with anti-programmed cell death ligand 1 antibody (aPD-L1) or with the phosphatidylinositol 3­kinase γ (PI3Kγ) inhibitor IPI-549 was further tested in MC38 mouse tumor model. RESULTS: PMA-NeoV not only promoted codelivery of the tumor vaccine but also potentiated vaccine immunogenicity. Moreover, compared with free NeoV, PMA-NeoV significantly increased the number of tumor-infiltrating lymphocytes, promoted the neoantigen-specific systemic immune response, and suppressed murine colon MC38 tumor growth. Furthermore, PMA-NeoV increased the expression of programmed cell death receptor-1 on T lymphocytes, and in combination with aPD-L1 eradicated seven of eight MC38 tumors by rescuing exhausted T lymphocytes. Moreover, we combined the PMA-NeoV with the IPI-549, a molecular switch that controls immune suppression, and found that this combination significantly suppressed tumor growth and eradicated five of eight inoculated tumors, by switching suppressive macrophages to their active state and activating T cells to prime a robust tumor immune microenvironment. CONCLUSIONS: We developed a tumor vaccine delivery system and presented a promising personalized tumor vaccine-based therapeutic regimen in which a tumor vaccine delivery system is combined with an aPD-L1 or PI3Kγ inhibitor to improve tumor immunotherapy outcomes.

TP53 mutations in circulating tumor DNA in advanced epidermal growth factor receptor-mutant lung adenocarcinoma patients treated with gefitinib.

Tumor protein p53 (TP53) is a tumor suppressor gene and TP53 mutations are associated with poor prognosis in non-small cell lung cancer. However, the in-depth classification of TP53 and its relationship with treatment response and prognosis in epidermal growth factor receptor (EGFR)-mutant tumors treated with EGFR tyrosine kinase inhibitors are unclear. Circulating tumor DNA was prospectively collected at baseline in advanced treatment-naïve EGFR-mutant lung adenocarcinoma patients treated with gefitinib in an open-label, single-arm, prospective, multicenter, phase 2 clinical trial (BENEFIT trial) and analyzed using next-generation sequencing. Survival was estimated using the Kaplan-Meier method. Of the 180 enrolled patients, 115 (63.9%) harbored TP53 mutations. The median progression-free survival (PFS) and overall survival (OS) of patients with TP53-wild type tumors were significantly longer than those of patients with TP53-mutant tumors. Mutations in exons 5-8 accounted for 80.9% of TP53 mutations. Mutations in TP53 exons 6 and 7 were significantly associated with inferior PFS and OS compared to wild-type TP53. TP53 mutation also influenced the prognosis of patients with different EGFR mutations. Patients with TP53 and EGFR exon 19 mutations had significantly longer PFS and OS than patients with TP53 and EGFR L858R mutations, and both groups had worse survival than patients with only EGFR mutations. Patients with TP53 mutations, especially in exons 6 and 7, had a lower response rate and shorter PFS and OS when treated with gefitinib. Moreover, TP53 exon 5 mutation divided TP53 mutations in disruptive and non-disruptive types.

Evaluation of the ex vivo liver viability using a nuclear magnetic resonance relaxation time-based assay in a porcine machine perfusion model.

There is a dearth of effective parameters for selecting potentially transplantable liver grafts from expanded-criteria donors. In this study, we used a nuclear magnetic resonance (NMR) relaxation analyzer-based assay to assess the viability of ex vivo livers obtained via porcine donation after circulatory death (DCD). Ex situ normothermic machine perfusion (NMP) was utilized as a platform for viability test of porcine DCD donor livers. A liver-targeted contrast agent, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), was injected into the perfusate during NMP, and the dynamic biliary excretion of the Gd-EOB-DTPA was monitored by measuring the longitudinal relaxation time (T1). The longitudinal relaxation rate (R1) of the bile was served as a parameter. The delay of increase in biliary R1 during early stage of NMP indicated the impaired function of liver grafts in both warm and cold ischemia injury, which was correlated with the change of alanine aminotransferase. The preservative superiority in cold ischemia of dual hypothermic oxygenated machine perfusion could also be verified by assessing biliary R1 and other biochemical parameters. This study allows for the dynamic assessment of the viability of porcine DCD donor livers by combined usage of ex situ NMP and NMR relaxation time based assay, which lays a foundation for further clinical application.

Rare case of apatinib acquired resistance induced by point mutation of WRN p.V697F through activation of the PI3K/AKT apoptosis-inhibiting pathway.

Targeted therapy has become the main treatment for non-small cell lung cancer (NSCLC). Apatinib is a new antiangiogenic antitumor drug developed in China which targets vascular endothelial growth factor receptor-2 (VEGFR-2). We recently treated a 50-year-old female patient who underwent a bronchoscopic biopsy and was subsequently pathologically diagnosed with squamous cell carcinoma of NSCLC. EML4-ALK and MINPP1 & PAPSS2-PTEN fusions were found to be present in tumor tissue and blood. Sequential targeted therapy was commenced with gemcitabine + cisplatin, docetaxel, tegafur, gimeracil, oteracil potassium capsules + carboplatin, and other third-line chemotherapy involving antineoplastic therapy, but unfortunately the patient showed primary drug resistance to this treatment regimen. Crizotinib was administered but was found to be ineffective. After two months of treatment, the disease had progressed and next generation sequencing (NGS) was subsequently performed. Apatinib was administered thereafter and the patient's symptoms improved after one week. Following administration for one month, CT scan revealed that the primary lung tumor lesions were significantly necrotic and they were narrowed. The patient's symptoms of coughing, phlegm production, and wheezing had also reduced. Her lung disease was under stable control 2.5 months later, but abdominal CT unfortunately revealed a suspected new nidus in the liver. A third gene mutation detection test showed that ALK and PTEN genetic mutations were obviously decreased; however, the patient was found to have developed WRN p.V697F (c.G2089T) point mutation, which was a new gene mutation. We suspected that the WRN gene mutation had led to apatinib resistance. We determined the absolute position of this point mutation to be chr8:30969131 with a transcript number of NM_000553.4. We retrieved information on human somatic cells from the ExAC, 1000 Genomes Browser, ESP database and PubMed databases. All the results indicated that the mutation identified in this study has not been previously reported worldwide.

Influence of adjuvant chemotherapy on survival for patients with stage IB and IIA non-small cell lung cancer.

BACKGROUND: The role of adjuvant chemotherapy (ACT) for patients with stage IB-IIA non-small cell lung cancer (NSCLC) according to the eighth edition of the AJCC TNM staging system remains controversial. METHODS: Data were collected from patients with NSCLC stage IB-IIA according to the eighth edition of the AJCC TNM staging system who underwent surgical resection from 2008 to 2015. The relationship between ACT and overall survival (OS) or disease-free survival (DFS) was analyzed using the Kaplan-Meier method and Cox proportional hazards model. RESULTS: The study included 648 patients with completely resected NSCLC stage IB-IIA; 312 underwent ACT after surgical resection and 336 were placed under observation. After propensity score matching, 247 pairs of patients were matched and the five-year OS was 88.08% and 83.12% (P = 0.13) in ACT and non-ACT settings, respectively. Subgroup analyses demonstrated that ACT treatment was correlated with an improved five-year OS in patients with visceral pleural invasion (VPI) in the 3 < tumor ≤ 4 cm subgroup (93.98% and 68.93%, P < 0.01). CONCLUSIONS: ACT was not significantly associated with improved five-year OS in stage IB-IIA NSCLC patients. However, further subgroup analysis showed that patients with VPI in the 3 < tumor ≤ 4 cm (T2aN0M0, stage IB) subgroup might benefit more from ACT. Further studies are required to validate the findings and better systemic strategies need to be developed in these patients. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: For patients with stage IB-IIA NSCLC according to the eighth edition of the AJCC TNM staging system, the effect of ACT remains unclear. ACT was not significantly associated with improved five-year OS in stage IB-IIA NSCLC patients. However, it was correlated with better DFS before or after PSM. Patients with VPI in the 3 < tumor ≤ 4 cm subgroup may benefit from ACT. WHAT THIS STUDY ADDS: ACT was not significantly associated with improved five-year OS in stage IB-IIA NSCLC patients. However, it was correlated with better DFS before or after PSM. Patients with VPI in the 3 < tumor ≤ 4 cm subgroup may benefit from ACT.

Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma.

BACKGROUND: The survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immunotherapy, collectively referred to as chemoimmunotherapy, for the treatment of squamous cell lung carcinoma (SQCLC) have been confirmed in recent clinical trials. Nevertheless, optimization of chemoimmunotherapy in order to enhance the efficacy of immune checkpoint inhibitors (ICIs) in SQCLC remains to be explored. METHODS: Cell lines, syngeneic immunocompetent mouse models, and patients' peripheral blood mononuclear cells were used in order to comprehensively explore how to enhance ectopic lymphoid-like structures (ELSs) and upregulate the therapeutic targets of anti-programmed death 1 (PD-1)/anti-PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), thus rendering SQCLC more sensitive to ICIs. In addition, molecular mechanisms underlying optimization were characterized. RESULTS: Low-dose chemotherapy contributed to an enhanced antigen exposure via the phosphatidylinositol 3-kinase/Akt/transcription factor nuclear factor kappa B signaling pathway. Improved antigen uptake and presentation by activated dendritic cells (DCs) was observed, thus invoking specific T cell responses leading to systemic immune responses and immunological memory. In turn, enhanced antitumor ELSs and PD-1/PD-L1 expression was observed in vivo. Moreover, upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and effectively synergized with anti-PD-1/PD-L1 mAbs. A possible mechanism underlying this synergy is the increase of activated type I macrophages, DCs, and cytotoxic CD8+ T cells, as well as the maintenance of intestinal gut microbiota diversity and composition. In contrast, when combining routine MTD chemotherapy with ICIs, the effects appeared to be additive rather than synergistic. CONCLUSIONS: We first attempted to optimize chemoimmunotherapy for SQCLC by investigating different combinatorial modes. Compared with the MTD chemotherapy used in current clinical practice, upfront metronomic chemotherapy performed better with subsequent anti-PD-1/PD-L1 mAb treatment. This combination approach is worth investigating in other types of tumors, followed by translation into the clinic in the future.

Comparison of Multiple Quantitative Evaluation Indices of Theoretical Knowledge and Clinical Practice Skills and Training of Medical Interns in Cardiovascular Imaging Using Blended Teaching and the Case Resource Network Platform (CRNP).

BACKGROUND This study aimed to compare multiple quantitative evaluation indices of levels of theoretical knowledge and clinical practice skills in training medical interns in cardiovascular imaging based on the use of the blended teaching (BT) online artificial intelligence (AI) case resource network platform (CRNP), including time and frequency indices and effectiveness of the CRNP. MATERIAL AND METHODS The study included 110 medical interns who were divided into the routine teaching (RT) group (n=55) and the blended teaching (BT) group (n=55). The two were assessed using the mini-clinical evaluation exercise (mini-CEX) that assessed clinical skills, attitudes, and behaviors and using an objective written questionnaire. The following four indices were compared between the RT and BT groups: the X-ray score (XS), the computed tomography angiography (CTA) score (CS), the cardiac magnetic resonance imaging (CMRI) score (MS), and the average score (AS). Seven assessment indicators included: the imaging description (ID), the qualitative diagnosis (QD), the differential diagnosis (DD), examination preparation (EP), interview skill (IS), position display (PD), and human care (HC). Indicators of CRNP use included: number of times (TN), average duration (AD), single maximum duration (SMD), and total duration (TD). RESULTS AS significantly correlated with AD (rAD=0.761) and TD (rTD=0.754), and showed moderate correlation with TN (rTN=0.595), but weak correlation with SMD (rSMD=0.404). CONCLUSIONS Levels of theoretical knowledge and clinical practice skills during medical intern training in cardiovascular imaging based on BT using the CRNP teaching technology improved theoretical knowledge and practical skills.

Exercise on quality of life and cancer-related fatigue for lymphoma survivors: a systematic review and meta-analysis.

BACKGROUND: People treated for lymphoma can experience several significant long-term and late effects, including fatigue and decreased quality of life. This study aimed to systematically review the evidence from randomized controlled trials (RCTs) and to conduct a meta-analysis of the effect of exercise on quality of life and other health outcomes for adults suffering from lymphoma. METHODS: We searched the following databases and sources: PubMed, Cochrane Library, Embase, Web of Science, and MEDLINE. Such studies would be included if they were RCT designs which focus on observing the evaluated health outcomes of exercise intervention for lymphoma patients or survivors, comparing with non-exercise or wait-list control groups. Two review authors independently screened search results, extracted data, and assessed the quality of trials. We used standardized mean differences for quality of life (QoL), fatigue, sleep quality, and depression. RESULTS: Six publications have met the inclusion criteria and the exercise interventions are short term. Slight improvement can be seen on QoL, fatigue, sleep quality, and depression due to exercise for lymphoma patients. Subgroup analysis was carried out according to the classification of mind-body exercise and aerobic exercise, and significant progress can be seen after mind-body exercise intervention in the area of fatigue and sleep. CONCLUSIONS: Short-term exercises do not appear to convey benefits to quality of life and other psychosocial outcomes. Subgroup analysis showed that physical activity together with mental exercise may be more beneficial to lymphoma patients, but it needs more research to verify this finding. The interpretation of this result should be cautious due to the baseline difference, completion efficiency of intervention process, and high heterogeneity.

Antitumor effects of Xi Huang pills on MDA­MB­231 cells in vitro and in vivo.

The management of patients with triple­negative breast cancer is challenging due to the lack of effective therapeutic options, aggressive behavior and relatively poor prognosis. Xi Huang pills (XHP) are a well­known traditional Chinese medicine that demonstrate anticancer activities. The aim of the present study was to investigate the antitumor effects of XHP on MDA­MB­231 cells in vitro and in vivo, and its potential underlying molecular mechanisms. In the present study, an MTT assay was used to evaluate the antiproliferative activity of XHP on MDA­MB­231 cells. In order to investigate the effects further, cell cycle distribution, apoptosis and mitochondrial membrane potential assays were performed, as well as western blot analyses. In addition, a tumor xenograft model was employed to investigate the effects of XHP in vivo. The results of the MTT assay demonstrated that the viability of MDA­MB­231 cells was markedly inhibited by XHP in a dose­ and time­dependent manner. The inhibitory effect of XHP on the viability of MDA­MB­231 cells was greater when compared with MCF­10A cells. An increase in apoptosis and loss of mitochondrial membrane potential was observed following 4, 8 and 12 mg/ml XHP treatment of MDA­MB­231 cells. The protein expression levels of cleaved caspase­3 were increased by 1.62­, 2.13­ and 2.19­fold, respectively, when compared with the untreated controls, whereas no effects on the expression of B­cell lymphoma 2 (Bcl­2) or Bcl­2­associated X protein (Bax) were observed. The results of the cell cycle distribution assay analysis demonstrated that XHP treatment arrested cells at the G2/M phase. In addition, XHP treatment decreased the expression of cyclin A and increased the expression of p21Cip1. In vivo experiments revealed that XHP inhibited the growth of MDA­MB­231 xenograft tumors without body weight loss, and demonstrated similar effects on the protein expression levels of cleaved caspase 3, cyclin A and p21Cip1 as observed in vitro. In conclusion, the viability of MDA­MB­231 cells was inhibited by XHP in a dose­dependent, time­dependent and cell­selective manner in vitro, and the potential underlying mechanisms may involve apoptosis and cell cycle arrest at the G2/M phase. XHP may induce apoptosis in MDA­MB­231 cells via the intrinsic pathway, which does not involve the Bcl­2/Bax ratio. G2/M phase arrest may have been due to the integrated action of decreased cyclin A expression and increased p21Cip1 expression. In addition, XHP inhibited the growth of xenograft tumors in the absence of body weight loss in vivo.

Bu-Fei decoction and modified Bu-Fei decoction inhibit the growth of non-small cell lung cancer, possibly via inhibition of apurinic/apyrimidinic endonuclease 1.

Human apurinic/apyrimidinic endonuclease 1 (APE1) is a ubiquitous multifunctional protein, which possesses DNA repair and redox activities. High levels of APE1 are associated with chemo­ and radioresistance, and poor prognosis in various types of cancer, including non­small cell lung cancer (NSCLC). Bu­Fei decoction (BFD) is a traditional Chinese herbal formula, which is believed to supplement Qi, clear away heat and nourish the lungs. BFD and modified Bu­Fei decoction (MBFD) have been used in China to treat patients with lung cancer. The present study aimed to evaluate the potential antitumor effects of BFD and MBFD on NSCLC in vitro and in vivo. In addition, the possible contribution of APE1 was examined. MTT assay was used to investigated the anti-tumor activity of BFD and MBFD on H1975 and H292 NSCLC cell lines. The DNA damage of cells in the control and the experimental groups was detected using comet assay. The in vivo anti-tumor effects of BFD and MBFD were evaluated in a NSCLC tumor nude mouse xenograft model. Polymerase chain reaction (PCR), reverse transcription­quantitative PCR (RT­qPCR) analysis and western blot analysis were applied to analyze the mRNA and protein expression levels of APE1 in H1975 and H292 cells, so as to the xenograft tumor tissues. The concentration of APE1 in mice plasma was determined using enzyme linked immunosorbent assay (ELISA). In vitro, BFD and MBFD inhibited the growth of cultured H1975 and H292 NSCLC cells. The results of a comet assay revealed that BFD and MBFD increased DNA damage. Furthermore, the expression levels of APE1 were decreased in response to BFD and MBFD at the mRNA and protein levels. In mice carrying NSCLC xenografts, BFD and MBFD inhibited tumor growth and decreased APE1 expression. In addition, in normal human lung bronchial epithelial BEAS­2B cells, the half maximal inhibitory concentrations of BFD and MBFD were much higher compared with in NSCLC cells, and they had no effect on DNA damage. These results suggested that BFD and MBFD may inhibit the growth of NSCLC, possibly by inhibiting APE1 expression.

Marsdenia tenacissima extract overcomes Axl- and Met-mediated erlotinib and gefitinib cross-resistance in non-small cell lung cancer cells.

Tyrosine kinase inhibitors (TKIs) are an effective treatment strategy for non-small cell lung cancer (NSCLC) patients harboring mutations that result in constitutive activation of the epidermal growth factor receptor (EGFR). However, most patients eventually develop resistance to TKIs. This occurs due to additional EGFR mutations or the activation of bypass signaling pathways. In our previous work, we demonstrated that Marsdenia tenacissima extract (MTE) restored gefitinib sensitivity in resistant NSCLC cells with EGFR T790M or K-ras mutations. However, the potential efficacy of MTE in NSCLC cells with resistance mediated by Axl and c-Met, and the related molecular mechanisms need to be elucidated. In this study we evaluated the ability of MTE to restore erlotinib/gefitinib sensitivity in TKI resistant HCC827/ER cells and xenograft mice models. Our results demonstrate that MTE overcomes erlotinib and gefitinib resistance driven by Axl and c-Met in vitro and in vivo. Combination therapy significantly suppressed EGFR downstream molecules and the c-Met and Axl activated bypass signaling pathways. Moreover, we observed that MTE is more efficient at restoring resistance to erlotinib than gefitinib. As the Axl and c-Met mediated bypass pathways share the same downstream signaling cascade as EGFR, simultaneous targeting of these pathways is a promising strategy to overcome acquired resistance of TKIs. Our results demonstrate that MTE treatment attenuates Axl phosphorylation and the associated epithelial-mesenchymal transition, suggesting MTE treatment may be a potential therapeutic strategy for overcoming erlotinib and gefitinib cross-resistance in NSCLC, especially for erlotinib resistance.

Social and content aware One-Class recommendation of papers in scientific social networks.

With the rapid development of information technology, scientific social networks (SSNs) have become the fastest and most convenient way for researchers to communicate with each other. Many published papers are shared via SSNs every day, resulting in the problem of information overload. How to appropriately recommend personalized and highly valuable papers for researchers is becoming more urgent. However, when recommending papers in SSNs, only a small amount of positive instances are available, leaving a vast amount of unlabelled data, in which negative instances and potential unseen positive instances are mixed together, which naturally belongs to One-Class Collaborative Filtering (OCCF) problem. Therefore, considering the extreme data imbalance and data sparsity of this OCCF problem, a hybrid approach of Social and Content aware One-class Recommendation of Papers in SSNs, termed SCORP, is proposed in this study. Unlike previous approaches recommended to address the OCCF problem, social information, which has been proved playing a significant role in performing recommendations in many domains, is applied in both the profiling of content-based filtering and the collaborative filtering to achieve superior recommendations. To verify the effectiveness of the proposed SCORP approach, a real-life dataset from CiteULike was employed. The experimental results demonstrate that the proposed approach is superior to all of the compared approaches, thus providing a more effective method for recommending papers in SSNs.

Taraxacum mongolicum extract induced endoplasmic reticulum stress associated-apoptosis in triple-negative breast cancer cells.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive and deadly breast cancer subtype with limited treatment options. It is necessary to seek complementary strategies for TNBC management. Taraxacum mongolicum, commonly named as dandelion, is a herb medicine with anti-cancer activity and has been utilized to treat mammary abscess, hyperplasia of mammary glands from ancient time in China, but the scientific evidence and action mechanisms still need to be studied. AIM OF THE STUDY: This study was intended to investigate the therapeutic effect and molecular mechanisms of dandelion extract in TNBC cell line. METHODOLOGY: Dandelion extract was prepared and purified, and then its chemical composition was determined. Cell viability was evaluated by MTT assay. Analysis of cell apoptosis and cell cycle was assessed by flow cytometry. The expression levels of mRNA and proteins were determined by real-time PCR and Western blotting, respectively. Caspase inhibitor Z-VAD-FMK and CHOP siRNA were used to confirm the cell apoptosis induced by dandelion extract. RESULTS: Dandelion extract significantly decreased MDA-MB-231cell viability, triggered G2/M phase arrest and cell apoptosis. Concurrently, it caused a markedly increase of cleaved caspase-3 and PARP proteins. Caspase inhibitor Z-VAD-FMK abolished the apoptosis triggered by dandelion extract. The three ER stress-related signals were strongly induced after dandelion treatment, including increased mRNA expressions of ATF4, ATF6, XBP1s, GRP78 and CHOP genes, elevated protein levels of phosphorylated PERK, eIF-2α, IRE1, as well as the downstream molecules of CHOP and GRP78. MDA-MB-231 cells transfected with CHOP siRNA significantly reduced apoptosis induced by dandelion extract. The underlying mechanisms at least partially ascribe to the strong activation of PERK/p-eIF2α/ATF4/CHOP axis. CONCLUSION: ER stress related cell apoptosis accounted for the anti-cancer effect of dandelion extract, and these findings support dandelion extract might be a potential therapeutic approach to treat TNBC.

Bu Fei Decoction attenuates the tumor associated macrophage stimulated proliferation, migration, invasion and immunosuppression of non-small cell lung cancer, partially via IL-10 and PD-L1 regulation.

Macrophages play a pivotal role in tumor microenvironment. Bu-Fei Decoction (BFD) is a classical formula of traditional Chinese medicine (TCM) to alleviate lung cancer related symptoms, whether it has antitumor effect or could influence cancer microenvironment deserves further study. The aim of the present study was to examine the antitumor effect of BFD on non-small cell lung cancer (NSCLC), and to investigate the underlying mechanisms through tumor associated macrophages (TAMs). M2-polarized TAMs were induced by Phorbol 12-myristate 13-acetate (PMA) and interleukin 4 (IL-4). The antitumor activity of BFD in vitro was investigated in A549 and H1975 cells using MTT assay. The in vivo anticancer effect of BFD was evaluated in athymic nude mouse xenograft model. The invasive and migration properties of NSCLC cells were measured using Transwell. The protein expression was assessed using western blotting, ELISA and immunohistochemistry. The gene expression was examined using RT-PCR. TAMs was successfully established. Conditioned medium from TAMs increased cell proliferation, migration and invasion in NSCLC cells (p<0.05). BFD showed dose-dependent inhibitory effect on cell proliferation, migration and invasion abilities induced by TAMs. TAMs and rhIL-10 promoted the mRNA and protein expression of PD-L1 in NSCLC cells (p<0.01). Anti­IL­10 antibodies inhibited the elevated PD-L1 expression induced by TAMs. In vitro, the expression of PD-L1 and IL-10 was inhibited by BFD dose-dependently. In vivo, BFD suppressed A549 and H1975 tumor growth and decreased the expression of IL-10, PD-L1 and CD206. The results showed that TAMs play an important role in tumor progression of NSCLC, which was associated with tumor proliferation, migration, invasion and immunosuppression. Moreover, the antitumor mechanism of BFD is related to interruption of the link between TAMs and cancer cells by inhibiting the expression of IL-10 and PD-L1 in vitro and in vivo. Our results demonstrated BFD's potential as a novel treatment for NSCLC.

Chinese medicine Bu-Fei decoction attenuates epithelial-mesenchymal transition of non-small cell lung cancer via inhibition of transforming growth factor ß1 signaling pathway in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine Bu-Fei decoction (BFD) has been utilized to treat patients with Qi deficiency for decades, with the advantages of invigorating vital energy, clearing heat-toxin and moistening lung, etc. According to previous clinical experience and trials, BFD has been found to indeed improve life quality of lung cancer patients and prolong survival time. Nevertheless, little is known on its potential mechanisms so far. Being regarded as a pivotal cytokine in the tumor microenvironment, transforming growth factor ß (TGF-ß) stands out as a robust regulator of epithelial-mesenchymal transition (EMT), which is closely linked to tumor progression. AIM OF THE STUDY: The present study was designed to explore whether BFD antagonized EMT via blocking TGF-ß1-induced signaling pathway, and then help contribute to create a relatively steady microenvironment for confining lung cancer. MATERIALS AND METHODS: This experiment was performed in lung adenocarcinoma A549 cells both in vitro and in vivo. In detail, the influences mediated by TGF-ß1 alone or in combination with different concentrations of BFD on migration were detected by wound healing and transwell assays, and the effects of BFD on cell viability were determined by cell counting kit-8 (CCK-8) assay. TGF-ß1, EMT relevant proteins and genes were evaluated by western blotting, confocal microscopy, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC) and enzyme-linked immuno sorbent assay (ELISA). Female BALB/C nude mice were subcutaneously implanted A549 cells and given BFD by gavage twice daily for 28 days. The tumor volume was monitored every 4 days to draw growth curve. The tumor weight, expression levels of EMT-related protein in tumor tissues and TGF-ß1 serum level were evaluated, respectively. RESULTS: BFD only exerted minor effects on A549 cell proliferation and this was in accordance with the in vivo result, which showed that the tumor growth and weight were not be restrained by BFD administration. However, the data elucidated that BFD could dose-dependently suppress EMT induced by TGF-ß1 in vitro via attenuating canonical Smad signaling pathway. In the A549 xenograft mouse model, BFD also inhibited protein markers that are associated with EMT and TGF-ß1 secretion into serum. CONCLUSIONS: Based on these above data, the conclusion could be put forward that BFD probably attenuated TGF-ß1 mediated EMT in A549 cells via decreasing canonical Smad signaling pathway both in vitro and in vivo, which may help restrain the malignant phenotype induced by TGF-ß1 in A549 cells to some extent.

Recent highlights of Chinese medicine for advanced lung cancer.

Owing to its unique superiority in improving quality of life and prolonging survival time among advanced lung cancer patients, Chinese medicine (CM) has, in recent years, received increased attentions worldwide. We utilized a bibliometric statistical method based on MEDLINE/GoPubMed to conduct a comprehensive analysis of the current application status of CM in lung cancer, by including annual and accumulated publications, origin distribution of countries and journals, and keywords with a higher frequency score. Then the relevant clinical trials and mechanistic studies were systematically summarized within the field according to research types. We have raised potential problems and provided potentially useful reference information that could guide similar studies in the future. The basic experimental results are highly consistent with clinical trials, leading us to conclude that CM can offer better overall therapeutic benefits when used in combination with routine Western medicine for patients with advanced lung cancer.

Green Tea Polyphenol Epigallocatechin-3-gallate-Alleviated Coxsackievirus B3-induced Myocarditis Through Inhibiting Viral Replication but Not Through Inhibiting Inflammatory Responses.

Viral myocarditis, which is mainly caused by coxsackievirus B3 (CVB3), affects about 5%-20% of the world population and still lacks efficient treatments. Green tea, a tonic and healthful beverage that was originated in ancient China, has been receiving considerable attention for its protective effect on cardiovascular diseases in recent years. In the present investigation, we aimed to explore the effect of green tea polyphenol epigallocatechin-3-gallate (EGCG) on CVB3-induced myocarditis and its underlying mechanism. Our study showed that EGCG could alleviate CVB3-induced myocarditis as evidenced by less cardiac injury and higher survival rate. Furthermore, we found that EGCG failed to downregulate the expression of inflammatory cytokines but could significantly inhibit the replication of CVB3. Furthermore, we found that EGCG treatment could downregulate the protein expression level of coxsackievirus and adenovirus receptor, the major receptor for CVB3 to infect cardiac myocytes. In conclusion, our data indicated that EGCG could ameliorate CVB3-induced myocarditis through inhibiting viral replication, which might provide a potential novel therapeutic strategy for viral myocarditis.

High-performance liquid chromatography coupled with tandem mass spectrometry technology in the analysis of Chinese Medicine Formulas: A bibliometric analysis (1997-2015).

There is a recognized challenge in analyzing traditional Chinese medicine formulas because of their complex chemical compositions. The application of modern analytical techniques such as high-performance liquid chromatography coupled with a tandem mass spectrometry has improved the characterization of various compounds from traditional Chinese medicine formulas significantly. This study aims to conduct a bibliometric analysis to recognize the overall trend of high-performance liquid chromatography coupled with tandem mass spectrometry approaches in the analysis of traditional Chinese medicine formulas, its significance and possible underlying interactions between individual herbs in these formulas. Electronic databases were searched systematically, and the identified studies were collected and analyzed using Microsoft Access 2010, Graph Pad 5.0 software and Ucinet software package. 338 publications between 1997 and 2015 were identified, and analyzed in terms of annual growth and accumulated publications, top journals, forms of traditional Chinese medicine preparations and highly studied formulas and single herbs, as well as social network analysis of single herbs. There is a significant increase trend in using high-performance liquid chromatography coupled with tandem mass spectrometry related techniques in analysis of commonly used forms of traditional Chinese medicine formulas in the last 3 years. Stringent quality control is of great significance for the modernization and globalization of traditional Chinese medicine, and this bibliometric analysis provided the first and comprehensive summary within this field.