[Mechanism of Qilongtian Capsules in treatment of acute lung injury based on network pharmacology prediction and experimental validation].

This study aimed to explore the mechanism of Qilongtian Capsules in treating acute lung injury(ALI) based on network pharmacology prediction and in vitro experimental validation. Firstly, UPLC-Q-TOF-MS/MS was used to analyze the main chemical components of Qilongtian Capsules, and related databases were used to obtain its action targets and ALI disease targets. STRING database was used to build a protein-protein interaction(PPI) network. Metascape database was used to conduct enrichment analysis of Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG). AutoDock software was used to perform molecular docking verification on the main active components and key targets. Then, the RAW264.7 cells were stimulated with lipopolysaccharide(LPS) for in vitro experiments. Cell viability was measured by MTT and ROS level was measured by DCFH-DA. NO content was measured by Griess assay, and IL-1ß, IL-6, and TNF-α mRNA expression was detected by RT-PCR. The predicted targets were preliminarily verified by investigating the effect of Qilongtian Capsules on downstream cytokines. Eighty-four compounds were identified by UPLC-Q-TOF-MS/MS. Through database retrieval, 44 active components with 589 target genes were screened out. There were 560 ALI disease targets, and 65 intersection targets. PPI network topology analysis revealed 10 core targets related to ALI, including STAT3, JUN, VEGFA, CASP3, and MMP9. KEGG enrichment analysis showed that Qilongtian Capsules mainly exerted an anti-ALI effect by regulating cancer pathway, AGE-RAGE, MAPK, and JAK-STAT signaling pathways. The results of molecular docking showed that the main active components in Qilongtian Capsules, including crenulatin, ginsenoside F_1, ginsenoside Rb_1, ginsenoside Rd, ginsenoside Rg_1, ginsenoside Rg_3, notoginsenoside Fe, notoginsenoside G, notoginsenoside R_1, notoginsenoside R_2, and notoginsenoside R_3, had good binding affinities with the corresponding protein targets STAT3, JUN, VEGFA, CASP3, and MMP9. Cellular experiments showed that Qilongtian Capsules at 0.1, 0.25, and 0.5 mg·mL~(-1) reduced the release of NO, while Qilongtian Capsules at 0.25 and 0.5 mg·mL~(-1) reduced ROS production, down-regulated mRNA expression of IL-1ß, IL-6, TNF-α, and inhibited the inflammatory cascade. In summary, Qilongtian Capsules may exert therapeutic effects on ALI through multiple components and targets.

Distal transradial access decreases radial artery occlusion rate in percutaneous coronary interventions.

BACKGROUND: To investigate the incidence of complications such as radial artery occlusion (RAO) after distal or conventional transradial access in percutaneous coronary interventions, and to compare the advantages and disadvantages of those two approaches. METHODS: In this retrospective study, the data of 110 patients received either distal transradial access (dTRA) (n=56 cases) or conventional transradial access (cTRA) (n=54 cases) in percutaneous coronary interventions were analyzed to compare the incidence of RAO. RESULTS: The incidence of RAO in the dTRA group significantly decreased compared with that in the cTRA group (P<0.05). Univariate analysis indicated that smoking (r=0.064, P=0.011), dTRA (r=0.431, P<0.001), cTRA (r=0.088, P=0.015), radial artery spasm (r=-0.021, P=0.016), and postoperative arterial compression time (r=0.081, P<0.001) were exposure factors for the incidence of RAO. In multivariable analysis, independent risk factors for RAO were postoperative arterial compression time (P=0.038) and dTRA (P<0.001). CONCLUSIONS: dTRA shortened the postoperative arterial compression time and decreased the incidence of RAO compared with conventional transradial approach.

[Rapid identification and differential markers of Curcumae Radix decoction pieces of different sources based on Heracles Neo ultra-fast gas phase electronic nose].

Since Curcumae Radix decoction pieces have multiple sources, it is difficult to distinguish depending on traditional cha-racters, and the mixed use of multi-source Curcumae Radix will affect its clinical efficacy. Heracles Neo ultra-fast gas phase electronic nose was used in this study to quickly identify and analyze the odor components of 40 batches of Curcumae Radix samples from Sichuan, Zhejiang, and Guangxi. Based on the odor fingerprints established for Curcumae Radix decoction pieces of multiple sources, the odor components was identified and analyzed, and the chromatographic peaks were processed and analyzed to establish a rapid identification method. Principal component analysis(PCA), discriminant factor analysis(DFA), and soft independent modeling cluster analysis(SIMCA) were constructed for verification. At the same time, one-way analysis of variance(ANOVA) combined with variable importance in projection(VIP) was employed to screen out the odor components with P<0.05 and VIP>1, and 13 odor components such as ß-caryophyllene and limonene were hypothesized as the odor differential markers of Curcumae Radix decoction pieces of diffe-rent sources. The results showed that Heracles Neo ultra-fast gas phase electronic nose can well analyze the odor characteristics and rapidly and accurately discriminate Curcumae Radix decoction pieces of different sources. It can be applied to the quality control(e.g., online detection) in the production of Curcumae Radix decoction pieces. This study provides a new method and idea for the rapid identification and quality control of Curcumae Radix decoction pieces.

Characteristics, prognostic determinants of monocytes, macrophages and T cells in acute coronary syndrome: protocol for a multicenter, prospective cohort study.

BACKGROUND: Acute coronary syndrome(ACS) is the leading cause of mortality and disability worldwide. Immune response has been confirmed to play a vital role in the occurrence and development of ACS. The objective of this prospective, multicenter, observational study is to define immune response and their relationship to the occurrence and progressive of ACS. METHODS: This is a multicenter, prospective, observational longitudinal cohort study. The primary outcome is the incidence of major adverse cardiovascular events (MACE) including in-stent restenosis, severe ventricular arrhythmia, heart failure, recurrent angina pectoris, and sudden cardiac death, and stroke one year later after ACS. Demographic characteristics, clinical data, treatments, and outcomes are collected by local investigators. Furthermore, freshly processed samples will be stained and assessed by flow cytometry. The expression of S100A4, CD47, SIRPα and Tim-3 on monocytes, macrophages and T cells in ACS patients were collected. FOLLOW-UP: during hospitalization, 3, 6 and 12 months after discharge. DISCUSSION: It is expected that this study will reveal the possible targets to improve the prognosis or prevent from occurrence of MACE in ACS patients. Since it's a multicenter study, the enrollment rate of participants will be accelerated and it can ensure that the collected data are more symbolic and improve the richness and credibility of the test basis. ETHICS AND DISSEMINATION: This study has been registered in Chinese Clinical Trial Registry Center. Ethical approval was obtained from the Affiliated Hospital of Guizhou Medical University. The dissemination will occur through the publication of articles in international peer-reviewed journals. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2200066382.

Long noncoding RNA SPRY4-IT1 acts as a miR-101-5p sponge to promote gastrointestinal stromal tumor progression by inhibiting ZEB1.

OBJECTIVES: Research on long noncoding RNAs (lncRNAs) has been conducted in different areas of oncology. Currently, the biological significance of lncRNAs and their regulatory features in gastrointestinal stromal tumors (GIST) remain largely unknown. We have previously identified SPRY4-IT1 overexpression in GIST through lncRNA sequencing of GIST tissues. Coincidentally, SPRY4-IT1 is an intron of the SPRY4 gene, and SPRY4 is specifically highly expressed in GIST. Thus the aim of the present study was to investigate the role of lncRNA SPRY4-IT1 in GIST pathogenesis. METHODS: Herein, we screened for SPRY4-IT1 and analyzed its possible phenotypes using Gene set enrichment analysis (GSEA). The phenotypes of GIST were verified using CCK-8, colony formation, and wound-healing assays. The ceRNA mechanism was determined by the location of lncRNA SPRY4-IT1, and its relationship to the Ago2 protein. The SPRY4-IT1/miR-101-5p/ZEB1 axis was predicted using online software and sequencing. Luciferase and pull-down assays were performed for verification. Pathway-associated and phenotype-associated proteins were detected by western blotting. RESULTS: Sequencing analysis revealed 117 differentially expressed lncRNAs in GIST and normal gastric tissue samples. Accordingly, SPRY4-IT1 was screened out and its phenotype was predicted by GSEA. Mechanistically, SPRY4-IT1 was identified as a competing endogenous RNA (ceRNA) that downregulated miR-101-5p and upregulated ZEB1, which activated extracellular signal-regulated kinase (ERK) signaling to stimulate GIST proliferation, invasion, and epithelial-mesenchymal transition. Although this effect was regulated by a negative feedback loop through SPRY4, it was still controlled by SPRY4-IT1. CONCLUSIONS: In GIST, we revealed a ceRNA mechanism by which SPRY4-IT1 modulates ZEB1 by sponging miR-101-5p, eventually driving tumor cell proliferation, migration, and epithelial-mesenchymal transition (EMT).

[Rapid identification of raw and sulfur-fumigated Paeoniae Radix Alba based on Heracles NEO ultra-fast gas phase electronic nose].

Since the current identification method for Paeoniae Radix Alba is complex in operation and long time-consuming with high requirements for technicians, the present study employed Heracles NEO ultra-fast gas phase electronic nose(E-nose) technology to identify raw and sulfur-fumigated Paeoniae Radix Alba decoction pieces in order to establish a rapid identification method for sulfur-fumigated Paeoniae Radix Alba. The odors of raw Paeoniae Radix Alba and its sulfur-fumigated products were analyzed by Heracles NEO ultra-fast gas phase E-nose to obtain the odor chromatographic information. The chemometric model was established, and the data were processed by principal component analysis(PCA), discriminant function analysis(DFA), soft independent modeling of class analogy(SIMCA), and partial least squares discriminant analysis(PLS-DA). The differential compounds of raw and sulfur-fumigated samples were qualitatively analyzed based on the Kovats retention index and Arochembase. As revealed by the comparison of gas chromatograms of raw and sulfur-fumigated Paeoniae Radix Alba, the heights of several peaks in the chromatograms before and after sulfur fumigation changed significantly. The peak(No.8) produced by ethylbenzene disappeared completely due to sulfonation reaction in the process of sulfur fumigation, indicating that ethylbenzene may be the key component in the identification of Paeoniae Radix Alba and its sulfur-fumigated products. In PCA, DFA, SIMCA, and PLS-DA models, the two types of samples were separated into two different regions, indicating that the established models can clearly distinguish between raw and sulfur-fumigated Paeoniae Radix Alba. The results showed that Heracles NEO ultra-fast gas phase E-nose technology could realize the rapid identification of raw and sulfur-fumigated Paeoniae Radix Alba, which provides a new method and idea for the rapid identification of sulfur-fumigated Chinese medicine.

Clinical observation and genetic analysis of a SYNS1 family caused by novel NOG gene mutation.

OBJECTIVE: Analyze the clinical and genetic characteristics of a rare Chinese family with Multiple synostoses syndrome and identify the causative variant with the high-throughput sequencing approach. METHODS: The medical history investigation, physical examination, imaging examination, and audiological examination of the family members were performed. DNA samples were extracted from the family members. The candidate variant was identified by performing whole-exome sequencing of the proband, then verified by Sanger sequencing in the family. RESULTS: The family named HBSY-018 from Hubei province had 18 subjects in three generations, and six subjects were diagnosed with conductive or mixed hearing loss. Meanwhile, characteristic features including short philtrum, hemicylindrical nose, and hypoplastic alae nasi were noticed among those patients. Symptoms of proximal interdigital joint adhesion and inflexibility were found. The family was diagnosed as Multiple synostoses syndrome type 1 (SYNS1).The inheritance pattern of this family was autosomal dominant. A novel mutation in the NOG gene c.533G>A was identified by performing whole-exome sequencing of the proband. The substitution of cysteine encoding 178th position with tyrosine (p.Cys178Tyr) was caused by this mutation, which was conserved across species. Co-segregation of disease phenotypes was demonstrated by the family verification. CONCLUSION: The family diagnosed as SYNS1 was caused by the novel mutation (c.533G>A) of NOG. The combination of clinical diagnosis and molecular diagnosis had improved the understanding of this rare disease and provided a scientific basis for genetic counseling in the family.

The nerve-tumour regulatory axis GDNF-GFRA1 promotes tumour dormancy, imatinib resistance and local recurrence of gastrointestinal stromal tumours by achieving autophagic flux.

Complete surgical resection, accessible therapeutic targets and effective tyrosine kinase inhibitors (TKIs) have not completely cured gastrointestinal stromal tumours (GISTs), with most patients suffering from residual tumours and recurrence. The existence of nerve infiltration in GIST provides a way for tumour cells to escape local resection and systemic targeted therapy, which may challenge the previous understanding of its behaviour patterns and inspire the development of more radical excision and more precise targeted therapy. Moreover, tumour dormancy has emerged as a major cause of drug resistance and tumour relapse. Among these pathways, the nerve-tumour regulatory axis GDNF-GFRA1 is activated in GISTs, assists tumour cells in achieving dormancy and protects them from apoptosis under environmental stress by enhancing autophagic flux. The concrete mechanism is that the GDNF-regulating interaction between GFRA1 and the lysosomal calcium channel MCOLN1 activates Ca2+-dependent TFEB signalling. Activated TFEB transcriptionally regulates intracellular lysosome levels, which could achieve feedback upregulation of cellular autophagy flux during TKI treatment. This dormancy-transition axis fills parts of the mechanistic vacancy before the onset of secondary mutations, and strategies for TKIs combined with targeting GFRA1-dependent autophagy have distinct promise as prospective clinical therapies.

[Efficacy-related substances of blood-activating and stasis-resolving medicinals derived from Curcuma plants: a review].

Derived from Curcuma plants, Curcumae Longae Rhizoma, Curcumae Rhizoma, Wenyujin Rhizoma Concisum, and Curcumae Radix are common blood-activating and stasis-resolving medicinals in clinical practice, which are mainly used to treat amenorrhea, dysmenorrhea, chest impediment and heart pain, and rheumatic arthralgia caused by blood stasis block. According to modern research, the typical components in medicinals derived from Curcuma plants, like curcumin, demethoxycurcumin, bisdemethoxycurcumin, curdione, germacrone, curcumol, and ß-elemene, have the activities of hemorheology improvement, anti-platelet aggregation, anti-thrombosis, anti-inflammation, anti-tumor, and anti-fibrosis, thereby activating blood and resolving stasis. However, due to the difference in origin, medicinal part, processing, and other aspects, the efficacy and clinical application are different. The efficacy-related substances behind the difference have not yet been systematically studied. Thus, focusing on the efficacy-related substances, this study reviewed the background, efficacy and clinical application, efficacy-related substances, and "prediction-identification-verification" research method of blood-activating and stasis-resolving medicinals derived from Curcuma plants, which is expected to lay a theoretical basis for the future research on the "similarities and differences" of such medicinals based on integrated evidence chain and to guide the scientific and rational application of them in clinical practice.

Low Distribution of TIM-3+ Cytotoxic Tumor-Infiltrating Lymphocytes Predicts Poor Outcomes in Gastrointestinal Stromal Tumors.

There are multiple tumor-infiltrating lymphocytes (TILs) and relevant immune checkpoints existing in gastrointestinal stromal tumor (GIST), which provides opportunities and rationales for developing effective immunotherapies. Recent studies have suggested that checkpoint TIM-3/Gal-9 plays a pivotal role on immune response in multiple tumors, similar to the PD-1/PD-L1, emerging as a potential therapeutic target. However, their functions in GIST are unrevealed. Hence, the expression of immune checkpoints TIM-3 and Gal-9, as well as the infiltration of CD8+ T cells and NK cells, is described in 299 cases of GIST specimens. The results showed that TIM-3 and Gal-9 are mainly expressed in TILs, rarely in tumor cells. Expression levels of TIM-3 and Gal-9 significantly differ in varying risks of GIST and exert opposite distribution trends. Indicated by prognosis analysis, high TIM-3 expression of TILs was associated with improved outcome, while low expression levels of TIM-3 in combination with low amounts of CD8+ and CD56+ TILs predict extremely poor survival. The integrated analysis of TIM-3+, CD8+, and CD56+ TILs as one biomarker is a reliable independent predictor of prognosis. In conclusion, low densities of TIM-3+ TILs are associated with poor survival, and integrated immune biomarkers lead to superior predictors of GIST prognosis.

Integrated Screens Identify CDK1 as a Therapeutic Target in Advanced Gastrointestinal Stromal Tumors.

Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumor (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with advanced GIST. Polyclonal emergence of KIT/PDGFRA secondary mutations is the main mechanism of imatinib progression, making it challenging to overcome KIT/PDGFRA-inhibitor resistance. It is unclear whether there are other therapeutic targets in advanced GIST. Using genome-wide transcriptomic profiling of advanced versus early-stage GIST and CRISPR knockout functional screens, we demonstrate that CDK1 is frequently highly expressed in advanced GIST but not in early-stage GIST across three patient cohorts. High expression of CDK1 was associated with malignancy in GIST. CDK1 was critically required for advanced GIST, including imatinib-resistant GIST. CDK1 ablation led to robust proliferation inhibition. A mass spectrometry-based proteomics screen further revealed that AKT is a novel substrate of CDK1 kinase in GIST. CDK1 bound AKT and regulated its phosphorylation, thereby promoting GIST proliferation and progression. Importantly, a pharmacologic inhibitor of CDK1, RO-3306, disrupted GIST cell proliferation in CDK1 highly expressed GIST but not in CDK1-negative GIST cells and nontransformed fibroblast cells. Treatment with RO-3306 reduced tumor growth in both imatinib-resistant and imatinib-sensitive GIST xenograft mouse models. Our findings suggest that CDK1 represents a druggable therapeutic target in GIST and warrants further testing in clinical trials. SIGNIFICANCE: These findings propose CDK1 as a novel cell-cycle-independent vulnerability in gastrointestinal stromal tumors, representing a new therapeutic opportunity for patients with advanced disease.

Exon 11 homozygous mutations and intron 10/exon 11 junction deletions in the KIT gene are associated with poor prognosis of patients with gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) with different types of mutations exhibit different clinical characteristics and prognosis. This study aimed to evaluate the prognostic value of mutations in KIT and PDGFRA in a large-scale cohort of GIST patients with current therapy including surgery and imatinib. METHODS: A total of 1163 patients diagnosed with GISTs between January 2006 and December 2018 were enrolled in this study. Mutation analysis was performed for exons 9, 11, 13, and 17 of KIT and exons 12 and 18 of PDGFRA. Mutations were grouped into 12 categories according to the gene, exon, and involved codons; they were analyzed considering the clinical characteristics, disease-free survival (DFS), and overall survival (OS) of patients with GISTs. RESULTS: In low-risk GISTs, we identified two predictors of worse DFS: tumor origin in the rectum and KIT exon 11 deletion involving two or more codons. In high-risk GISTs treated with R0 resection and imatinib, patients with KIT exon 11 homozygous mutations and KIT intron 10/exon 11 junction deletions demonstrated the highest recurrence rate, indicating that these mutations can be independent prognostic factors of DFS. The presence of KIT exon 11 homozygous mutations also independently influenced OS. CONCLUSION: Low-incidence mutations such as KIT exon 11 homozygous mutations or intron 10/exon 11 junction deletions in GISTs should be carefully evaluated to explore novel treatment strategies, as tumors with these mutations have a high recurrence rate and a very poor prognosis after surgery followed by imatinib adjuvant treatment.

Clinicopathologic characteristics, diagnostic clues, and prognoses of patients with multiple sporadic gastrointestinal stromal tumors: a case series and review of the literature.

BACKGROUND: Most sporadic gastrointestinal stromal tumors (GISTs) occur as solitary tumors, while multiple sporadic GISTs are extremely rare and often misdiagnosed as metastatic GISTs, leading to inappropriate treatment. This study aimed to investigate the clinicopathological characteristics, diagnostic clues, and prognoses of multiple sporadic GISTs. METHODS: Twenty-seven patients with multiple sporadic GISTs and 11 patients with metastatic GISTs mimicking sporadic GISTs were analyzed. The clinicopathological characteristics, genetic mutation types, and prognoses were summarized. In addition, 1066 cases of primary GISTs with a single lesion diagnosed at the same hospital were included as controls. RESULTS: Compared with 1066 cases of primary GIST with a single lesion, multiple sporadic GISTs occurred at an older age, were more common in women than in men, and were located mainly in the stomach. They were generally small in size, had a low mitotic index and were more often rated as very low risk/low risk. Mutation analysis of all available lesions revealed different KIT/PDGFRA mutation patterns among tumors from the same patients. No patient relapsed during the follow-up period. Among 11 patients with metastatic GISTs that mimicked multiple sporadic GISTs, multiple lesions from the same patient always had concordant pathological and mutational characteristics; namely, they carried an identical KIT/PDGFRA mutation, and the mitotic index was usually high. CONCLUSIONS: The prognoses of patients with multiple sporadic GISTs were not worse than those of patients with a single lesion of the same risk under the same treatment. When it was difficult to distinguish multiple sporadic GISTs from metastatic GISTs, multiple lesions in the same patient carried different KIT/PDGFRA mutation patterns, which supported tumor multiplicity, while the concordant hypermitotic phase in multiple lesions of GISTs suggested that the tumor was metastatic.

Aberrant accumulation of Dickkopf 4 promotes tumor progression via forming the immune suppressive microenvironment in gastrointestinal stromal tumor.

BACKGROUND: Drug resistance and tumor recurrence are the major concerns in clinical practices of gastrointestinal stromal tumor (GIST), with the urgent requirement for exploring undiscovered pathways driving malignancy. To deal with these, recent studies have made many efforts to explore prognosis indicators and establish potential therapeutic targets. METHODS: Expression profiles of different risks of GISTs were described and abundant clinical evidences supported our findings in this study. Following exploration in vitro by cell experiments and verification in vivo using tumor microarray were taken to elucidate the underlying mechanism, which drove the malignancy in GIST. RESULTS: Dickkopf 4 (DKK4), as the canonical Wnt pathway antagonist, was unexpectedly and universally upregulated in high-risk GISTs, and aberrant accumulation of DKK4 was closely correlated with poor prognosis. In addition, tumor-derived DKK4 could decrease immune cells infiltration and activation in the tumor microenvironment, which decreased the antitumor effects in return. And this phenomenon was recurrent in human tumor specimens. CONCLUSIONS: Our findings identified DKK4 as a proper tumor biomarker for prognosis predicting and recurrence monitoring, and suggested a novel immune-escape mechanism driving malignancy in GIST, which might be a potential therapeutic target to improve the effects of canonical RTK therapy and combined immunotherapy.

Isocitrate Dehydrogenase Mutations in Glioma: From Basic Discovery to Therapeutics Development.

Isocitrate dehydrogenase (IDH) is a key rate-limiting enzyme in the Krebs cycle that plays an important role in energy metabolism. In recent years, it has been found that IDH mutations are closely related to the occurrence and development of glioma, and it is a notable potential therapeutic target. First, IDH mutations can produce high levels of 2-hydroxyglutaric acid (2-HG), thereby inhibiting glioma stem cell differentiation. At the same time, IDH mutations can upregulate vascular endothelial growth factor (VEGF) to promote the formation of the tumor microenvironment. In addition, IDH mutations can also induce high levels of hypoxia-inducible factor-1α (HIF-1α) to promote glioma invasion. Ultimately, these changes will lead to the development of glioma. Currently, a large number of IDH inhibitors and vaccines have entered clinical trials, representing progress in the treatment of glioma patients.

Standard Approach to Gastrointestinal Stromal Tumors - Differences between China and Europe.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. With the considerable research and application of molecular-targeted therapy for GISTs in the last two decades, GISTs have become a model of multidisciplinary oncological treatment. Although Western clinical guidelines are available for GISTs, such as those by the European Society of Medical Oncology (ESMO), the clinical situations in China are different from those in European countries. There are distinct differences between the clinical practice, diagnostic methods, surgical approach, and availability of new targeted agents in China and those in Europe. This review summarizes the Chinese GIST consensus guidelines compared to the European ones, which may provide an optimal approach to the diagnosis and management of GIST patients.

[Sesquiterpenes with anti-metastasis breast cancer activity from Chloranthus henryi].

To study sesquiterpenes with anti-metastasis breast cancer activity from Chloranthus henryi, ten sesquiterpenes ,zedoarofuran (1), chlorajapolide D (2), 4ß, 8ß-dihydroxy-5α(H)-eudesm-7(11)-en-8, 12-olide (3), curcolonol (4), lasianthuslactone A (5), chlomultin C (6), (1E,4Z)-8-hydroxy-6-oxogermacra-1(10), 4, 7(11) -trieno-12, 8-lactone (7), shizukanolide E (8) , shizukanolide F (9) , 9α-hydroxycurcolonol (10), and five bis-sesquiterpenes, shizukaol B (11), shizukaol C (12) , cycloshizukaol A (13) , sarcandrolide B (14) , henriol A(15), were isolated by using different kinds of column chromatography methods from the ethyl acetate part of Ch.henryi and their structures were identified based on spectroscopic methods. Compounds 2, 8, 9, and 10 were obtained from the genus Chloranthus for the first time. Compounds 2, 5, 8-10, 12,and 14 were obtained from this plant for the first time. Some isolated compounds were subjected to evaluate the anti-metastasis breast cancer activity by using pharmacological methods, and only compounds 4, 11, and 12 were potent active.

ITGBL1 Predicts a Poor Prognosis and Correlates EMT Phenotype in Gastric Cancer.

Integrin, beta-like 1 (ITGBL1), a ß-integrin-related extracellular matrix protein, was found more commonly up-regulated in gastric cancer (GC) by screening and analyzing Gene Expression Omnibus (GEO) and Oncomine databases, reminding us to explore its prognostic significance in GC. In our current study, we observed that ITGBL1 expression was significantly up-regulated in GC compared with normal controls in clinical specimens. In addition, elevated ITGBL1 expression was positively correlated with patients' tumor-node-metastasis (TNM) stage and distant metastasis. Kaplan-Meier analysis indicated that high ITGBL1 expression was significantly associated with shorter survival times in GC patients. Multivariate Cox regression analysis confirmed ITGBL1 expression as an independent prognostic factor in GC. Gene set enrichment analysis (GSEA) of multiple GEO datasets revealed a close relationship between ITGBL1 expression and the KRAS/epithelial-mesenchymal transition (EMT) signaling pathway. In conclusion, these data provide evidences that ITGBL1 is a potential predictor and may be involved in cancer cell invasion and metastasis via inducing EMT, and the ITGBL1-related pathways may represent a novel therapeutic strategy for treatment of GC.

Targeting mTORC2 component rictor inhibits cell proliferation and promotes apoptosis in gastric cancer.

The mammalian target of rapamycin (mTOR) kinase acts downstream of phosphoinositide 3-kinase/Akt and plays an important role in tumor growth and progression of gastric cancer. It is well characterized that mTOR complex1 (mTORC1) controls cell metabolism and proliferation, whereas the contribution of mTOR complex2 (mTORC2) and its key component, Rictor, remains poorly understood. Therefore, we investigated clinical significance of Rictor expression by immunohistochemical analysis of 391 tissue samples from gastric cancer patients. In addition, the roles of Rictor in cell proliferation, apoptosis, migration and invasion in vitro were evaluated by RNA interference. The results showed that over expression of Rictor was associated with increased tumor size, depth of tumor invasion, lymph node metastasis and advanced TNM stage, together with poorer overall and relapse-free survival. Stable sh-RNA mediated down-regulation of Rictor significantly inhibited SGC7901 and MGC803 gastric cancer cells proliferation, migration and invasion. Furthermore, Rictor knockdown attenuated cell cycle progression and enhanced apoptosis, synergistic with treatment of mTORC1 inhibitor rapamycin owing to abrogating the feedback activation of Akt. Our findings identify Rictor as an important mediator of tumor progression and metastasis, providing the rationale for targeting both mTORC1 and mTORC2 as part of therapeutic strategy for gastric cancer.

[Clinicopathological classification and prognostic factors of gastrointestinal neuroendocrine neoplasms: an analysis of 119 cases].

OBJECTIVE: To investigate the clinical characteristics, pathological classification and prognostic factors of gastrointestinal neuroendocrine neoplasms (GI-NENs). METHODS: Clinicopathological data of 119 GI-NENs patients at Shanghai Renji Hospital from November 2007 to December 2016 were analyzed retrospectively. According to the classification and grading criteria of the WHO Neuroendocrine Tumor 2010 edition, patients were classified pathologically to realize the malignant degree of tumors. The overall survival rate was calculated by Kaplan-Meier curve, the prognostic risk factors were analyzed by Cox regression model, and the factors including the platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) were included in the analysis in addition to the routine clinicopathological factors. RESULTS: Of 119 patients with GI-NENs, there were 83 cases (69.7%) of male and 36 cases (30.3%) of female. The age of patients ranged from 24 to 86 (median 61) years. Tumor locations included the stomach(n=70, 58.8%), duodenum(n=10, 8.4%), small intestine(n=2, 1.7%), appendix(n=3, 2.5%), colon(n=12, 10.1%), and rectum(n=22, 18.5%). The tumor diameter was 0.6 to 20 cm, the mean diameter was 5.4 cm, and the median diameter was 4 cm. There were 25 cases of G1 neuroendocrine tumor (NET), 7 cases of G2 NET and 87 cases of G3 neuroendocrine carcinoma (NEC). Among the 119 patients, 113 cases (95%) had complete follow-up, and the median follow-up was 75 (1 to 112) months. The 5-years overall survival rate was 58.4%. The survival rate of G1 NET, G2 NET and G3 NEC were 100%, 71.4%, 44.4%, and the difference was statistically significant (P=0.000). Univariate analysis showed that age ≥61 years (P=0.000), tumor located in the stomach, duodenum and colon (P=0.041), tumor size ≥4 cm (P=0.002), pathology classification of G3 NEC (P=0.000), late TNM staging (P=0.000) and blood PLR ≥133 (P=0.017) were associated with lower 5-year survival rate, but blood NLR level was not(P=0.263). Multivariate analysis showed that the patient age (HR=3.036, 95%CI: 1.548 to 5.956, P=0.001), the pathology classification(HR = 1.852, 95%CI:1.099 to 3.122, P=0.021), lymph node metastasis (HR=2.635, 95%CI:1.198 to 5.797, P=0.016) and distant metastasis (HR=2.685, 95%CI:1.383 to 5.214, P=0.004) were independent risk factors affecting the prognosis of patients, but the blood PLR level was not (HR=1.735, 95%CI: 0.947 to 3.176, P=0.074). CONCLUSIONS: The malignant degree of GI-NEN is quite high, and the prognosis of patients is relatively poor. The age, pathological type and TNM staging are closely related to the prognosis of patients. Preoperative blood PLR may play a role in the prediction of prognosis, but preoperative blood NLR is not related with the prognosis of patients.