Targeting inflammatory macrophages rebuilds therapeutic efficacy of DOT1L inhibition in hepatocellular carcinoma.

Epigenetic reprogramming is a promising therapeutic strategy for aggressive cancers, but its limitations in vivo remain unclear. Here, we showed, in detailed studies of data regarding 410 patients with human hepatocellular carcinoma (HCC), that increased histone methyltransferase DOT1L triggered epithelial-mesenchymal transition-mediated metastasis and served as a therapeutic target for human HCC. Unexpectedly, although targeting DOT1L in vitro abrogated the invasive potential of hepatoma cells, abrogation of DOT1L signals hardly affected the metastasis of hepatoma in vivo. Macrophages, which constitute the major cellular component of the stroma, abrogated the anti-metastatic effect of DOT1L targeting. Mechanistically, NF-κB signal elicited by macrophage inflammatory response operated via a non-epigenetic machinery to eliminate the therapeutic efficacy of DOT1L targeting. Importantly, therapeutic strategy combining DOT1L-targeted therapy with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited cancer regression. Moreover, we found that the densities of macrophages in HCC determined malignant cell DOT1L-associated clinical outcome of the patients. Our results provide insight into the crosstalk between epigenetic reprogramming and cancer microenvironments and suggest that strategies to influence the functional activities of inflammatory cells may benefit epigenetic reprogramming therapy.

Clinical characteristics, treatment and prognosis of infants with retinoblastoma: a multicenter, 10-year retrospective analysis.

BACKGROUND: To summarize the characteristics and treatment, and analyze the prognosis of large number of infants with retinoblastoma (RB) in China through a multicenter, 10-year retrospective analysis. METHODS: The data of RB infants were collected from multiple centers. The characteristics and survival prognosis were analyzed. The overall survival (OS) rate was estimated by the Kaplan-Meier method. Multivariate Cox survival analysis was to evaluate the independent risk factors affecting the prognosis of RB infants. RESULTS: A total of 373 RB infants (202 boys and 171 girls) were included, the median age was 6.22 months (10 days to 11.93 months). The median follow-up time of RB infants was 18.4 (1.02-122.81 months). After excluding the lost to follow-up cases, the OS rate was 97.7% (345/353). Kaplan-Meier survival analysis indicated that 9 cases died and the median survival time was not reached. Univariate analysis of prognostic factors revealed eye affected, presenting signs, left eye stage and recurrence to be poor prognostic factors for OS rate in RB infants (all P < 0.05). Multivariate Cox regression analyses for OS showed recurrence (HR = 1.376, 95% CI: 0.878-2.156, P = 0.048) was an independent factor for prognosis of infants with RB. The median survival time of infants underwent chemotherapy + intra-arterial chemotherapy (IAC) + enucleation + vitrectomy was the longest than other treatments (n = 9, 47.64 months, OS = 100%, all P < 0.05). There was a history of RB in 17 infants' lineal relatives. Kaplan-merier survival analysis indicated 1 case died and the median survival time was not reached. CONCLUSION: Recurrence is an independent factor for prognosis of RB infants, which still needs attention after treatment. Early screening, comprehensive treatments and follow-up of patients may lead to improvements of prognosis of RB infants.

Prognostic factors for intermediate- or high-risk neuroblastomas in children in China.

BACKGROUND: Evidence regarding the characteristics and prognosis of neuroblastoma (NBL) in China is limited. We aimed to investigate the characteristics and prognosis of intermediate- or high-risk NBL in children in China. METHODS: We included 147 patients with intermediate- or high-risk NBL evaluated from January 2006 to March 2015. The patients were aged 1 month to 15.5 years, 66% of them were boys, and 117 (79.6%) were diagnosed with high-risk NBL. RESULTS: After a median follow-up of 32.5 months, 80 (45.6%) patients survived, with a median survival time of 48 months (95% confidence interval [CI]: 36.41-59.59). High-risk patients (hazard ratio [HR]: 12.467; 95% CI: 11.029-12.951), partial response (PR) (HR: 1.200; 95% CI: 1.475-2.509) or progression disease (PD) (HR: 1.924; 95% CI: 1.623-3.012) after induction chemotherapy, and intracranial metastasis (HR: 3.057; 95% CI: 0.941-4.892) were independent risk factors for survival (p < 0.05) and postrelapse survival (p < 0.05). NBL relapse, male sex, and PR or PD after induction chemotherapy were risk factors for event-free survival (p < 0.05). CONCLUSIONS: In addition to previously established independent risk factors, such as age, risk group, and relapse, efficacy of induction chemotherapy and intracranial metastasis play significant roles in the prognosis of NBL.

Adsorption-Catalysis-Conversion of Polysulfides in Sandwiched Ultrathin Ni(OH)2 -PANI for Stable Lithium-Sulfur Batteries.

Strong adsorption and catalysis for lithium polysulfides (LiPSs) are critical toward the electrochemical stability of Li-S batteries. Herein, a hollow sandwiched nanoparticle is put forward to enhance the adsorption-catalysis-conversion dynamic of sulfur species. The outer ultrathin Ni(OH)2 nanosheets not only confine LiPSs via both physical encapsulation and chemical adsorption, but also promote redox kinetics and accelerate the conversion of sulfur species, which is revealed by experiments and theoretical calculations. Meanwhile, the inner hollow polyaniline soft core provides a strong chemical bonding to LiPSs after vulcanization, which can chemically adsorpt LiPSs, and synergistically confine the shuttle effect. Moreover, the Ni(OH)2 nanosheets with a large specific area can enhance the wettability of electrolyte, and the flexible hollow sandwiched structure can accommodate the volume expansion, promoting sulfur utilization and structural stability. The obtained cathode exhibits excellent electrochemical performance with an initial discharge capacity of 1173 mAh g-1 and a small capacity decay of 0.08% per cycle even after 500 cycles at 0.2 C, among the best results of Ni(OH)2 -based materials for Li-S batteries. It is believed that the combination of adsorption-catalysis-conversion will shed a light on the development of cathode materials for stable Li-S batteries.

Identification of geographical origin and different parts of Wolfiporia cocos from Yunnan in China using PLS-DA and ResNet based on FT-NIR.

INTRODUCTION: Wolfiporia cocos, as a kind of medicine food homologous fungus, is well-known and widely used in the world. Therefore, quality and safety have received worldwide attention, and there is a trend to identify the geographic origin of herbs with artificial intelligence technology. OBJECTIVE: This research aimed to identify the geographical traceability for different parts of W. cocos. METHODS: The exploratory analysis is executed by two multivariate statistical analysis methods. The two-dimensional correlation spectroscopy (2DCOS) images combined with residual convolutional neural network (ResNet) and partial least square discriminant analysis (PLS-DA) models were established to identify the different parts and regions of W. cocos. We compared and analysed 2DCOS images with different fingerprint bands including full band, 8900-6850 cm-1 , 6300-5150 cm-1 and 4450-4050 cm-1 of original spectra and the second-order derivative (SD) spectra preprocessed. RESULTS: From all results: the exploratory analysis results showed that t-distributed stochastic neighbour embedding was better than principal component analysis. The synchronous SD 2DCOS is more suitable for the identification and analysis of complex mixed systems for the small-band for Poria and Poriae cutis. Both models of PLS-DA and ResNet could successfully identify the geographical traceability of different parts based on different bands. The 10% external verification set of the ResNet model based on synchronous 2DCOS can be accurately identified. CONCLUSION: Therefore, the methods could be applied for the identification of geographical origins of this fungus, which may provide technical support for quality evaluation.

A new risk-stratification system for hepatoblastoma in children under six years old and the significance for prognosis evaluation-a 14-year retrospective study from a single center.

BACKGROUND: This study explores and analyzes the clinical characteristics and prognostic factors of hepatoblastoma (HB) in children under 6 years old and establishes a new risk-stratification system for individualized therapy. METHODS: The clinical data of 382 pediatric patients under 6 years old (231 males and 151 females) who had been diagnosed with HB by pathology between May 2005 and May 2019 were collected. By analyzing the risk factors influencing the survival rate of patients with HB, a new risk-stratification system was established, and it was compared with previous risk-stratification systems by a receiver operating characteristic (ROC) curve. RESULTS: (1) According to a Kaplan-Meier survival analysis, the one-year, three-year, and five-year overall survival (OS) was 93.7, 84.0, and 73.9%, respectively, and the event-free survival (EFS) was 90.5, 79.2, and 67.5%, respectively. (2) The independent risk factors influencing prognosis in pediatric patients with HB were alpha-fetoprotein (AFP) < 100 ng/ml or > 1000 ng/ml (HR = 3.341, P = 0.005); platelet count > 400 × 109/L (pooled hazard ratio [HR] = 2.123, P = 0.026); PRETEXT stage IV (HR = 4.026, P = 0.001); vascular involvement (HR = 2.178, P = 0.019); distant metastasis (HR = 2.634, P = 0.010);and multifocality (HR = 2.215, P = 0.012). (3) A new risk-stratification system was established and divided into three groups: low risk, moderate risk, and high risk. There were statistical differences among the three groups (P = 0.002). Compared with the previous risk-staging systems, there was no significant difference in the survival rate. Although the effect in the guiding therapy was the same, the area under the curve for the ROC curve was 0.835 (95% CI: 0.784-0.885) for the new stratification system. CONCLUSION: This new risk-stratification system had a better predictive value for the prognosis of pediatric patients with HB than other stratification systems.

Biological features and clinical outcome in infant neuroblastoma: a multicenter experience in Beijing.

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, with 37% of patients diagnosed during infancy. This study is aimed at evaluating the survival outcome in infants diagnosed with neuroblastoma. This was a retrospective cohort study including patients under the age of 12 months with neuroblastoma from four tertiary referral centers in Beijing, China (Beijing Children's Hospital, Beijing Tongren Hospital, Peking University First Hospital, and Capital Institute of Pediatrics). Two hundred and forty-seven infants with neuroblastoma were included (male = 132 and female = 115). 91.1% (n = 225) patients were classified as having low-risk or intermediate-risk disease and 8.9% (n = 22) as having high-risk disease. The most common metastatic site is distant lymph node (n=89, 36.0%), followed by liver (n=57, 23.1%), bone (n=42, 17.0%), bone marrow (n=37, 15.0%), soft tissue (n=25, 10%), and central nervous system (n=4, 1.6%). MYCN amplification was present in 9.9% of tumor samples, chromosome 1p or 11q aberration in 14%. Treatment involved surgery alone in 9.7% of patients (n=24, all with low-risk disease), surgery followed by adjuvant chemotherapy in 50.2% (n=124), neoadjuvant chemotherapy followed by surgery in 40.1% (n=97), and chemotherapy alone in 0.8% (n=2). 4.9% (n=12) patients died, and the major cause of death is disease progression. Three-year event-free and overall survival were 91.6%±2.1% and 97.4%±1.1%, respectively, in patients with low- or intermediate-risk disease, and 58.7%±11.5% and 63.6%±11.2%, respectively, in those with high-risk disease.Conclusions: Infants with neuroblastoma achieve a reasonable clinical outcome when treated with surgery with or without chemotherapy using a risk-stratified approach in China. Such information will facilitate counseling, therapeutic decision-making, and development of adapted standard-of-care guidelines for future patients in the country. What is Known: • NB is a disease of infancy; 37% of patients are diagnosed as infants. • Most children younger than 12 months of age have a good prognosis even in the presence of metastatic disease. What is New: • Infants with neuroblastoma achieve reasonable clinical outcome when treated with surgery with or without chemotherapy using a risk-stratified approach in China. • CNS metastasis in infants with neuroblastoma is very rare at diagnosis and had a worse prognosis than those without metastasis.

Clinical characteristics and prognostic factors of hepatoblastoma in 316 children aged under 3 years - a 14-year retrospective single-center study.

BACKGROUND: The aim of the present study was to summarize the clinical characteristics of in children aged under 3 years and analyze the related factors affecting the prognosis. METHODS: The clinical data of 316 children aged under 3 years (192 males and 124 females) who were admitted to Beijing Tongren Hospital with a pathological diagnosis of HB between May 2005 and May 2019 were analyzed retrospectively. The factors influencing the therapeutic effects on and survival of HB in children with HB were analyzed. RESULTS: (1) The median age of the enrolled patients was 1.45 years. The most common initial symptom was an abdominal mass (69.0%). The average serum alpha-fetoprotein (AFP) level and platelet count at the initial visit were (97,406.5 ± 5022.8) ng/mL and (418 ± 206) × 109/L, respectively. The epithelial type was the main pathological type (51.9%). According to the PRETEXT preoperative typing system, the most common stage was stage III (57.0%), whereas according to the postoperative Evans staging system, the most common stage was stage IV (41.8%). At the initial visit, 62 cases (19.6%) had vascular invasion, 52 cases (16.5%) had extrahepatic tumor extension, and 20 cases (6.3%) had tumor rupture. Distant metastasis occurred in 132 cases, and the most common metastatic site was the lung (80.3%). The incidence in East China was relatively high (35.4%). (2) The children were followed up until May 2020 (the median follow-up duration was 62 months). It was found that 194 patients had complete remission and 62 had partial remission. The Kaplan-Meier survival analysis showed that the overall survival was 95.3, 88.2, and 79.8% at 1 year, 3 years, and 5 years, respectively, and the event-free survival was 91.1, 83.2, and 75.1%, respectively. The Cox regression analysis showed that AFP level, platelet count, PRETEXT IV, vascular invasion, and distant metastasis at the initial visit were independent risk factors for the prognosis of children with HB (p < 0.05 in all). CONCLUSION: The prognosis of HB was correlated with the AFP level, platelet count, PRETEXT staging, vascular invasion, and distant metastasis at initial diagnosis.

[Pleurodesis with an Autologous Blood Patch in the Treatment of Persistent Air Leak after Lung Resection].

Objective To evaluate the efficacy and risks of autologous blood patch pleurodesis in patients with persistent air leak(PAL)after lung resection. Methods A total of 97 patients with PAL after lung resection in Beijing Shijitan Hospital from October 2014 to October 2019 were retrospectively reviewed,including 53 treated by autologous blood patch pleurodesis and 44 by the conventional way.The therapeutic effect,adverse reactions and complications were analyzed. Results All the patients with PAL were cured with autologous blood patch pleurodesis.Most air leaks(81.1%)ceased within 48 hours after treatment,and the left 18.9% patients got cured after a repeat.The mean tube retention time and the mean in-hospital stay were 8.4 days and 10.0 days in the autologous blood patch pleurodesis group and 13.5 days and 15.3 days in the conventional treatment group.A prolonged drainage time(P=0.00)and in-hospital stay(P=0.00)were observed in the conventional treatment group.No severe complications were observed except two patients developed slight fever and cutaneous emphysema. Conclusion In our experience,the autologous blood patch pleurodesis is an effective way with low risk of adverse reactions in the treatment of PAL.

[A new nor-sesquiterpene glycoside from Corydalis edulis].

This study is to investigate the chemical constituents from the whole plant Corydalis edulis. The chemical constituents were separated and purified by macroporous resin D101, silica gel, Sephadex LH-20, ODS, and semi-preparative HPLC. Their structures were determined by physicochemical properties and spectroscopic data. Four compounds were isolated from the dichloromethane and water extracts of the whole plant C. edulis, and identified as 6'-ß-D-xylosylicariside B2(1),(3S,5R,6S,7E)-5,6-epoxy-3-hydroxy-7-megastigmen-9-one(2), loliolide(3), and 5,5'-dimethoxybiphenyl-2,2'-diol(4), respectively. Compound 1 is a new compound, of which the absolute configuration was established by electronic circular dichroism(ECD) calculations. Compound 4 is obtained from the plants of Papaveraceae family for the first time. Compounds 2 and 3 are firstly isolated from the Corydalis genus.

Identification of metabolism-associated pathways and genes involved in male and female liver cancer patients.

Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. HCC is influenced by sex and multiple metabolic abnormalities. The present study aimed to compare the overall metabolic changes between male and female HCC patients and identify key metabolic genes. Metabolic genes and pathways were identified based on analyses of publicly available data. Differential expression analysis, gene set enrichment analysis, survival analysis and transcriptional regulation analysis were employed to explore sex differences and identify key metabolic genes in HCC. The results suggested that female patients had more severe metabolic gene expression abnormalities and pathway deregulation than male patients. This study identified 9 key metabolic genes, and only upregulated ALDH1A2 independently increased overall survival risk in patients. Bioinformatic analyses suggest that upregulated GATA3 and TAL1 activate ALDH1A2 and then disrupt amino acid and carbohydrate metabolism, which may increase the risk of HCC. This study identified a novel contribution of upregulated ALDH1A2 to HCC. Future studies are needed to elucidate the potential metabolic mechanism of the role of ALDH1A2 in HCC.

Data Fusion of Fourier Transform Mid-Infrared (MIR) and Near-Infrared (NIR) Spectroscopies to Identify Geographical Origin of Wild Paris polyphylla var. yunnanensis.

Origin traceability is important for controlling the effect of Chinese medicinal materials and Chinese patent medicines. Paris polyphylla var. yunnanensis is widely distributed and well-known all over the world. In our study, two spectroscopic techniques (Fourier transform mid-infrared (FT-MIR) and near-infrared (NIR)) were applied for the geographical origin traceability of 196 wild P. yunnanensis samples combined with low-, mid-, and high-level data fusion strategies. Partial least squares discriminant analysis (PLS-DA) and random forest (RF) were used to establish classification models. Feature variables extraction (principal component analysis-PCA) and important variables selection models (recursive feature elimination and Boruta) were applied for geographical origin traceability, while the classification ability of models with the former model is better than with the latter. FT-MIR spectra are considered to contribute more than NIR spectra. Besides, the result of high-level data fusion based on principal components (PCs) feature variables extraction is satisfactory with an accuracy of 100%. Hence, data fusion of FT-MIR and NIR signals can effectively identify the geographical origin of wild P. yunnanensis.

Ophiopogon Polysaccharide Promotes the In Vitro Metabolism of Ophiopogonins by Human Gut Microbiota.

Gut microbiota play an important role in metabolism of intake saponins, and parallelly, the polysaccharides deriving from herbal products possess effects on gut microbiota. Ophiopogonis Radix is a common Chinese herb that is popularly used as functional food in China. Polysaccharide and steroidal saponin, e.g., ophiopogonin, mainly ophiopogonin D (Oph-D) and ophiopogonin D' (Oph-D'), are the major constituents in this herb. In order to reveal the role of gut microbiota in metabolizing ophiopogonin, an in vitro metabolism of Oph-D and Oph-D' by human gut microbiota, in combination with or without Ophiopogon polysaccharide, was conducted. A sensitive and reliable UPLC-MS/MS method was developed to simultaneously quantify Oph-D, Oph-D' and their final metabolites, i.e., ruscogenin and diosgenin in the broth of microbiota. An elimination of Oph-D and Oph-D' was revealed in a time-dependent manner, as well as the recognition of a parallel increase of ruscogenin and diosgenin. Ophiopogon polysaccharide was shown to stimulate the gut microbiota-induced metabolism of ophiopogonins. This promoting effect was further verified by increased activities of ß-D-glucosidase, ß-D-xylosidase, α-L-rhamnosidase and ß-D-fucosidase in the broth. This study can be extended to investigate the metabolism of steroidal saponins by gut microbiota when combined with other herbal products, especially those herbs enriched with polysaccharides.

Comparison and Identification for Rhizomes and Leaves of Paris yunnanensis Based on Fourier Transform Mid-Infrared Spectroscopy Combined with Chemometrics.

Paris polyphylla, as a traditional herb with long history, has been widely used to treat diseases in multiple nationalities of China. Nevertheless, the quality of P. yunnanensis fluctuates among from different geographical origins, so that a fast and accurate classification method was necessary for establishment. In our study, the geographical origin identification of 462 P. yunnanensis rhizome and leaf samples from Kunming, Yuxi, Chuxiong, Dali, Lijiang, and Honghe were analyzed by Fourier transform mid infrared (FT-MIR) spectra, combined with partial least squares discriminant analysis (PLS-DA), random forest (RF), and hierarchical cluster analysis (HCA) methods. The obvious cluster tendency of rhizomes and leaves FT-MIR spectra was displayed by principal component analysis (PCA). The distribution of the variable importance for the projection (VIP) was more uniform than the important variables obtained by RF, while PLS-DA models obtained higher classification abilities. Hence, a PLS-DA model was more suitably used to classify the different geographical origins of P. yunnanensis than the RF model. Additionally, the clustering results of different geographical origins obtained by HCA dendrograms also proved the chemical information difference between rhizomes and leaves. The identification performances of PLS-DA and the RF models of leaves FT-MIR matrixes were better than those of rhizomes datasets. In addition, the model classification abilities of combination datasets were higher than the individual matrixes of rhizomes and leaves spectra. Our study provides a reference to the rational utilization of resources, as well as a fast and accurate identification research for P. yunnanensis samples.

[Data fusion and multi-components quantitative analysis for identification and quality evaluation of Gentiana rigescens from different geographical origins].

The accumulation of secondary metabolites of traditional Chinese medicine (TCM) is closely related to its origins. The identification of origins and multi-components quantitative evaluation are of great significance to ensure the quality of medicinal materials. In this study, the identification of Gentiana rigescens from different geographical origins was conducted by data fusion of Fourier transform infrared (FTIR) spectroscopy and high performance liquid chromatography (HPLC) in combination of partial least squares discriminant analysis; meanwhile quantitative analysis of index components was conducted to provide an accurate and comprehensive identification and quality evaluation strategy for selecting the best production areas of G. rigescens. In this study, the FTIR and HPLC information of 169 G. rigescens samples from Yunnan, Sichuan, Guangxi and Guizhou Provinces were collected. The raw infrared spectra were pre-treated by multiplicative scatter correction, standard normal variate (SNV) and Savitzky-Golay (SG) derivative. Then the performances of FTIR, HPLC, and low-level data fusion and mid-level data fusion for identification were compared, and the contents of gentiopicroside, swertiamarin, loganic acid and sweroside were determined by HPLC. The results showed that the FTIR spectra of G. rigescens from different geographical origins were different, and the best pre-treatment method was SNV+SG-derivative (second derivative, 15 as the window parameter, and 2 as the polynomial order). The results showed that the accuracy rate of low- and mid-level data fusion (96.43%) in prediction set was higher than that of FTIR and HPLC (94.64%) in prediction set. In addition, the accuracy of low-level data fusion (100%) in the training set was higher than that of mid-level data fusion (99.12%) in training set. The contents of the iridoid glycosides in Yunnan were the highest among different provinces. The average content of gentiopicroside, as a bioactive marker in Chinese pharmacopoeia, was 47.40 mg·g⁻¹, and the maximum was 79.83 mg·g⁻¹. The contents of loganic acid, sweroside and gentiopicroside in Yunnan were significantly different from other provinces (P<0.05). In comparison of total content of iridoid glycosides in G. rigescens with different geographical origins in Yunnan, it was found that the amount of iridoid glycosides was higher in Eryuan Dali (68.59 mg·g⁻¹) and Yulong Lijiang (66.68 mg·g⁻¹), significantly higher than that in Wuding Chuxiong (52.99 mg·g⁻¹), Chengjiang Yuxi (52.29 mg·g⁻¹) and Xundian Kunming (46.71 mg·g⁻¹) (P<0.05), so these two places can be used as a reference region for screening cultivation and excellent germplasm resources of G. rigescens. A comprehensive and accurate method was established by data fusion of HPLC-FTIR and quantitative analysis of HPLC for identification and quality evaluation of G. rigescens, which could provide a support for the development and utilization of G. rigescens.

[Phenylpropanoid amides from whole plants of Corydalis edulis].

Ten phenylpropanoid amides were isolated from the whole plants of Corydalis edulis Maxim. by various of column chromatographies including silica gel, Sephadex LH-20, and ODS. Their structures were identified on the basis of physicochemical properties, MS, NMR, and IR spectroscopic data. These compounds were identified as N-trans-sinapoyl-3-methoxytyramine-4'-O-ß-glucoside(1), N-trans-sinapoyl-3-methoxytyramine(2), N-trans-sinapoyltyramine(3), N-trans-p-coumaroyltyramine(4), N-trans-sinapoyl-7-hydroxytyramine(5), N-cis-feruloyltyramine(6), N-cis-p-coumaroyltyramine(7), N-trans-feruloyltyramine(8), N-trans-feruloyl-3-methoxytyramine(9), and N-trans-feruloyl-7-hydroxytyramine(10). Compound 1 is a new compound. Compounds 2-7 are obtained from the plants of Papaveraceae for the first time, while compounds 8-10 are firstly isolated from C. edulis.

Clinical, cellular, and bioinformatic analyses reveal involvement of WRAP53 overexpression in carcinogenesis of lung adenocarcinoma.

Lung cancer, of which non-small cell lung cancer accounts for 80%, remains a leading cause of cancer-related mortality and morbidity worldwide. Our study revealed that the expression of WD repeat containing antisense to P53 (WRAP53) is higher in lung-adenocarcinoma specimens than in specimens from adjacent non-tumor tissues. The prevalence of WRAP53 overexpression was significantly higher in patients with tumor larger than 3.0 cm than in patients with tumor smaller than 3.0 cm. The depletion of WRAP53 inhibits the proliferation of lung-adenocarcinoma A549 and SPC-A-1 cells via G1/S cell-cycle arrest. Several proteins interacting with WRAP53 were identified through co-immunoprecipitation and liquid chromatography/mass spectrometry. These key proteins indicated previously undiscovered functions of WRAP53. These observations strongly suggested that WRAP53 should be considered a promising target in the prevention or treatment of lung adenocarcinoma.

Hint1 suppresses migration and invasion of hepatocellular carcinoma cells in vitro by modulating girdin activity.

Histidine triad nucleotide-binding protein 1 (Hint1) is a haploinsufficient tumor suppressor gene. Its role in cancer cell migration has not been previously speculated. In the current study, we examined the expression of Hint1 in metastatic and non-metastatic lymph nodes of hepatocellular carcinoma (HCC) patients and further elucidated the effect of Hint1 expression on girdin expression and phosphorylation of AKT and ERK1/2 and on the migration of HCC cells in vitro. Expression of Hint1 and girdin in primary HCC tissues and metastatic and non-metastatic lymph nodes was determined by RT-PCR assays. HepG2 cells were transfected with plasmid vectors overexpressing Hint1 or small interfering RNA (siRNA) targeting Hint1, girdin, Hint1 plus girdin, or the scrambled RNA. Migration and invasion of HCC cells were examined by wound and Transwell assays. Protein expression was detected by immunofluorescence and immunoblotting assays. RT-PCR assays revealed that the messenger RNA (mRNA) transcript levels of Hint1 were markedly lower than those of primary HCC tissues and non-metastatic lymph nodes (P < 0.01). By contrast, the mRNA transcript levels of girdin were significantly higher than non-metastatic lymph nodes (P < 0.05). Furthermore, siRNA knockdown of HINT1 resulted in a significant increase in the mRNA transcript levels of girdin in HepG2 cells (P < 0.05). Wound assays and Transwell assays showed that Hint1 knockdown by siRNA significantly enhanced the migration and invasion of HepG2 cells compared to HepG2 cells transfected with scrambled siRNA. Hint1 knockdown also led to significantly increased phosphorylation of girdin and AKT in HepG2 cells (P < 0.05), which, however, was effectively aborted by girdin knockdown by siRNA (P < 0.05). Hint1 is downregulated in metastatic lymph nodes and is implicated in migration and invasion of HCC cells in vitro by modulating girdin and AKT expression and phosphorylation. The Hint1-girdin-AKT signaling axis should be further dissected for its role in HCC migration and invasion and may be therapeutically targeted to suppress tumor growth and metastasis.

Downregulation of RUVBL1 inhibits proliferation of lung adenocarcinoma cells by G1/S phase cell cycle arrest via multiple mechanisms.

Lung cancer remains a leading cause of cancer-related mortality and morbidity worldwide, of which non-small cell lung cancer (NSCLC) accounts for 80 %. RUVBL1 is a highly conserved eukaryotic AAA+ adenosine 5'-triphosphatase (ATPase) that has many functions highly relevant to cancer. We therefore attempted to determine the potential role of RUVBL1 in the biogenesis of lung adenocarcinoma and obtained some interesting results. Our study revealed that RUVBL1 expression was higher in lung adenocarcinoma specimens than in those of adjacent non-tumor tissues and in lung cancer cell lines than in normal lung cell lines. RUVBL1 knockdown via siRNA reduced proliferation and caused G1/S phase cell cycle arrest in lung adenocarcinoma cell lines. The G1/S phase cell cycle arrest triggered by RUVBL1 downregulation could be attributed, at least in part, to repression of the AKT/GSK-3ß/cyclin D1 pathway and probably to the activation of IRE1α-mediated endoplasmic reticulum (ER) stress. We thus demonstrated for the first time that a knockdown of RUVBL1 could effectively inhibit the proliferation of lung adenocarcinoma A549 and H292 cells through the induction of G1/S phase cell cycle arrest via multiple mechanisms. These observations strongly suggested that RUVBL1 should be considered a promising target for the prevention or therapy of lung adenocarcinoma.

Investigation of chemical diversity in different parts and origins of ethnomedicine Gentiana rigescens Franch using targeted metabolite profiling and multivariate statistical analysis.

Gentiana rigescens, an ethnomedicine, is widely cultivated in Yunnan province of China. Although a wide range of metabolites including iridoid glycosides, flavonoids and triterpenoids have been reported in this ethnomedicine, the data on accumulation and distribution of metabolites in certain parts are limited. In this study, targeted metabolic fingerprinting of iridoid glycosides based on liquid chromatography-ultraviolet detection-tandem mass spectrometry (LC-UV-MS/MS) was developed to investigate the metabolic similarities and differences in different parts and origins. Thirty-one compounds, including iridoid glycosides and flavonoids, were detected from targeted metabolite profiling and plausibly assigned to the different parts of G. rigescens. Multivariate statistical analysis was designed to reveal close chemical similarities between all the selected samples and to identify key metabolites characteristic of the standard. The results suggested that accumulation and distribution of metabolites in aerial and underground parts were different. Moreover, root samples tended to be grouped on the basis of the geographical closeness of region. Five metabolites can be considered as potential markers for the classification of underground parts from different regions. These results provided chemical information on the potential pharmaceutical value for further research, making G. rigescens ideal for the rational usage of different parts and exploitation of the source.