[Research prospect of preclinical model construction and precision therapy in ameloblastoma].

Ameloblastoma (AM) is a benign odontogenic tumor with unknown etiology. It is prone to recurrence and has a potential for malignant transformation. Patients often show high rates of relapse after curettage, or suffer from structural and functional damage of jaw after partial resection. Whole-genome sequencing data revealed that BRAF mutations and SMO mutations were common and likely to be mutually exclusive in AM. It was also reported that BRAF inhibitors were effective in several patients carrying BRAFV600E mutation. However, reliable preclinical models are urgently needed for exploring targeted therapy as it's so difficult to conduct large clinical trials in this tumor. Patient-derived cell models in vitro and xenograft models in vivo are frequently used preclinical models. In fact, benign tumor cells generally showed a finite proliferative capacity in two-dimensional culture, and most likely, they could exhibit altered cellular phenotype after immortalization. Moreover, this benign tumor presented low chances of subcutaneous engraftment in nude mice. Accordingly, humanized mouse xenograft model needs more exploration. Yet, it is worth mentioning that a three-dimensional organoid model presents a high potential in culturing stem-cell-like epithelial cells in AM, and it would further be used in recapitulating corresponding tumors and developing targeted medicines. In this paper, we review research progress in preclinical models and the genetic variations of AM, and raise drug screening prospect of the current organoid models, which may pave the way for the possible personalized medicine in AM.

Nomograms for predicting survival in patients with gastric carcinoid or neuroendocrine carcinoma based on the SEER database.

OBJECTIVE: The aim of this study was to construct a competent model that can effectively predict the prognosis of patients with gastric carcinoid (GC) or neuroendocrine carcinoma (NEC). PATIENTS AND METHODS: Data of patients with GC or NEC were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2017. Univariable and multivariable Cox analysis was used to determine the independent factors for patients with GC or NEC. Nomograms were established based on the independent factors and the results were evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: A total of 214 patients with GC and 65 patients with gastric NEC were extracted from the SEER database. Independent prognostic factors for patients with GC were M stage, gender, age, and chemotherapy. Independent prognostic factors for patients with gastric NEC included age, M stage, and chemotherapy. ROC curves, calibration curves, and DCA confirmed that the nomograms can precisely predict the prognosis of patients with GC and NEC. CONCLUSIONS: The nomograms can effectively predict survival in patients with GC or NEC, which may assist the clinician in their decision-making and quantitatively judge the prognosis of individual patients.

[A prospective cohort study on the association between grip strength and cognitive function in adults aged 50 years and above].

Objective: To evaluate the association between grip strength (GS) and cognitive function in a population-based longitudinal cohort of Chinese adults aged ≥50 years. Methods: The study population of 3 600 adults was from the baseline survey and two rounds of follow up of World Health Organization (WHO) study of global ageing and adult health (SAGE) in five districts of Shanghai (Hongkou, Huangpu, Minhang, Qingpu and Pudong) after excluding individuals with self-report stroke and depression. The effects of baseline GS on cognitive function and its changes were evaluated. Factor analysis was applied to generate an overall cognition score based on verbal recall trials, verbal fluency test, forward digit span test and backward digit span test. Linear mixed effects model was used to examine the predictive capability of baseline GS for changes in cognitive function. Results: A total of 3 600 participants aged (61.2±8.1) years at baseline survey were included in this study, including 1 668 (46.3%) men and 1 932 (53.7%) women. The average of baseline GS and total cognitive function score were (28.19±12.18) kg and (58.93±14.56) respectively. Cognitive function score declined significantly during the follow-up, however, the changes were different among different age groups, education level groups and household income groups. After adjusted for age, education level, marital status, household income, co-morbidity of chronic conditions, drinking status, smoking status, physical activity level, vegetable/fruit intakes and BMI, no relationships between the baseline GS and cognitive score at baseline survey and at 1st follow-up were observed, however, compared with lower GS quartile group, there was a significant relationship between higher baseline GS level and better cognitive function at 2nd follow-up. The participants with highest GS quartile had better cognitive performance over time (male: ß=1.938,95%CI:0.644-3.231,P=0.003, female: ß=2.192,95%CI:0.975-3.409,P<0.001 and those aged 50-64 years: ß=1.652,95%CI:0.646-2.659,P=0.001) than those with the lowest quartile. Conclusions: Higher baseline GS was significantly related to better cognitive function with slow decline. Thus, it is an indicator of cognitive function in middle-aged and elderly Chinese.

[Expression and clinical significance of CXC chemokine ligand 10 in glioma].

Objective: To analyze the expression of CXC chemokine ligand 10 (CXCL10) in glioma and its clinical significance through bioinformatics. Methods: The expression level of CXCL10 in glioma, and its prognostic significance, gene ontology (GO) function annotation, Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment and the correlation of tumor cell purity were analyzed in TCGA, CGGA, MetaScape, TIMER databases. In addition, 34 clinical glioma tissues were collected for Western Blot and immunohistochemistry to further verify the correlation between CXCL10 and glioma. Results: CGGA and TCGA database analysis showed that with the increase of WHO grade, the expression of CXCL10 in gliomas increased (P<0.01). The overall survival rate of patients with high CXCL10 expression was significantly lower than that of patients with low expression (χ2 =148.1,P<0.05). Among patients with grade Ⅳ glioblastoma who received radiotherapy or chemotherapy, the patients with low CXCL10 expression were associated with good survival (χ2 =6.714,P<0.05;χ2 =5.618,P<0.05). Moreover, GO and KEGG analysis showed that genes co-expressed with CXCL10 were mainly enriched in the biological processes such as cytokine-mediated signaling pathways, regulating adaptive immune responses and inflammatory responses. Furthermore, TIMER database analysis showed that CXCL10 was negatively correlated with the purity of glioma cells (LGG: r=-0.129;GBM: r=-0.165;P<0.05). Similarly, clinical sample analysis also showed that the expression level of CXCL10 increased in glioma, and it increased with the grade of glioma (all P<0.05). Conclusion: The expression of CXCL10 is up-regulated in glioma as well as it increased with the malignant degree of glioma. At the same time, the high expression of CXCL10 in glioma is closely related to the poor prognosis of patients.

[Association between grip strength, rapid gait speed and cognition in people aged 50 and above in Shanghai during 2009-2010].

Objective: To investigate the association between grip strength, rapid gait speed and cognition in people aged 50 and above in Shanghai. Methods: Cross-sectional data was collected from the World Health Organization (WHO) study on global ageing and adult health (SAGE) wave 1 (2009-2010). A questionnaire survey was conducted among 8 643 participants aged 50 years old and above selected by using multistage random cluster sampling strategies in Shanghai. Factor analysis was applied to evaluate and generate cognitive function overall score.Association between grip strength, rapid gait speed and cognition was examined by a two-level hierarchical linear model. Results: A total of 8 175 participants were included in this study, who were (62.9±9.7) years old, including 3 782 (46.3%) males. The average grip strength and rapid gait speed of participants were (27.46±12.01) kg and (1.44±0.43) m/s respectively. The average scores of verbal recall (VR), verbal fluency (VF), forward digit span (FDS), backward digit span (BDS) and total cognitive scores were (5.72±0.09), (12.67±0.35), (6.84±0.10), (4.32±0.14) and (60.50±0.95) respectively. Grip strength was positively associated with VR, VF, FDS, BDS and overall cognition (standardized ß=0.036, 0.079, 0.042, 0.046 and 0.043 respectively, P<0.05), and rapid gait speed was also positively associated with VR, VF and overall cognition (standardized ß=0.040, 0.031, 0.039 respectively, P<0.05) after adjusted for age, sex, residence, education level, marital status, household income, co-morbidity of chronic conditions, BMI, drinking, smoking, fruits, vegetables intake and physical activities. Conclusion: Grip strength and rapid gait speed are both positively associated with cognitive function of people aged 50 and above, which would be indicators to evaluate their cognition.

ROS Plays a Role in the Neonatal Rat Intestinal Barrier Damages Induced by Hyperoxia.

BACKGROUND: Hyperoxia treats a subset of critical neonatal illnesses but induces intestinal damage in neonatal pups. In this process, the intestinal flora and mucosal epithelium might be altered by hyperoxia. So the changes of the intestinal flora and mucosal epithelium were studied. METHODS: Neonatal rats were randomized into the model group that was exposed to hyperoxia and the control group that was maintained under normoxic conditions; then, intestinal lavage fluid and intestinal tissues were harvested. ELISA was used to detect D-lactic acid (D-LA), endotoxin (ET), diamine oxidase (DAO), intestinal fatty acid binding protein (i-FABP), liver-type fatty acid binding protein (L-FABP) and cytokines in the intestinal lavage of neonatal rats during hyperoxia. The intestinal zonula occluden-1 (ZO-1), occlusion protein (Occludin), and closure protein-4 (Claudin-4) of neonatal pups were detected by immunohistochemistry, western blotting, and real-time Polymerase chain reaction (RT-PCR) during hyperoxia. NCM460 cell survival rates were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) during hyperoxia and administration of N-acetyl-L-cysteine (NAC). The expression levels of ZO-1, Occludin, and Claudin-4 in NCM460 cells were detected by immunohistochemistry, western blotting, and RT-PCR during hyperoxia and NAC. RESULTS: D-LA, ET, L-FABP, i-FABP, DAO, TNF-α, IL-10, and IFN-γ were significantly increased by hyperoxia, while ZO-1, Occludin, and Claudin-4 were clearly decreased in the hyperoxia group compared with the control group. NAC promoted cell survival, which was inhibited by hyperoxia. The cellular expression levels of ZO-1, Occludin, and Claudin-4, which were lowered by hyperoxia, were increased by NAC. CONCLUSION: Hyperoxia causes injury of the intestinal mucosa, and ROS plays a role in this intestinal damage during hyperoxia.

hUC-MSCs secreted exosomes inhibit the glioma cell progression through PTENP1/miR-10a-5p/PTEN pathway.

OBJECTIVE: The mesenchymal stem cells (MSCs) have been widely studied for their anti-tumor property, due to the characteristic of homing towards tumor sites and immunosuppression. Nevertheless, the underlying molecular mechanisms that link MSCs to the targeted tumor cells, such as glioma, are not clear. MATERIALS AND METHODS: Here, we examined the inhibitory properties and new molecular mechanisms of the human umbilical cord (hUC-MSCs) derived exosomes on the human glioma U87 cells using a co-culture system in vitro. The cell counting kit-8 (CCK-8) assay was performed to measure the anti-tumor activity of hUC-MSCs derived exosomes. The cell apoptosis was assessed by flow cytometry and the immunoblotting assay was applied in order to assess the associated proteins level. The data revealed that hUC-MSCs derived exosomes could repress cell proliferation and induce cell apoptosis. RESULTS: Mechanistically, we identified that lncRNA PTENP1 could be packaged into exosome from hUC-MSCs, transferred to U87 cells, and then stabilized PTEN by binding miR-10a-5p competitively. CONCLUSIONS: Therefore, our data suggested that the exosomes from hUC-MSCs possess a higher anti-tumor capacity, at least partially, via regulating miR-10a-5p/PTEN signaling, which thereby may represent a possible target for early diagnosis and treatment of glioma clinically.

[Association between edentulism and cognition among people aged 50 and over].

Objective: To investigate the association between edentulism and cognition in people aged 50 and over in China. Methods: Cross-sectional data was collected from the first wave of World Health Organization Study on global AGEing and adult health in China, among people aged 50 and over in China. A comprehensive cognitive test was used to assess cognitive functions, including verbal recall (VR), verbal fluency (VF), forward digit span (FDS) and backward digit span (BDS) among the subjects. Association between edentulism and cognition was examined by a two-level (individual level and community level) linear model. Results: A total of 12 843 individuals aged 50 years and over were included for analysis, with an average age of (63.0±9.3) years. The overall prevalence of edentulism was 11.0%. The edentulous adults had lower mean scores of VR (4.55), VF (10.88), FDS (6.25), BDS (2.96) and overall cognition (49.15) (P<0.001). Edentulism was negatively associated with VR (ß=-0.216, 95%CI: -0.370 - -0.062), FDS (ß=-0.186, 95%CI: -0.293 - -0.078) and overall cognition (ß=-1.703, 95%CI: -3.025 - -0.381) after adjusted for age, sex, residence, education level, marital status, household income, co-morbidity of chronic conditions, BMI, smoking and drinking alcohol. Conclusion: Edentulism was related with lower cognition level in people aged 50 and over in China.

[Association between low handgrip strength and air pollution among people aged 50 years and over].

Objective: To examine the association between long-term exposure to ambient PM(2.5) combined with indoor air pollution and handgrip strength among people aged 50 and over. Methods: Data were from the first wave of World Health Organization Study on global AGEing and adult health in China. Ambient annual concentration of PM(2.5) was estimated by using the satellite data we also investigated the use of fuels and chimneys as indoor air pollution. A two-level (individual level and community level) linear model was applied to examine the association between long-term exposure to ambient PM(2.5) combined with indoor air pollution and the handgrip strength. Results: A total of 13 175 individuals aged 50 years and over were included for analysis. The handgrip strength was (26.67±0.54) kg. Ambient PM(2.5) was found to be significantly associated with the risk of decreased handgrip strength. Outdoor PM(2.5) concentration was negatively correlated with handgrip strength (ß=-0.23, 95%CI: -0.31 - -0.14) decrease in handgrip strength after adjusting for gender, age, residence, education, household assets, intake of vegetables and fruits, smoking and drinking, physical activity. In rural area, compared to those who used solid fuel, use of clean fuel increased (ß=1.41, 95%CI: 0.36-2.46) handgrip strength. But in urban area, we did not find any statistically significant association between the use of clean fuel and handgrip strength (ß=0.19, 95%CI: -0.95-1.32). Conclusion: This study found that long-term exposure to ambient PM(2.5) combined with indoor air pollution was significantly associated with low handgrip strength among people aged 50 years and over, this suggested that ambient PM(2.5) might serve as one of the risk factors for low physical function seen in the people aged 50 years and over.

[Association between frailty and sleep duration among people aged 50 years and over].

Objective: To investigate the association between sleep duration and frailty among people aged 50 years and over. Methods: Cross-sectional data was collected from the first wave of World Health Organization Study on global AGEing and adult health in China. Frailty index was constructed on the proportion of deficits, out of the 40 variables. A two-level (individual level and community level) linear model was performed to identify the related factors on frailty. All the models were stratified by age, gender, residence (urban/rural). Restricted cubic spline was performed to graphically evaluate the dose-response association between self-reported sleep duration and frailty. Results: A total of 13 175 individuals aged 50 years and over participated in this study. Without adjusting on any confounding factors, shorter or longer sleep duration significantly increased the risk of weakness compared with normal sleep time (OR=2.05, 95%CI: 1.71-2.44; OR=1.35, 95%CI: 1.12-1.63). After adjusting for confounding factors such as gender, age, residence, education, family assets, vegetable, smoking, drinking and physical activity, a positive association between short sleep duration and frailty was noticed compared with normal sleep time (aOR=1.60, 95%CI: 1.27-2.01). The results of stratified analysis on sex, age and urban and rural areas showed that, after adjusting for gender, age, residence, education level, family assets, intake of vegetables and fruits, smoking, drinking and physical activity, only shorter sleep duration was positively correlated with the risk of weakness. In addition, among people aged 65 years and over, adjusted for confounding factors, the risk of weakness increased by 91%, compared with normal sleep time (aOR=1.91, 95%CI: 1.46-2.49). The dose-response curve also showed that the sleep duration and frailty present an approximate "U" shaped relationship. Conclusion: Short sleep duration might be associated with frailty.

[Clinicopatholigic features of renal cell carcinoma associated with chromosome X inversion harboring gene fusions involving TFE3].

Objective: To study the clinicopathologic features, immunophenotype, characteristic FISH pattern and prognosis of renal cell carcinoma (RCC) associated with chromosome X inversion harboring gene fusions involving TFE3. Methods: Ten cases of NONO-TFE3 RCC and four cases of RBM10-TFE3 RCC were investigated at Nanjing Jinling Hospital from 2009 to 2016 by clinicopathological findings, immunohistochemistry, and genetic analysis. Results: Morphologically, the distinct pattern of secretory endometrioid subnuclear vacuolization was overlapped with clear cell papillary RCC, and often accompanied by sheets of epithelial cells in NONO-TFE3 RCC. Most cases of RBM10-TFE3 RCC presented with the biphasic feature that acinar, tubular and papillary patterns of epithelioid cells combined with sheets of small cells with "pseudorosette-like" architectures. In addition, cytoplasmic vacuolization, nuclear groove, and psammoma bodies were also observed. Immunohistochemically, all NONO-TFE3 RCC cases were immunoreactive for TFE3, CD10, RCC markers, and PAX8, and negative for CK7, Cathepsin K, Melan A, HMB45, Ksp-cadherin, vimentin, and CD117. All 4 cases of RBM10-TFE3 RCC showed moderate to strong immunoreactivity for TFE3, Cathepsin K, CD10, Ksp-cadherin, E-cadherin, P504s, RCC marker, PAX8, and vimentin but negative for TFEB, HMB45 and CK7. CKpan and Melan A were at least focally expressed. The antibody to Ki-67 showed labeling of 3%-8% (mean 5%). There were some expression discrepancies of immunochemistry between different histological patterns. PAX8, CKpan, P504s, and Ksp-cadherin were expressed in epithelioid areas but not in small-cell areas. Ki-67 labeling index of epithelioid areas was higher than that in small-cell areas. In molecular analysis, NONO-TFE3 fusion transcripts were identified in 6 patients. The fusion points were between exon 7 of NONO and exon 6 of TFE3 in 5 patients and between exon 9 of NONO and exon 5 of TFE3 in one patient. All 4 cases of RBM10-TFE3 RCC demonstrated to have RBM10-TFE3 fusion transcripts and the fusion points were between exon 5 of TFE3 and exon 17 of RBM10. Using TFE3 break-apart FISH assay, all 10 cases of NONO-TFE3 RCC showed characteristic patterns of equivocal split signals with a distance of nearly 2 signal diameters. All 4 cases of RBM10-TFE3 RCC showed colocalized or subtle split signals with a distance of <1 signal diameter, which was considered as negative results. Long-term follow-up was available for 7 patients of NONO-TFE3 RCC and 4 patients of RBM10-TFE3 RCC. All patients were alive with no evidence of disease. Conclusions: Two rare genotypes, NONO-TFE3 RCC and RBM10-TFE3 RCC, are reported in this study. Both of these two tumors show specific morphology and good prognosis, along with the positive TFE3 staining and the equivocal or false-negative TFE3 FISH results, which could be missed. PCR detection or next-generation sequencing can determine the genotype.

The clinical implications of mean platelet volume and mean platelet volume/platelet count ratio in locally advanced esophageal squamous cell carcinoma.

As a hallmark of platelet activation, mean platelet volume (MPV) has been identified to be associated with various malignancies. However, the correlation between MPV, mean platelet volume/platelet count ratio (MPR), and esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study is to clarify the relevance of MPV and MPR in patients with locally advanced ESCC. Four hundred and fifty-seven cases with newly diagnosed locally advanced ESCC followed by radical surgery and 240 healthy subjects matched for age and gender were included in this study. We retrospectively compared various hematological variables between groups and analyzed the correlation between MPV, MPR, and patients' clinicopathologic characteristics. Preoperative MPV and MPR were found to be significantly decreased in locally advanced ESCC when compared to healthy controls, they were (8.14 ± 1.09 fL vs. 10.23 ± 0.78 fL, P < 0.0001) and (0.03875 ± 0.02645 vs. 0.04463 ± 0.00972, P = 0.001), respectively. In addition, patients with advanced tumor length (≥4 cm) tended to have lower MPV levels (8.03 ± 1.11 fL versus 8.33 ± 1.21 fL, P = 0.005), while there was no difference between other subgroups. Moreover, decreased MPR was significantly correlated with advanced tumor length (P < 0.001) when divided at a median of 0.03420. Decreased MPV and MPR were significantly associated with locally advanced ESCC. Thus, they might be helpful in screening and risk stratification for locally advanced ESCC in combination with other approaches.

14-3-3ζ binds the proteasome, limits proteolytic function and enhances sensitivity to proteasome inhibitors.

14-3-3 proteins are a family of master regulators of intracellular signaling, yet their impact on proteasome function is unknown. We demonstrate that 14-3-3ζ binds the 11S proteasome activator, limiting proteasome assembly and cellular capacity for protein degradation. To define the functional impact of 14-3-3ζ proteasomal binding in myeloma cells, silencing and overexpression experiments are performed. We find that downregulation of 14-3-3ζ impairs myeloma cell growth and confers resistance to clinically used proteasome inhibitors. In a large cohort of newly diagnosed myeloma patients, elevated expression of 14-3-3ζ is associated with high risk myeloma genetic subtypes and worse prognosis overall. Our work demonstrates the important role of 14-3-3ζ in regulating proteasome function, myeloma cell growth and sensitivity to therapeutics, and suggests regulation of 14-3-3ζ as a new approach in myeloma therapy.

The use of lncRNA analysis for stratification management of prognostic risk in patients with NSCLC.

OBJECTIVE: Lung cancer is the most frequent cancer in China and worldwide. Long noncoding RNAs (lncRNAs) have been shown to play important regulatory roles in human cancer biology. The aim of the present study was to investigate the relationship between genomics and prognosis among lung cancer patients. PATIENTS AND METHODS: We collected specimens from non-small cell lung cancer (NSCLC) patients after surgery. Q-PCR was performed to investigate the expression level of lncRNAs in cancerous and adjacent normal tissue. Patients were divided into different risk groups according to lncRNA expression levels and then follow-up. RESULTS: The lncRNAs HOTAIR, H19 and MALAT1 were up-regulated, while PANDAR and TUG1 were down-regulated in NSCLC cancer tissues compared with the corresponding adjacent normal tissue. After two years of follow-up time, the disease-free survival time (DFS) curves were significantly different between the high-risk, moderate-risk and low-risk patient groups. CONCLUSIONS: Our results suggest that lncRNAs are involved in the process of NSCLC and that the use of genetic analysis for stratification management of prognostic risk could help us to implement individualized treatment for patients with NSCLC and ultimately to improve the patient prognosis.

[Efficiency and adverse effects of the effective therapy applying etoposide + cisplatin and its subsequent maintenance therapy with different durations in patients with small cell lung cancer].

OBJECTIVE: To explore the efficiency and adverse effects of the effective EP (etoposide + cisplatin) therapy and its subsequent maintenance therapy with different durations in patients with small cell lung cancer (SCLC). METHODS: Clinical data of 104 SCLC patients diagnosed and treated at the Jilin Province Cancer Hospital between September 2010 and December 2013 were retrospectively analyzed.Among them, 35 patients were subsequently treated with a 4-week maintenance therapy following the original therapeutic regimen after the effective EP therapy (4-week maintenance therapy group), 35 patients were treated with a subsequent 6-week maintenance therapy (6-week maintenance therapy group), and 34 patients were treated without maintenance therapy (control group).52 patients were in limited stage, and 52 patients were in extensive stage. The progression-free survival (PFS), overall survival (OS) and adverse effects in the 4-week maintenance therapy group, 6-week maintenance therapy group and control group were analyzed. RESULTS: The median PFS in the control group, 4-week maintenance therapy group and 6-week maintenance therapy group was 4.0, 3.5, and 4.0 months, respectively, and the median OS was 9.0, 10.0 and 12.0 months, respectively, showing no significant difference among the groups (P>0.05 for all). The median PFS was prolonged by 2 months as compared with the control group after the 4-week maintenance therapy in the patients with complete remission in first-line chemotherapy (P=0.041), while the median OS was not improved (P=0.131). Neither the median PFS nor median OS showed statistically significant difference between each two groups in the patients with partial remission in first-line chemotherapy (P>0.05 for all). In the limited stage, the median PFS in the control group, 4-week maintenance therapy group, and 6-week maintenance therapy group was 5.0, 6.5, and 4.0 months, respectively, and median OS was 11.0, 13.5, and 13.0 months, respectively, the differences showed no statistical significance (P>0.05 for all). In the extensive stage, the median PFS in the control group, 4-week maintenance therapy group, and 6-week maintenance therapy group was 3.0, 3.0, and 3.5 months, respectively, showing significant differences (P=0.015); the median OS was 6.5, 8.0, and 8.0 months, respectively, presenting no statistically significant differences (P=0.096). In addition, the PFS in the 6-week maintenance therapy group was significantly improved as compared with that in the control group (P=0.016). Compared with the control group, the incidence rates of nausea (grade 3-4), vomiting, hypodynamia, leukopenia, neutropenia, and thrombocytopenia in the 4-week maintenance therapy group and 6-week maintenance therapy group were increased significantly (P<0.05 for all), however, the side effects were tolerable. CONCLUSION: Prolonging the treatment cycle of EP therapy can improve the PFS in SCLC patients in first-line CR chemotherapy and extensive stage.

Inhibition of mTOR complex 2 induces GSK3/FBXW7-dependent degradation of sterol regulatory element-binding protein 1 (SREBP1) and suppresses lipogenesis in cancer cells.

Cancer cells feature increased de novo lipogenesis. Sterol regulatory element-binding protein 1 (SREBP1), when presented in its mature form (mSREBP1), enhances lipogenesis by increasing transcription of several of its target genes. Mammalian target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, are master regulators of cellular survival, growth and metabolism. A role for mTORC1 in the regulation of SREBP1 activity has been suggested; however, the connection between mTORC2 and SREBP1 has not been clearly established and hence is the focus of this study. mTOR kinase inhibitors (for example, INK128), which inhibit both mTORC1 and mTORC2, decreased mSREBP1 levels in various cancer cell lines. Knockdown of rictor, but not raptor, also decreased mSREBP1. Consistently, reduced mSREBP1 levels were detected in cells deficient in rictor or Sin1 compared with parent or rictor-deficient cells with re-expression of ectopic rictor. Hence it is mTORC2 inhibition that causes mSREBP1 reduction. As a result, expression of the mSREBP1 target genes acetyl-CoA carboxylase and fatty-acid synthase was suppressed, along with suppressed lipogenesis in cells exposed to INK128. Moreover, mSREBP1 stability was reduced in cells treated with INK128 or rictor knockdown. Inhibition of proteasome, GSK3 or the E3 ubiquitin ligase, FBXW7, prevented mSREBP1 reduction induced by mTORC2 inhibition. Thus mTORC2 inhibition clearly facilitates GSK3-dependent, FBXW7-mediated mSREBP1 degradation, leading to mSREBP1 reduction. Accordingly, we conclude that mTORC2 positively regulates mSREBP1 stability and lipogenesis. Our findings reveal a novel biological function of mTORC2 in the regulation of lipogenesis and warrant further study in this direction.

Inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs response of cancer cells to DR5-mediated apoptosis and T cell-induced killing.

Inhibition of B-Raf/MEK/ERK signaling is an effective therapeutic strategy against certain types of cancers such as melanoma and thyroid cancer. While demonstrated to be effective anticancer agents, B-Raf or MEK inhibitors have also been associated with early tumor progression and development of secondary neoplasms. The ligation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with its receptor, death receptor 5 (DR5), leading to induction of apoptosis, offers a promising anticancer strategy. Importantly, this is also a natural immunosurveillance mechanism against cancer development. We previously demonstrated that activated B-Raf/MEK/ERK signaling positively regulates DR5 expression. Hence, our current work sought to address whether B-Raf/MEK/ERK inhibition and the consequent suppression of DR5 expression impede cancer cell response to DR5 activation-induced apoptosis and activated immune cell-induced killing. We found that both B-Raf (for example, PLX4032) and MEK inhibitors (for example, AZD6244 and PD0325901) effectively inhibited ERK1/2 phosphorylation and reduced DR5 levels in both human thyroid cancer and melanoma cells. Similar to the observed effect of genetic knockdown of the B-Raf gene, pre-treatment of cancer cell lines with either B-Raf or MEK inhibitors attenuated or abolished cellular apoptotic response induced by TRAIL or the DR5 agonistic antibody AMG655 or cell killing by activated T cells. Our findings clearly show that inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs DR5 activation-induced apoptosis and T cell-mediated killing of cancer cells. These findings suggest a potential negative impact of B-Raf or MEK inhibition on TRAIL- or DR5-mediated anticancer therapy and on TRAIL/DR5-mediated immune-clearance of cancer cells.

Diagnosis of ovarian metastasis from gestational trophoblastic neoplasia by 3D power Doppler ultrasound and dynamic contrast-enhanced magnetic resonance imaging: case report.

Choriocarcinoma is a highly malignant disease of trophoblastic cells, which affects young women in the reproductive years. The main sites of metastasis from choriocarcinoma are lung, vagina, liver, gastrointestinal tract and kidneys, and the involvement of the ovaries is extremely rare. The diagnosis of ovarian metastasis is made mainly by two-dimensional ultrasonography (2DUS) with color Doppler, which shows a large vessel in the center of the mass. The three-dimensional power Doppler ultrasound (3D power Doppler) and dynamic contrast-enhanced magnetic resonance imaging (MRI) are new diagnostic modalities not yet published in literature. We report a case of metastatic choriocarcinoma with left ovary involvement in a 48-year-old woman with history of molar pregnancy and irregular follow-up of this disease. We emphasize the main findings by 2DUS with color Doppler, 3D power Doppler and dynamic contrast-enhanced MRI. 3D power Doppler is able to improve the assessment of anatomical relationships of vessels with the ovarian mass, while the resonance angiography allows us to evaluate the anatomic relations of the mass and adjacent structures, as well as the iliac vessels. The 3D power Doppler and dynamic contrast-enhanced MRI are promising methods in the evaluation of metastasis arising from gestational trophoblastic tumors.

Oncogenic role of EAPII in lung cancer development and its activation of the MAPK-ERK pathway.

Cancer progression involves multiple complex and interdependent steps, including progressive proliferation, angiogenesis and metastases. The complexity of these processes requires a comprehensive elucidation of the integrated signaling networks for better understanding. EAPII interacts with multiple cancer-related proteins, but its biological significance in cancer development remains unknown. In this report we identified the elevated level of EAPII protein in non-small-cell lung carcinoma (NSCLC) patients and NSCLC cell lines in culture. The oncogenic role of EAPII in lung cancer development was demonstrated using NSCLC cells with genetic manipulations that influence EAPII expression: EAPII overexpression increases proliferation of NSCLC cells with an accelerated transition of cell cycle and facilitates xenograft tumor growth in vivo; EAPII knockdown results in apoptosis of NSCLC cells and reduces xenograft tumor formation. To further explore the mechanism of EAPII's oncogenic role in lung cancer development and to elucidate the potential signaling pathway(s) that EAPII may impact, we employed antibody array to investigate the alternation of the major signaling pathways in NSCLC cells with altered EAPII level. We found that EAPII overexpression significantly activated Raf1 and ERK1/2, but not c-Jun N-terminal kinase and p38 pathways. Consistently, the protein and mRNA levels of MYC and cyclin D1, which are targets of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway, are significantly increased by EAPII overexpression. Taken together, we demonstrated that EAPII is an oncogenic factor and the activation of MAPK-ERK signaling pathway by EAPII may contribute to lung cancer development.