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Pancreatic ductal adenocarcinoma (PDAC) usually presents infrequent infiltration of T lymphocytes. The known immune-checkpoint inhibitors to date focus on activating T cells and manifest limited effectiveness in PDAC. SIGLEC15 was identified as a novel tumor-associated macrophage (TAM)-related immune-checkpoint in other cancer types, while its immunosuppressive role and clinical significance remained unclear in PDAC. In our study, SIGLEC15 presented immunosuppressive relevance in PDAC via bioinformatic analysis and expressed on TAM and PDAC cells. SIGLEC15

PDF - 59KB, Quantitative RT-PCR analyses for Pim-1, Pim-2, and Pim-3.

PDF - 28KB, Supplemental Table 1. Primer sequences for PCR to generate the coding region of the gene below. Supplemental Table 2. Primer sequences for quantitative RT-PCR. Supplemental Table 3. The proteins interact with TCTP and interaction region.

Translationally controlled tumor protein (TCTP/TPT1) was identified from a yeast 2-hybrid screen and shown to interact with Pim-3, a member of the proto-oncogene Pim family with serine/threonine kinase activity. TCTP was aberrantly expressed in human pancreatic cancer cells and malignant ductal epithelial cells, but not in normal pancreatic duct epithelial cells adjacent to tumor foci of human pancreatic cancer tissue. Moreover, TCTP colocalized with Pim-3 both in human pancreatic cancer cells and in clinical tissues. Mapping studies revealed that the interaction between Pim-3 and TCTP occurred through the C-terminal region of Pim-3 and N-terminal region of TCTP. Although Pim-3 had no effect on TCTP expression or phosphorylation, overexpression of TCTP increased the amount of Pim-3 in a dose-dependent manner. Interestingly, RNAi-mediated ablation of TCTP expression reduced Pim-3 protein but not mRNA, through a mechanism involving the ubiquitin–proteasome degradation system. As a consequence of Pim-3 instability and subsequent degradation, tumor growth in vitro and in vivo was inhibited by arresting cell-cycle progression and enhancing apoptosis. Furthermore, TCTP and Pim-3 expression were significantly correlated in pancreatic adenocarcinoma specimens, and patients with highly expressed TCTP and Pim-3 presented with a more advanced tumor stage. These observations indicate that TCTP enhances Pim-3 stability to simultaneously promote and prevent cell-cycle progression and apoptosis, respectively. Hence, TCTP and Pim-3 serve a pivotal role in human pancreatic cancer with important ramifications for clinical diagnostic and therapeutic implications.Implications: The present study provides a new idea and experimental evidence for recognizing TCTP/Pim-3 pathway as a target for therapy in human pancreatic cancer. Mol Cancer Res; 11(12); 1508–20. ©2013 AACR.

Autophagy-lysosome system plays a variety of roles in human cancers. In addition to being implicated in metabolism, it is also involved in tumor immunity, remodeling the tumor microenvironment, vascular proliferation, and promoting tumor progression and metastasis. Transcriptional factor EB (TFEB) is a major regulator of the autophagy-lysosomal system. With the in-depth studies on TFEB, researchers have found that it promotes various cancer phenotypes by regulating the autophagolysosomal system, and even in an autophagy-independent way. In this review, we summarize the recent findings about TFEB in various types of cancer (melanoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, colorectal cancer, breast cancer, prostate cancer, ovarian cancer and lung cancer), and shed some light on the mechanisms by which it may serve as a potential target for cancer treatment.

PDF - 30KB, Supplementary Materials an Methods including antibody, patient and tissue samples, and scoring of TCTP, and a Pim-3 in human pancreatic cancer tissues section.

Background Autophagy regulators play important roles in the occurrence and development of a variety of tumors and are involved in immune regulation and drug resistance. However, the modulatory roles and prognostic value of autophagy regulators in pancreatic cancer have not been identified. Methods Transcriptomic data and survival information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to construct a risk score model. Important clinical features were analyzed to generate a nomogram. In addition, we used various algorithms, including ssGSEA, CIBERSORT, XCELL, EPIC, TIMER, and QUANTISEQ, to evaluate the roles of autophagy regulators in the pancreatic cancer immune microenvironment. Furthermore, the mutation landscape was compared between different risk groups. Results Pan cancer analysis indicated that most of the autophagy regulators were upregulated in pancreatic cancer and were correlated with methylation and CNV level. MET, TSC1, and ITGA6 were identified as the prognostic autophagy regulators and used to construct a risk score model. Some critical clinical indicators, such as age, American Joint Committee on Cancer (AJCC) T stage, AJCC N stage, alcohol and sex, were combined with the risk model to establish the nomogram, which may offer clinical guidance. In addition, our study demonstrated that the low score groups exhibited high immune activity and high abundances of various immune cells, including T cells, B cells, and NK cells. Patients with high risk scores exhibited lower half inhibitory concentration (IC50) values for paclitaxel and had downregulated expression profiles of PD1, CTLA4, and LAG3. Mutation investigation indicated that the high risk groups exhibited a higher mutation burden and higher mutation number compared to the low risk groups. additionally, we verified our risk stratification method using cytology and histology data from our center, and the results are satisfactory. Conclusion We speculated that autophagy regulators have large effects on the prognosis, immune landscape and drug sensitivity of pancreatic cancer. Our model, which combines critical autophagy regulators and clinical indicators, will provide guidance for clinical treatment.

Pancreatic neuroendocrine tumors (PanNETs) are indolent pancreatic tumors derived from neuroendocrine cells in pancreatic islets. To date, reliable predictors for identifying patients at high risk for recurrence after curative cancer resection are lacking. We aimed to determine independent predictors for high-risk PanNETs and patient outcomes after surgery. We analyzed relevant clinicopathological parameters in 319 consecutive patients of derivation cohort 1 and 106 patients of validation cohort 2 who underwent pancreatectomy and were diagnosed with PanNETs. Association of tumor characteristics with recurrence-free survival (RFS) and overall survival (OS) was evaluated using Cox regression. PanNET grade 3 (G3), pancreatic duct dilatation, and perineural invasion were independent prognostic factors for RFS and were significantly associated with early recurrence (within 1.5 years) of PanNETs after curative resection (P = 0.019, P

The selective pressure imposed by chemotherapy creates a barrier to tumor eradication and an opportunity for metastasis and recurrence. As a newly discovered stemness marker of pancreatic ductal adenocarcinoma (PDAC), the impact of CD9 on tumor progression and patient's prognosis remain controversial.A total of 179 and 211 PDAC patients who underwent surgical resection with or without neoadjuvant chemotherapy, respectively, were recruited for immunohistochemical analyses of CD9 expression in both tumor and stromal areas prior to statistical analyses to determine the prognostic impact and predictive accuracy of CD9.The relationship between CD9 and prognostic indicators was not significant in the non-neoadjuvant group. Nevertheless, CD9 expression in both tumor (T-CD9) and stromal areas (S-CD9) was significantly correlated with the clinicopathological features in the neoadjuvant group. High levels of T-CD9 were significantly associated with worse OS (p = 0.005) and RFS (p = 0.007), while positive S-CD9 showed the opposite results (OS: p = 0.024; RFS: p = 0.008). Cox regression analyses identified CD9 in both areas as an independent prognostic factor. The TS-CD9 risk-level system was used to stratify patients with different survival levels. The combination of TS-CD9 risk level and TNM stage were accurate predictors of OS (C-index: 0.676; AIC: 512.51) and RFS (C-index: 0.680; AIC: 519.53). The calibration curve of the nomogram composed of the combined parameters showed excellent predictive consistency for 1-year RFS. These results were verified using a validation cohort.Neoadjuvant chemotherapy endows CD9 with a significant prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.

ObjectiveThis study retrospectively characterized the immune infiltrating profile in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs).MethodsTumor tissues from the 109-patient Fudan cohort and a 73-patient external validation set were evaluated by immunohistochemistry for 9 immune cell types: tumor-infiltrating neutrophils (TINs), tumor-associated macrophages (TAMs), CD11c+ dendritic cells, anti-NCR1+ natural killer (NK) cells, CD4+ and CD8+ T cells, CD45RO+ memory T cells, FOXP3+ regulatory T cells (Tregs), and CD20+ B cells.ResultsTINs were primarily distributed in the intratumoral area, dendritic cells and NK cells were scattered evenly in intratumoral and stromal areas, and Tregs were rarely detected. The remaining 5 cell types were primarily present in peritumoral stroma. Total TINs (P < .001) and TAMs (P = .002) increased as NF-PanNET grade rose. Kaplan-Meier analyses showed that high intratumoral TINs, total TAMs, and stromal CD4+ T-cell infiltration correlated with shorter recurrence-free survival (RFS, P = .010, P = .027, and P = .035, respectively) and overall survival (OS, P = .017, P = .029, and P = .045, respectively). Additionally, high intratumoral CD8+ T cell infiltration correlated with prolonged RFS (P = .039). Multivariate Cox regression demonstrated that intratumoral TINs, World Health Organization (WHO) classification, and eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8th TNM) were independent factors for RFS (P = .043, P = .023, and P = .029, respectively), whereas intratumoral TINs and WHO classification were independent factors for OS (P = .010 and P = .007, respectively). Furthermore, the combination of TINs, WHO classification, and AJCC8th TNM remarkably improved prognostic accuracy for RFS. These results have been verified in the external validation set.ConclusionIntratumoral TINs are an independent and unfavorable predictor of postoperative NF-PanNETs. A combination of TINs, WHO classification, and AJCC8th TNM could improve prognostic accuracy for RFS.

Background: This study aimed to summarize the surgical and therapeutic activities of non-functional pancreatic neuroendocrine tumors (NF-PanNETs) and perform survival analyses of a 15-year single-institutional cohort of NF-PanNETs. Methods: In total, 1001 patients with neuroendocrine neoplasms treated at Fudan University Shanghai Cancer Center were screened for inclusion, and 509 patients with NF-PanNETs from 2006 to 2020 were included. For time trend analyses, the 15-year study period was randomly divided into three periods. Survival analyses used the Kaplan–Meier method and Cox regression models. Results: The total number of resected NF-PanNETs increased over the 15-year study period, from 5 resections in 2006 to 94 resections in 2020. A significant decrease in the tumor size was observed, from a mean of 4.0 cm to 3.3 cm, and to 3.0 cm in the most recent period (p = 0.006). Minimally invasive techniques gradually increased from 3.5% to 12.9%, and finally to 46.4% in the most recent period (p < 0.001). In non-metastatic and resected tumors, the tumor size (p < 0.001), positive lymph node (p < 0.001), adjuvant treatment (p = 0.048), and tumor grade (p < 0.001) were independent prognostic factors for recurrence-free survival (RFS). The microvascular invasion (p = 0.024) and tumor grade (p = 0.013) were independent prognostic factors for overall survival (OS). A malignant transformation from NET into neuroendocrine carcinoma was observed. Conclusions: An increasing number of NF-PanNETs resection and minimally invasive surgery was shown. In non-metastatic and resected tumors NF-PanNETs, tumor size, positive lymph node, adjuvant treatment, and tumor grade were independent predictors of RFS. Microvascular invasion and tumor grade were independent prognostic factors for OS.

Hernandezine (Her) is a bisbenzylisoquinoline alkaloid extracted from the traditional Chinese herbal medicine Thalictrum glandulosissimum. Evidence shows that Her is a natural agonist of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and induces apoptosis and autophagy in tumor cells. In this study, we investigated the role of autophagy in Her-induced cell death in human pancreatic cancer cell lines. We showed that Her dose-dependently suppressed cell proliferation, promoted autophagy and induced autophagic death in pancreatic ductal adenocarcinoma (PDAC) cell lines Capan-1 and SW1990. The IC50 values of Her in inhibition of Capan-1 and SW1990 cells were 47.7 μM and 40.1 μM, respectively. Immunoblotting showed that Her (1−40 μM) promoted the conversion of LC3-I to LC3-II, and Her exerted concentration-dependent and time-dependent effects on autophagy activation in PDAC cells. In transmission electron microscopy and fluorescence image analysis, we found that autophagic vacuoles were significantly increased in Her-treated cells. Knockdown of ATG5, a key gene in the autophagy pathway, alleviated the activation of autophagy by Her. These results demonstrated that Her induced autophagy in PDAC cells. Intensely activated autophagy could promote cell death. The autophagy inhibitors, BafA1 and HCQ significantly inhibited Her-induced cell death, implying that Her induced autophagic cell death in PDAC cells. Moreover, we showed that Her activated autophagy by increasing the phosphorylation of AMPK and decreasing the phosphorylation of mTOR/p70S6K. Knockdown of AMPKα relieves the autophagic cell death induced by Her. Furthermore, Her concentration-dependently enhanced reactive oxygen species (ROS) generation in PDAC cells. Antioxidants could reduce the phosphorylation of AMPK and suppress autophagic cell death induced by Her. Our study provides evidence for the development of Her as a therapeutic agent for the treatment of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is usually diagnosed at an advanced stage when curative surgery is no longer an option. Robust diagnostic biomarkers with high sensitivity and specificity for early detection are urgently needed. Systems biology provides a powerful tool for understanding diseases and solving challenging biological problems, allowing biomarkers to be identified and quantified with increasing accuracy, sensitivity, and comprehensiveness. Here, we present a comprehensive overview of efforts to identify biomarkers of PDAC using genomics, transcriptomics, proteomics, metabonomics, and bioinformatics. Systems biology perspective provides a crucial "network" to integrate multi-omics approaches to biomarker identification, shedding additional light on early PDAC detection.

Increasing numbers of studies have elucidated the role of competitive endogenous RNA (ceRNA) networks in carcinogenesis. However, the potential role of the paclitaxel-related ceRNA network in the innate mechanism and prognosis of pancreatic cancer has not been identified.Comprehensive bioinformatics analyses were performed to identify drug-related miRNAs (DRmiRNAs), drug-related mRNAs (DRmRNAs) and drug-related lncRNAs (DRlncRNAs) and construct a ceRNA network. The ssGSEA and CIBERSORT algorithms were utilized for immune cell infiltration analysis. Additionally, we validated our paclitaxel-related ceRNA regulatory axis at the gene expression level; functional experiments were conducted to explore the biological functions of the key genes.A total of 182 mRNAs, 13 miRNAs, and 53 lncRNAs were confirmed in the paclitaxel-related ceRNA network. In total, 6 mRNAs, 4 miRNAs, and 6 lncRNAs were identified to establish a risk signature and exhibited optimal prognostic effects. The mRNA signature can predict the abundance of immune cell infiltration and the sensitivity of different chemotherapeutic drugs and may also have a guiding effect in immune checkpoint therapy. A potential PART1/hsa-mir-21/SCRN1 axis was confirmed according to the ceRNA theory and was verified by qPCR. The results indicated that PART1 knockdown markedly increased hsa-mir-21 expression but inhibited SCRN1 expression, weakening the proliferation and migration abilities.We hypothesized that the paclitaxel-related ceRNA network strongly influences the innate mechanism, prognosis, and immune infiltration of pancreatic cancer. Our risk signatures can accurately predict survival outcomes and provide a clinical basis.

CACNA1E is a gene encoding the ion-conducting α1 subunit of R-type voltage-dependent calcium channels, whose roles in tumorigenesis remain to be determined. We previously showed that CACNA1E was significantly mutated in patients with non-small cell lung cancer (NSCLC) who were long-term exposed to household air pollution, with a mutation rate of 19% (15 of 79 cases). Here we showed that CACNA1E was also mutated in 207 (12.8%) of the 1616 patients with NSCLC in The Cancer Genome Atlas (TCGA) datasets. At mRNA and protein levels, CACNA1E was elevated in tumor tissues compared to counterpart non-tumoral lung tissues in NSCLCs of the public datasets and our settings, and its expression level was inversely associated with clinical outcome of the patients. Overexpression of wild type (WT) or A275S or R249G mutant CACNA1E transcripts promoted NSCLC cell proliferation with activation of epidermal growth factor receptor (EGFR) signaling pathway, whereas knockdown of this gene exerted inhibitory effects on NSCLC cells in vitro and in vivo. CACNA1E increased current density and Ca

Platelets are believed to promote tumor growth and metastasis in several tumor types. The prognostic role of blood platelets in pancreatic ductal adenocarcinoma (PDAC) remains controversial, and the prognostic value of tumor-infiltrating platelets (TIPs) remains unknown.A total of 303 patients who underwent curative pancreatectomy for PDAC were enrolled from two independent centers in China and divided into three cohorts. Paired preoperative blood samples and surgical specimens from all patients were analyzed. The correlations between patient outcomes and preoperative blood platelet counts and the presence of TIPs, respectively, were analyzed. TIPs were identified by immunohistochemical staining of CD42b. Prognostic accuracy was estimated by concordance index (C-index) and Akaike information criterion (AIC).TIPs, but not preoperative blood platelet counts, were associated with overall survival (OS; all P 0.001) and recurrence-free survival (RFS; all P 0.001) in the training, testing, and validation sets. Positive CD42b expression predicted poor postsurgical survival. Incorporation of TIPs improved the predictive accuracy of the 8th edition American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for OS in each of the three cohorts (C-index: 0.7164, 0.7569, and 0.7050, respectively; AIC: 472, 386, and 1019, respectively). The new predictor system was validated by incorporating TIPs with the 7th edition AJCC TNM staging system (C-index: 0.7052, 0.7623, and 0.7157; AIC: 476, 386, and 1015).TIPs were an independent prognostic factor that could be incorporated into the AJCC TNM staging system to refine risk stratification and predict surgical outcomes of patients with PDAC.

Pancreatic neuroendocrine tumors (PanNETs) are heterogeneous; thus, individual prognostic prediction is important. Clinicopathological features, like TNM stage, grade, and differentiation, are independent clinical predictors. However, single predictors are insufficient, as patients sharing similar clinicopathological features usually show distinct prognoses. Accordingly, novel nomograms and risk stratifications have been developed for more accurate PanNET prognostic prediction. Moreover, the exploration of molecular mechanisms has identified novel prognostic predictors for PanNET. Multi-analyte assays of molecular biomarkers provide a deeper understanding of PanNET features; however, the priority, and the optimal combination of classic and novel predictors for PanNET prognosis prediction remain unclear. In this review, we summarized the patterns and predictors of PanNET prognosis and discussed their clinical utility; we emphasized that PanNET at different stages have different superior predictor, and that multi-analyte assays are more sensitive than mono-analyte biomarkers. Therefore, combined biomarkers improve the accuracy of surveillance and optimize decision-making in clinical practice.

Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.

Background: Pancreatic ductal adenocarcinoma (PDAC) progression is mediated by mutations in driver genes and a complex stroma that is mainly dependent on the Sonic hedgehog (Shh) signaling pathway. However, the association between driver genes and Shh-pathway proteins and their potential prognostic significance remain unclear. Methods: We analyzed protein expressions of the KRAS, TP53, SMAD4, and CDKN2A/P16 driver genes and the Shh-pathway molecules, including Shh, glioma-associated oncogene (Gli) 1, Gli2, and smoothened (SMO) by immunohistochemistry using tissue microarrays in 237 patients with resectable PDAC and statistically determined their prognostic significance. Results: SMAD4lost mutation was associated with shorter survival outcomes [overall survival (OS): Hazard ratio (HR) 1.887, p < 0.001]; recurrence-free survival (RFS): HR 1.886, p < 0.001) and abnormal p53 immunolabeling was associated with poor OS (HR 1.436, p = 0.011) in patients with PDAC. The mutational status of p16 had no effect on patient survival. High levels of SMO and Gli1 expression were associated with poor survival outcomes in both univariate and multivariate analyses. Pearson's χ2 test showed a medium correlation between the SMAD4lost mutation and Shh (R = 0.343) and Gli1 (R = 0.505) expression levels (p < 0.001). Patients with the SMAD4lost mutation and high levels of Shh and Gli1 expression showed the poorest survival outcomes (RFS: HR 2.976; OS: HR 3.598; p < 0.001 for both) compared with other patients in the study. Conclusion: Loss of SMAD4 associated with a strongly activated Shh pathway resulted in poor survival outcomes in patients with resected PDAC.

Air pollution has been classified as Group 1 carcinogenic to humans, but the underlying tumorigenesis remains unclear. In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China attributed to severe air pollution generated by combustion of smoky coal, providing a unique opportunity to dissect lung carcinogenesis of air pollution. Here we analyzed the somatic mutations of 164 non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used. Whole genome sequencing revealed a mean of 289 somatic exonic mutations per tumor and the frequent C:G → A:T nucleotide substitutions in Xuanwei NSCLCs. Exome sequencing of 2010 genes showed that Xuanwei and CR NSCLCs had a mean of 68 and 22 mutated genes per tumor, respectively (p, Highlights • Somatic genomic mutations of air pollution-related lung cancer were characterized. • Mutations in air pollution-related lung cancers were 3 times as high as lung cancers from control regions. • 167 of the 2010 genes had higher mutation rates in patients from highly polluted region than those from control regions. • The mutation rates of 70 genes were associated with patients' lifetime benzo(a)pyrene exposure.

Due to the gear fault signal are often covered by complex noisy even under varying-speed running condition, and it is difficult to simulate the gear fault impact in practical work. To address the problem, a simulation scheme of gear fault is proposed in this paper. In the proposed approach, the gear fault model is built in UG at first. Subsequently, the model is imported in ADAMS, in which the meshing force instead of the vibration signal from a gearbox in real world is extracted, and then the envelope of the meshing force signal is extracted. Finally, the envelope order spectrum analysis scheme is used to obtain the feature order of gear faults. Simulation is conducted to verify the validity of the proposed method.

This paper proposed a new method of gear fault diagnosis in gearbox. Mainly it stresses on the combination of time synchronous average (TSA) and envelope analysis, using TSA technique to eliminate the random noises in the gearbox. Then, the clear rotation frequency, gear mesh frequency and their harmonics can be obtained through the envelope spectrum analysis. Simulation study indicates that this method can effectively detect the gear faults with a high accuracy.

Rolling element bearing (REB) is one of important components in the condition monitoring and faults diagnosis of machinery. In this paper, a REB fault diagnosis system is presented, which is developed by using LabVIEW. In the system, vibration signals are picked by acceleration sensors and acquired by NI USB data acquisition card at first. Then, the fault diagnosis can be performed in the time-frequency domain by various time-frequency methods. The experiments show that the presented system can be used to extract the bearing fault features and diagnoses the failures effectively.

This paper proposed a new method of rolling element bearing (REB) fault diagnosis for metallurgical machinery. Mainly it stresses on the combination of spectral kurtosis (SK) and supports vector machine (SVM), using genetic algorithm (GA) to optimize the parameters of support vector machine at the same time. Thus, this study aims to integrate SK, GA and SVM in order to develop an intelligent REB fault detector for metallurgical machineries. Simulation study indicates that this method can effectively detect the REB faults with a high accuracy.

Cyclin D1, an oncogenic G1 cyclin which can be induced by environmental carcinogens and whose over-expression may cause dysplasia and carcinoma, has been shown to be a target for cancer chemoprevention and therapy. In this study, we investigated the effects and underlying mechanisms of action of a polyprenylated xanthone, gambogenic acid (GEA) on gefitinib-sensitive and -resistant lung cancer cells. We found that GEA inhibited proliferation, caused G1 arrest and repressed colony-forming activity of lung cancer cells. GEA induced degradation of cyclin D1 via the proteasome pathway, and triggered dephosphorylation of GSK3β which was required for cyclin D1 turnover, because GSK3β inactivation by its inhibitor or specific siRNA markedly attenuated GEA-caused cyclin D1 catabolism. GEA induced autophagy of lung cancer cells, possibly due to activation of GSK3β and inactivation of AKT/mTOR signal pathway. These results indicate that GEA is a cyclin D1 inhibitor and a GSK3β activator which may have chemopreventive and therapeutic potential for lung cancer.

The boronic acid dipeptide bortezomib inhibits the chymotrypsin-like activity of the 26S proteasome and shows significant therapeutic efficacy in multiple myeloma. However, recent studies suggest that bortezomib may have more complex mechanisms of action in treating cancer. We report here that the endocytosis and lysosomal degradation of the receptor tyrosine kinase C-KIT are required for bortezomib- but not tyrosine kinase inhibitor imatinib-caused apoptosis of t (8;21) leukemia and gastrointestinal stromal tumor cells, suggesting that C-KIT may recruit an apoptosis initiator. We show that C-KIT binds and phosphorylates heat shock protein 90β (Hsp90β), which sequestrates apoptotic protease activating factor 1 (Apaf-1). Bortezomib dephosphorylates pHsp90β and releases Apaf-1. Although the activated caspase-3 is not sufficient to cause marked apoptosis, it cleaves the t (8;21) generated acute myeloid leukemia 1-eight twenty one (AML1-ETO) and AML1-ETO9a fusion proteins, with production of cleavage fragments that perturb the functions of the parental oncoproteins and further contribute to apoptosis. Notably, bortezomib exerts potent therapeutic efficacy in mice bearing AML1-ETO9a–driven leukemia. These data show that C-KIT-pHsp90β-Apaf-1 cascade is critical for some malignant cells to evade apoptosis, and the clinical therapeutic potentials of bortezomib in C-KIT–driven neoplasms should be further explored.

Tumour burden is one of the most important prognosticators for pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate the predictive significance of metabolic tumour burden measured by (18)F-FDG PET/CT in patients with resectable PDAC.Included in the study were 122 PDAC patients who received preoperative (18)F-FDG PET/CT examination and radical pancreatectomy. Metabolic tumour burden in terms of metabolic tumour volume (MTV) and total lesion glycolysis (TLG), pathological tumour burden (tumour size), serum tumour burden (baseline serum CA19-9 level), and metabolic activity (maximum standard uptake value, SUVmax) were determined, and compared for their performance in predicting overall survival (OS) and recurrence-free survival (RFS).MTV and TLG were significantly associated with baseline serum CA19-9 level (P = 0.001 for MTV, P 0.001 for TLG) and tumour size (P 0.001 for MTV, P = 0.001 for TLG). Multivariate analysis showed that MTV, TLG and baseline serum CA19-9 level as either categorical or continuous variables, but not tumour size or SUVmax, were independent risk predictors for both OS and RFS. Time-dependent receiving operating characteristics analysis further indicated that better predictive performances for OS and RFS were achieved by MTV and TLG compared to baseline serum CA19-9 level, SUVmax and tumour size (P 0.001 for all).MTV and TLG showed strong consistency with baseline serum CA19-9 level in better predicting OS and RFS, and might serve as surrogate markers for prediction of outcome in patients with resectable PDAC.