Noncoding RNA-mediated molecular bases of chemotherapy resistance in hepatocellular carcinoma.

Despite the significant progress in decreasing the occurrence and mortality of hepatocellular carcinoma (HCC), it remains a public health issue worldwide on the basis of its late presentation and tumor recurrence. To date, apart from surgical interventions, such as surgical resection, liver transplantation and locoregional ablation, current standard antitumor protocols include conventional cytotoxic chemotherapy. However, due to the high chemoresistance nature, most current therapeutic agents show dismal outcomes for this refractory malignancy, leading to disease relapse. Nevertheless, the molecular mechanisms involved in chemotherapy resistance remain systematically ambiguous. Herein, HCC is hierarchically characterized by the formation of primitive cancer stem cells (CSCs), progression of epithelial-mesenchymal transition (EMT), unbalanced autophagy, delivery of extracellular vesicles (EVs), escape of immune surveillance, disruption of ferroptosis, alteration of the tumor microenvironment and multidrug resistance-related signaling pathways that mediate the multiplicity and complexity of chemoresistance. Of note, anecdotal evidence has corroborated that noncoding RNAs (ncRNAs) extensively participate in the critical physiological processes mentioned above. Therefore, understanding the detailed regulatory bases that underlie ncRNA-mediated chemoresistance is expected to yield novel insights into HCC treatment. In the present review, a comprehensive summary of the latest progress in the investigation of chemotherapy resistance concerning ncRNAs will be elucidated to promote tailored individual treatment for HCC patients.

Therapy for advanced cholangiocarcinoma: Current knowledge and future potential.

Cholangiocarcinoma (CCA) is a biliary epithelial tumour that can emerge at any point in the biliary tree. It is commonly classified based on its anatomical site of development into intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PCC) and distal cholangiocarcinoma (DCC), each of which is associated with varying patient demographics, molecular characteristics and treatment options. CCA patients have poor overall prognoses and 5-year survival rates. Additionally, CCA is often diagnosed at an advanced stage, with surgical treatment restricted to early-stage disease. Owing to an increase in the incidence of ICC, that of CCA is also on the rise, with a corresponding increase in the associated mortality, particularly in South America and Asia. Therefore, the development of an effective treatment is crucial to improve the survival of CCA patients. We aimed to systematically review the current understanding of advanced CCA treatment and discuss potential effective strategies.

Traffic-related metrics and adverse birth outcomes: A systematic review and meta-analysis.

Given the inconsistency of epidemiologic evidence for associations between maternal exposures to traffic-related metrics and adverse birth outcomes, this manuscript aims to provide clarity on this topic. Pooled meta-estimates were calculated using random-effects analyses. Subgroup analyses were conducted by study area, study design, and Newcastle-Ottawa quality score (NOS). Funnel plots and Egger's test were conducted to evaluate the publication bias, and Fail-safe Numbers (Fail-safe N) were measured to evaluate the robustness of models. From the initial 740 studies (last search, July 11, 2019), 26 studies were included in our analysis. The pooled odds ratio for the change in small for gestational age associated with per 500 m decrease in the distance to roads was 1.016 (95% CI: 1.004, 1.029). Subgroup analyses revealed significant positive associations between term low birth weight and traffic density in higher-quality literatures with higher NOS [1.060 (95% CI: 1.002, 1.121)], cohort studies [1.020 (95% CI: 1.006, 1.033)], and studies in North America [1.018 (95% CI: 1.005, 1.131)]. The buffer of traffic density made no difference in the effect size. Traffic density seemed to be a better indicator of traffic pollution than the distance to roads.

Associations between the incidence and mortality rates of type 2 diabetes mellitus and long-term exposure to ambient air pollution: A 12-year cohort study in northern China.

BACKGROUND: Ambient air pollution has recently been related to type 2 diabetes mellitus (T2DM), a disease that has caused an economic and health burden worldwide. Evidence of an association between air pollution and T2DM was reported in the United States and Europe. However, few studies have focused on the association with high levels of air pollutants in a developing country. OBJECTIVES: We conducted a 12-year cohort study to assess the incidence and mortality of T2DM associated with long-term exposure to PM10, SO2, and NO2. METHODS: A retrospective cohort with participants from four cities in northern China was conducted to assess mortality and incidence of T2DM from 1998 to 2009. Incidence of T2DM was self-reported, and incident intake of an antidiabetic drug or injection of insulin simultaneously and mortality of T2DM was obtained from a family member and double checked against death certificates provided from the local center for disease control and prevention. Individual pollution exposures were the mean concentrations of pollutants estimated from the local environmental monitoring centers over the survival years. Hazard ratios (HRs) were estimated using Cox regression models after adjusting for potential confounding factors. RESULTS: A total of 39 054 participants were recruited into the mortality cohort, among which 59 subjects died from T2DM; 38 529 participants were analyzed in the incidence cohort, and 1213 developed new cases of T2DM. For each 10 µg/m3 increase in PM10, SO2, and NO2, the adjusted HRs and 95% confidence interval (CI) for diabetic incidence were 1.831 (1.778, 1.886), 1.287 (1.256, 1.318), and 1.472 (1.419, 1.528), respectively. Similar results can be observed in the analysis of diabetic mortality with HRs (95% CI) up to 2.260 (1.732, 2.950), 1.130 (1.042, 1.225), and 1.525 (1.280, 1.816), respectively. CONCLUSIONS: Our results suggested that long-term exposure to high levels of PM10, SO2, and NO2 increase risk of incident and mortality of T2DM in China.

The role of tumour microenvironment: a new vision for cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a relatively rare malignant and lethal tumour derived from bile duct epithelium and the morbidity is now increasing worldwide. This disease is difficult to diagnose at its inchoate stage and has poor prognosis. Therefore, a clear understanding of pathogenesis and major influencing factors is the key to develop effective therapeutic methods for CCA. In previous studies, canonical correlation analysis has demonstrated that tumour microenvironment plays an intricate role in the progression of various types of cancers including CCA. CCA tumour microenvironment is a dynamic environment consisting of authoritative tumour stromal cells and extracellular matrix where tumour stromal cells and cancer cells can thrive. CCA stromal cells include immune and non-immune cells, such as inflammatory cells, endothelial cells, fibroblasts, and macrophages. Likewise, CCA tumour microenvironment contains abundant proliferative factors and can significantly impact the behaviour of cancer cells. Through abominably intricate interactions with CCA cells, CCA tumour microenvironment plays an important role in promoting tumour proliferation, accelerating neovascularization, facilitating tumour invasion, and preventing tumour cells from organismal immune reactions and apoptosis. This review summarizes the recent research progress regarding the connection between tumour behaviours and tumour stromal cells in CCA, as well as the mechanism underlying the effect of tumour stromal cells on the growth of CCA. A thorough understanding of the relationship between CCA and tumour stromal cells can shed some light on the development of new therapeutic methods for treating CCA.

Ferroptosis, a new form of cell death, and its relationships with tumourous diseases.

Ferroptosis is a newly discovered type of cell death that differs from traditional apoptosis and necrosis and results from iron-dependent lipid peroxide accumulation. Ferroptotic cell death is characterized by cytological changes, including cell volume shrinkage and increased mitochondrial membrane density. Ferroptosis can be induced by two classes of small-molecule substances known as class 1 (system Xc- inhibitors) and class 2 ferroptosis inducers [glutathione peroxidase 4 (GPx4) inhibitors]. In addition to these small-molecule substances, a number of drugs (e.g. sorafenib, artemisinin and its derivatives) can induce ferroptosis. Various factors, such as the mevalonate (MVA) and sulphur-transfer pathways, play pivotal roles in the regulation of ferroptosis. Ferroptosis plays an unneglectable role in regulating the growth and proliferation of some types of tumour cells, such as lymphocytoma, ductal cell cancer of the pancreas, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Here, we will first introduce the discovery of and research pertaining to ferroptosis; then summarize the induction mechanisms and regulatory pathways of ferroptosis; and finally, further elucidate the roles of ferroptosis in human tumourous diseases.

Identification of potential key molecular biomarkers in lung adenocarcinoma by bioinformatics analysis.

Background: Lung cancer is one of the most common malignant tumors in the world, of which the rate of incidence has continuously increased over recent years. Lung adenocarcinoma (LUAD) is the most frequent pathological type of lung cancer. Methods: In order to discover the key markers for the occurrence and development of LUAD, we collected messenger RNA (mRNA) expression datasets in the Gene Expression Omnibus (GEO), namely, GSE2514, GSE7670, and GSE40275. The differentially expressed genes (DEGs) were screened using the online interface between GEO and R (GEO2R). Then, DEGs were functionally annotated in the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Next, a protein-protein interaction (PPI) network was drawn by using the Search Tool for the Retrieval of Interacting Genes (STRING) web tool and Cytoscape software. Finally, Kaplan-Meier plotter was utilized to analyze the overall survival (OS) of the hub genes. The correlation between fibroblast growth factor 2 (FGF2) and immune infiltration was studied by TIMER web services. Results: In this study, we obtained a total of 284 DEGs through the intersection of 3 datasets, and found that DEGs were highly related to biological processes such as "cell adhesion", "cell differentiation", and "cell proliferation". After that, the hub genes were obtained by analyzing the PPI network. Finally, we found that the abnormal expression of hub genes is obviously related to poor prognosis in LUAD patients. The expression level of FGF2 was positively correlated with the immune infiltration in LUAD. Conclusions: In general, the DEGs and hub genes can provide new research targets for the development of LUAD, as well as potential diagnosis and treatment strategies for disease treatment. In particular, FGF2 expression was found to be involved in the immune microenvironment of LUAD.

Associations between ambient air pollutants and blood pressure among children and adolescents: A systemic review and meta-analysis.

OBJECTIVE: Numerous epidemiological studies have investigated the effects of short-term and long-term exposure to ambient air pollution on hypertension and blood pressure among children and adolescents. However, the results were controversial. To provide researchers reliable evidence, this meta-analysis was performed. METHODS: We searched all published studies in four databases examining the effects of particulate matter (PM10, PM2.5 and PM1.0), nitrogen oxide (NO2), sulfur dioxide (SO2), ozone (O3) and carbon monoxide (CO) on hypertension and blood pressure in children and adolescents. Overall risk estimates associated with per 10 µg/m3 increase of air pollution were analyzed by a random-effect model for articles with significant heterogeneity, otherwise, a fixed-effect model was applied. Subgroup analysis was conducted for studies with significant heterogeneity. RESULTS: Of 3918 identified literatures, 154 were evaluated in-depth with 15 satisfying inclusion criteria. Increased risk of hypertension was associated with long-term PM10 exposure (OR = 1.17, 95% confidence interval [CI]:1.13, 1.21). For systolic blood pressure (SBP), significant results were found for short-term PM10 (ß = 0.26, 95% CI: -0.00, 0.53) exposure, long-term PM2.5 (ß = 1.80, 95% CI: 0.94, 2.65) and PM10 (ß = 0.50, 95% CI: 0.19, 0.81) exposure. The corresponding estimates of diastolic blood pressure (DBP) were 0.32 mmHg (95% CI: 0.19, 0.45) for short-term PM10 exposure, 1.06 mmHg (95% CI: 0.32, 1.80), 0.34 mmHg (95% CI: 0.11, 0.57) and 0.44 mmHg (95% CI: 0.25, 0.63) for long-term PM2.5, PM10 and NO2 exposure, respectively. Stratified analyses showed stronger effects of PM10 on blood pressure among studies with ≥50% boys' percentage (0.57 mmHg [95% CI: 0.44, 0.70] for SBP, 0.44 mmHg, [95% CI: 0.34, 0.54] for DBP, respectively) and articles using models to estimate exposure (0.90 mmHg [95% CI: 0.20 1.59] for SBP). CONCLUSION: Ambient air pollution was associated with higher hypertension prevalence and elevated blood pressure in children and adolescents.

Long-term exposure to high particulate matter pollution and incident hypertension: a 12-year cohort study in northern China.

Numerous cohort studies have reported the association of long-term exposure to particulate matter <10 µm in diameter (PM10) and hypertension in American and European countries. However, these results have been inconsistent and subject to various confounding factors. The study aimed to explore the effect of long-term exposure to high-level concentrations of PM10 on incident hypertension in a large-scale cohort from northern China. A retrospective cohort study of 39,054 participants aged between 23 and 98 years old from four cities in northern China was followed from 1998 to 2009. Excluding those with hypertension, 37,386 non-hypertensive participants (overall population) were followed for self-reported hypertension. The individuals' exposure to PM10 was the mean concentration during the follow-up period, according to the data of local environmental monitoring centers. Hazard ratios (HRs) were calculated by Cox proportional hazards models. The adjusted potential confounding factors included sociodemographic information, lifestyle, and diet. There were 2619 (7.0%) incident cases of hypertension among the overall population. In multivariable models, the HR (95% CI) of incident hypertension was 1.537 (1.515, 1.560) for each 10 µg/m3 increase in PM10. Stratified analyses showed individuals (age <65) were prone to developing hypertension. Moreover, the effects of PM10 increased and produced an HR (95% CI) of 1.555 (1.527, 1.584) for the healthy population in the sensitivity analysis. We found that the association between long-term exposure to PM10 air pollution and incident hypertension was significantly positive.

A positive feedback loop between Periostin and TGFß1 induces and maintains the stemness of hepatocellular carcinoma cells via AP-2α activation.

BACKGROUND: Liver cancer stem cells (LCSCs) play key roles in the metastasis, recurrence, and chemotherapeutic resistance of hepatocellular carcinoma (HCC). Our previous research showed that the POSTN gene is closely related to the malignant progression and poor prognosis of HCC. This study aimed to elucidate the role of POSTN in generating LCSCs and maintaining their stemness as well as the underlying mechanisms. METHODS: Human HCC tissues and matched adjacent normal tissues were obtained from 110 patients. Immunohistochemistry, western blotting (WB), and RT-PCR were performed to detect the expression of POSTN and stemness factors. The roles of transforming growth factor (TGF)-ß1 and AP-2α in the POSTN-induced stemness transformation of HCC cells were explored in vitro and in vivo using LCSCs obtained by CD133+ cell sorting. RESULTS: The high expression of POSTN was correlated with the expression of various stemness factors, particularly CD133, in our HCC patient cohort and in TCGA and ICGC datasets. Knockdown of POSTN expression decreased the abilities of HCC cell lines to form tumours in xenograft mouse models. Knockdown of POSTN expression also suppressed cell viability and clone formation, invasion, and sphere formation abilities in vitro. Knockdown of AP-2α attenuated the generation of CD133+ LCSCs and their malignant behaviours, indicating that AP-2α was a critical factor that mediated the POSTN-induced stemness transformation and maintenance of HCC cells. The role of AP-2α was verified by using a specific αvß3 antagonist, cilengitide, in vitro and in vivo. Activation of POSTN could release TGFß1 from the extracellular matrix and initiated POSTN/TGFß1 positive feedback signalling. Furthermore, we found that the combined use of cilengitide and lenvatinib suppressed the growth of HCC cells with high POSTN expression more effectively than the use of lenvatinib alone in the patient-derived xenograft (PDX) mouse model. CONCLUSIONS: The POSTN/TGFß1 positive feedback pathway regulates the expression of stemness factors and the malignant progression of HCC cells by regulating the transcriptional activation of AP-2α. This pathway may serve as a new target for targeted gene therapy in HCC.

Associations of sirtuins with clinicopathological variables and prognosis in human ovarian cancer.

Ovarian cancer (OC) is the fifth most frequent cause of cancer-associated mortality worldwide, and is accompanied by asymptomatic progression. Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide-dependent protein deacetylases, comprising seven members (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7). Accumulating evidence has demonstrated that SIRTs act as prognostic estimators in certain types of cancer such as lung cancer, prostate cancer, gastric cancer, breast cancer and colorectal cancer. However, it remains unknown whether individual SIRTs can serve as independent prognostic factors in OC. In the present study, the Kaplan-Meier plotter online database was utilized to examine the prognostic values of SIRT mRNA expression in patients with OC. The results demonstrated that the overexpression of SIRT3, SIRT5, SIRT6 and SIRT7 mRNAs was associated with a good prognosis in patients, whereas elevated mRNA levels of SIRT1 and SIRT4 indicated poor survival in patients with OC. In addition, among the favorable predictors, SIRT3, SIRT5, SIRT6 and SIRT7 overexpression were associated with overall survival (OS), according to clinical characteristics, such as histological classification, clinical stage, pathology grade, drug therapy and tumor protein p53 mutation status in patients with OC. Similarly, SIRT4 mRNA overexpression was associated with poor OS in pathological grade III cancer. High SIRT1 and SIRT4 expression were associated with unfavorable OS at all clinical stages. Furthermore, SIRT1 and SIRT4 were negatively associated with OS in drug-treated patients. In summary, the present study demonstrated that the SIRT family is associated with the prognosis of human OC, suggesting that individual SIRTs may also act as prognostic predictors in patients.

Is triglyceride associated with adult depressive symptoms? A big sample cross-sectional study from the rural areas of central China.

OBJECTIVE: Previous studies have produced contradictive results on the association between serum lipids and depressive symptoms. The present study aimed to examine the association between serum lipids and depression of adults among rural residents in central China. METHODS: This study was part of the baseline investigation of the Henan Rural Cohort Study, with 10089 participants aged 18-79 years from March to June 2017 in Xinxiang, central China. Depression were assessed with the Patient Health Questionnaire (PHQ-2). Serum lipids were profiled using ROCHE Cobas C501 automatic biochemical analyzer. The associations were estimated by odds ratios (ORs) using logistic regression models adjusted for different multiple confounders. RESULTS: The crude prevalence of depression was 4.12%. ORs (95% CI) for depressive symptoms of atherosclerosis index (AI) and triglycerides (TG) were 1.040 (0.973, 1.111) (P = 0.254) and 1.074 (1.018, 1.133) (P = 0.009), respectively. Adjustment for all covariates selected further strengthened the association of AI, TG and depression, with ORs (95% CI) of 1.095 (1.001, 1.199) (P = 0.049) and 1.088 (1.022, 1.158) (P = 0.008), respectively. In the final model, age, socio-economic status (SES), net personal income and physical activity (PA) had a negative association with depression. Sleep quality, BMI, numbers of co-morbidity chronic diseases, and fresh vegetables intake every day had the opposite. LIMITATION: The cross-sectional design limits the ability to make causal inference about the proposed associations. CONCLUSIONS: TG may be an independent risk factor associated with depressive symptoms. Further studies are needed to explore associations between long-term abnormal changes of cholesterol and depression of general adults.

Association between long-term exposure to Sulfur dioxide pollution and hypertension incidence in northern China: a 12-year cohort study.

Several studies have researched the short-term effect of sulfur dioxide (SO2) exposure on hypertension. However, no evidence has provided the relationship between long-term high pollution exposure of SO2 and morbidity of hypertension in cohort studies in China. This retrospective cohort study aimed to evaluate this association. We used Cox proportional hazards regression models to examine the hazard ratios (HR) for hypertension risks from 1998 to 2009 associated with accumulative exposure of air SO2 among adults in northern China. Annual average concentrations of sulfur dioxide (SO2) were obtained from 15 local environmental monitoring centers. Hypertension was identified according to self-reported diagnostic time and treatment for hypertension with anti-hypertensive medication. Among 37,386 participants, 2619 new cases of hypertension were identified during 426,334 person-years. In the fully adjusted model, HR and 95% confidence interval (CI) of hypertension incidence for each 10 µg/m3 increase in SO2 were 1.176 (1.163 and 1.189). Results from stratified analyses suggested that effects of SO2 on hypertension morbidity were more pronounced in participants < 60 years old, tea drinkers, and those with high education, high poultry consumption, and active (occasional and frequent) exercise. We found that long-term exposure to high levels of SO2 increased the risk of incidence of hypertension in China.

An investigation of the accuracy of an IMRT dose distribution using two- and three-dimensional dosimetry techniques.

Complex dose delivery techniques like intensity-modulated radiation therapy (IMRT) require dose measurement in three dimensions for comprehensive validation. Previously, we demonstrated the feasibility of the "PRESAGE/optical-computed tomography (CT)" system for the three-dimensional verification of simple open beam dose distributions where the planning system was known to be accurate. The present work extends this effort and presents the first application of the PRESAGE/optical-CT system for the verification of a complex IMRT distribution. A highly modulated 11 field IMRT plan was delivered to a cylindrical PRESAGE dosimeter (16 cm in diameter and 11 cm in height), and the dose distribution was readout using a commercial scanning-laser optical-CT scanner. Comparisons were made with independent GAFCHROMIC EBT film measurements, and the calculated dose distribution from a commissioned treatment planning system (ECLIPSE). Isodose plots, dose profiles, gamma maps, and dose-volume histograms were used to evaluate the agreement. The isodose plots and dose profiles from the PRESAGE/optical-CT system were in excellent agreement with both the EBT measurements and the ECLIPSE calculation at all points except within 3 mm of the outer edge of the dosimeter where an edge artifact occurred. Excluding this 3 mm rim, gamma map comparisons show that all three distributions mutually agreed to within a 3% (dose difference) and 3 mm (distance-to-agreement) criteria. A 96% gamma pass ratio was obtained between the PRESAGE and ECLIPSE distributions over the entire volume excluding this rim. In conclusion, for the complex IMRT plan studied, and in the absence of inhomogeneities, the ECLIPSE dose calculation was found to agree with both independent measurements, to within 3%, 3 mm gamma criteria.

Capsaicin and sorafenib combination treatment exerts synergistic anti­hepatocellular carcinoma activity by suppressing EGFR and PI3K/Akt/mTOR signaling.

Capsaicin (8­methyl N­vanillyl­6 nonenamide) is a natural plant extract that has antitumor properties and induces apoptosis and autophagy in various types of malignancies, including hepatocellular carcinoma (HCC). Sorafenib is a multi­kinase inhibitor that improves the survival of patients with advanced HCC. In the present study, capsaicin and sorafenib were found to inhibit the growth of LM3, Hep3B and HuH7 cells. In addition, the combination of capsaicin and sorafenib exerted a synergistic inhibitory effect on HCC cell growth. In LM3 cells, capsaicin and sorafenib combination treatment achieved a markedly stronger induction of apoptosis by increasing caspase­3, Bax and poly(ADP­ribose) polymerase activity and inhibiting Bcl­2, and induction of autophagy by upregulating the levels of beclin­1 and LC3A/B II, enhancing P62 degradation. The combination of capsaicin and sorafenib also inhibited cell invasion and metastasis via upregulation of E­cadherin and downregulation of N­cadherin, vimentin, matrix metalloproteinase (MMP)2 and MMP9. Additional studies suggested an association between the abovementioned anticancer activities and inhibition of the epidermal growth factor receptor/phosphoinositide 3 kinase/Akt/mammalian target of rapamycin pathway. Taken together, these data confirm that capsaicin and sorafenib combination treatment inhibits the growth, invasion and metastasis of HCC cells and induces autophagy in a synergistic manner, supporting its potential as a therapeutic option for HCC.

Comprehensive anti-tumor effect of Brusatol through inhibition of cell viability and promotion of apoptosis caused by autophagy via the PI3K/Akt/mTOR pathway in hepatocellular carcinoma.

Brusatol, a natural quassinoid isolated from a traditional Chinese herbal medicine known as Bruceae Fructus, has recently been reported to possess powerful cytotoxic effects against various cancer cell lines, highlighting its potential as an anti-cancer drug. However, the precise molecular mechanisms by which Brusatol exerts its anti-cancer effects remain poorly understood in hepatocellular carcinoma (HCC). In this study, we demonstrated that Brusatol inhibited cell viability, proliferation and induced apoptosis in liver cancer lines. Furthermore, Brusatol could activate autophagy in diverse liver cell lines, and the autophagy inhibitor chloroquine (CQ) reversed Brusatol-induced apoptosis in Bel7404 cells. In addition, we found that Brusatol inhibited PI3K/Akt/mTOR. Brusatol may also inhibit invasion, migration and the epithelial-mesenchymal transition (EMT). In a human liver xenograft tumor model in nude mice, immunohistochemistry showed that Brusatol significantly inhibited tumor invasion and proliferation. Taken together, these results revealed that Brusatol effectively inhibited proliferation and induced apoptosis in HCC through autophagy induction, probably via the PI3K/Akt/mTOR pathway, and inhibited tumor invasion and migration in vivo and in vitro. All above indicated that Brusatol is an encouraging anti-tumor drug candidate or a supplement to the current chemotherapeutic systematic plan.

Ribosomal protein S15a promotes tumor angiogenesis via enhancing Wnt/ß-catenin-induced FGF18 expression in hepatocellular carcinoma.

Ribosomal protein s15a (RPS15A) plays a promotive role in the mRNA/ribosome interactions during early translation. Our previous study has found that inhibiting RPS15A expression can decrease proliferation and induce cell cycle arrest in hepatocellular carcinoma (HCC) cell lines. However, the mechanism underlying the involvement of RPS15A in HCC pathogenesis and the clinical significance of RPS15A expression remain unclear. In this study, an evaluation of RPS15A expression in 110 surgically resected HCCs and matched tumor-adjacent normal tissues revealed an overexpression of RPS15A in HCC, which was correlated with worse survival. In addition, tumor tissue with higher RPS15A expression demonstrated a higher microvascular density (MVD). Subsequently, two HCC cell lines, Huh7 (low-level constitutive RPS15A expression) and HepG2 (high RPS15A expression) were used to further evaluate the role of RPS15A in angiogenesis. The co-culture experiment of HCC cells with endothelial cells revealed that the induced overexpression of RPS15A in Huh7 cells increased the angiogenic potential of HUVEC in a paracrine fashion; conversely, knockdown of RPS15A in HepG2 cells showed an opposite effect. Further analysis indicated that RPS15A modulated FGF signaling by enhancing Wnt/beta-catenin-mediated FGF18 expression in HCC cells. FGF18, in turn, through binding to its FGFR3 receptor on endothelial cells, can activate the AKT and ERK pathway and promotes angiogenesis in a tumor microenvironment. Our in vivo experiment further confirmed that inhibition of RPS15A expression in HCC xenografts dramatically hindered tumor growth and inhibited tumor angiogenesis. Together, our findings suggest that RPS15A promotes angiogenesis in HCCs by enhancing Wnt/beta-catenin induced FGF18 expression. The RPS15A/FGF18 pathway may be a rational target for anti-angiogenic therapy of HCC.

Three-dimensional imaging of whole rodent organs using optical computed and emission tomography.

We explore the potential of optical computed tomography (optical-CT) and optical emission computed tomography (optical-ECT) in a new area-whole organ imaging. The techniques are implemented on an in-house prototype benchtop system with improved image quality and the capacity to image larger samples (up to 3 cm) than previous systems based on stereo microscopes. Imaging performance tests confirm high geometrical accuracy, accurate relative measurement of linear attenuation coefficients, and the ability to image features at the 50-microm level. Optical labeling of organ microvasculature was achieved using two stains deposited via natural in vivo circulatory processes: a passive absorbing ink-based stain and an active fluorescin FITC-lectin conjugate. The lectin protein binds to the endothelial lining, and FITC fluorescense enables optical-ECT imaging. Three-dimensional (3-D) optical-CT images have been acquired of a normal rat heart and left lung and a mouse right lung showing exquisite detail of the functional vasculature and relative perfusion distribution. Coregistered optical-ECT images were also acquired of the mouse lung and kidney. Histological sections confirmed effective labeling of microvasculature throughout the organs. The advantages of optical-CT and optical-ECT include the potential for a unique combination of high resolution and high contrast and compatibility with a wide variety of optical probes, including gene expression labeling fluorescent reporter proteins.

A practical three-dimensional dosimetry system for radiation therapy.

There is a pressing need for a practical three-dimensional (3D) dosimetry system, convenient for clinical use, and with the accuracy and resolution to enable comprehensive verification of the complex dose distributions typical of modern radiation therapy. Here we introduce a dosimetry system that can achieve this challenge, consisting of a radiochromic dosimeter (PRESAGE) and a commercial optical computed tomography (CT) scanning system (OCTOPUS). PRESAGE is a transparent material with compelling properties for dosimetry, including insensitivity of the dose response to atmospheric exposure, a solid texture negating the need for an external container (reducing edge effects), and amenability to accurate optical CT scanning due to radiochromic optical contrast as opposed to light-scattering contrast. An evaluation of the performance and viability of the PRESAGE/OCTOPUS, combination for routine clinical 3D dosimetry is presented. The performance of the two components (scanner and dosimeter) was investigated separately prior to full system test. The optical CT scanner has a spatial resolution of < or = 1 mm, geometric accuracy within 1 mm, and high reconstruction linearity (with a R2 value of 0.9979 and a standard error of estimation of approximately 1%) relative to independent measurement. The overall performance of the PRESAGE/OCTOPUS system was evaluated with respect to a simple known 3D dose distribution, by comparison with GAFCHROMIC EBT film and the calculated dose from a commissioned planning system. The "measured" dose distribution in a cylindrical PRESAGE dosimeter (16 cm diameter and 11 cm height) was determined by optical-CT, using a filtered backprojection reconstruction algorithm. A three-way Gamma map comparison (4% dose difference and 4 mm distance to agreement), between the PRESAGE, EBT and calculated dose distributions, showed full agreement in measurable region of PRESAGE dosimeter (approximately 90% of radius). The EBT and PRESAGE distributions agreed more closely with each other than with the calculated plan, consistent with penumbral blurring in the planning data which was acquired with an ion chamber. In summary, our results support the conclusion that the PRESAGE optical-CT combination represents a significant step forward in 3D dosimetry, and provides a robust, clinically effective and viable high-resolution relative 3D dosimetry system for radiation therapy.

EphA1 activation promotes the homing of endothelial progenitor cells to hepatocellular carcinoma for tumor neovascularization through the SDF-1/CXCR4 signaling pathway.

BACKGROUND: Endothelial progenitor cells (EPCs) can migrate to the tumor tissue and enhance the angiogenesis of hepatocellular carcinoma (HCC); thus, they are associated with a poor prognosis. However, the specific molecular mechanism underlying the homing of EPCs to the HCC neovasculature remains unrevealed. METHODS: Co-culture experiments of endothelial progenitor cells with HCC cells with modulation of EphA1 were performed in vitro. Using EPCs as angiogenic promoters by injecting them into HCC xenograft-bearing nude mice via their tail veins to test homing ability of EPCs changed according to different EphA1 level in HCC xenograft. RESULTS: In this study, we found that the up-regulation of EphA1 expression in HCC cells could affect not only the chemotaxis of EPCs to tumor cells and endothelial cells (ECs) but also the tube formation ability of EPCs in a paracrine fashion. Further, we revealed that the increased expression of EphA1 in HCC cells led to an increased SDF-1 concentration in the tumor microenvironment, which in turn activated the SDF-1/CXCR4 axis and enhanced the recruitment of EPCs to HCC. In addition, the EphA1-activated SDF-1 expression and secretion was partially mediated by the PI3K and mTOR pathways. In vivo experiments demonstrated that blocking EphA1/SDF-1/CXCR4 signaling significantly inhibited the growth of HCC xenografts. Using immunohistochemistry and immunofluorescence assays, we verified that the inhibition of tumor angiogenesis was at least partially caused by the decreased number of EPCs homing to tumor tissue. CONCLUSIONS: Our findings indicate that targeting the EphA1/SDF-1 signaling pathway might be a therapeutic anti-angiogenesis approach for treating HCC.