bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective and therapeutic effects of nanoliposomal quercetin on acute liver injury in rats
Authors: Liu Xiangyan , Zhang Yang , Liu Ling , Pan Yifeng , Hu Yu , Yang Pu , Liao Mingmei 
Published: March 2020

Abstract
Background
Quercetin, a pigment (flavonoid) found in many plants and foods, has good effects on protecting liver function but poor solubility and bioavailability in vivo. A drug delivery system can improve the accumulation and bioavailability of quercetin in liver. In this study, we used liposomal nanoparticles to entrap quercetin and evaluated its protective and therapeutic effects on drug-induced liver injury in rats.

Methods
The nanoliposomal quercetin was prepared by a thin film evaporation-high pressure homogenization method and characterized by morphology, particle size and drug content. Acute liver injury was induced in rats by composite factors, including carbon tetrachloride injection, high-fat corn powder intake and ethanol drinking. After pure quercetin or nanoliposomal quercetin treatment, liver function was evaluated by detecting serum levels of glutamic-pyruvic transaminase (GPT), glutamic-oxal acetic transaminase (GOT) and direct bilirubin (DBIL). Histology of injured liver tissues was evaluated by hematoxylin and eosin staining.

Results
On histology, liposomal nanoparticles loading quercetin were evenly distributed spherical particles. The nanoliposomal quercetin showed high bioactivity and bioavailability in rat liver and markedly attenuated the liver index and pathologic changes in injured liver tissue. With nanoliposomal quercetin treatment, the serum levels of GPT, GOT and DBIL were significantly better than treated with pure quercetin. Using liposomal nanoparticles to entrap quercetin might be an effective strategy to reduce hepatic injury and protect hepatocytes against damage.

Conclusion
Liposomal nanoparticles may improve the solubility and bioavailability of quercetin in liver. Furthermore, nanoliposomal quercetin could effectively protect rats against acute liver injury and may be a new hepatoprotective and therapeutic agent for patients with liver diseases.
Targeting PI3K in alveolar rhabdomyosarcoma (aRMS)
Authors: Crosswell H. E. , Peng Q. , Prince C. , De P. , Durden D. L. 
Published: March 2020

10025 Background: aRMS is a pediatric solid tumor with a poor prognosis despite aggressive therapy. HGF/c-Met & PTEN-PI3K-AKT pathways are aberrant, leading to aRMS growth & metastasis. We hypothesize that recapitulating the tumor suppressor (TS) function of PTEN with small molecular inhibitors (SMIs) may control aRMS. SMIs of HGF/c-Met & PI3K pathways were examined for their control of aRMS growth & migration. Design/Methods: Pax3/fkhr-associated aRMS cells, RH30, were infected with MIEG3/PTEN (RH30MP1), MIEG3 retroviral vector (RH30MV1) or CMV-driven luciferase (RH30Luc). Migration was assessed by a transwell migration chamber; proliferation with a MTT assay; biochemical analysis by Western blot. Tumor growth and spontaneous lung metastasis in IACUC-approved animal experiments, in which cell lines were injected s.c. in nude mice, were analysed by bioluminescent imaging (BLI) or by direct measurements. Students t-test (p<.05) determined significance. Results: Western analysis revealed RH30 cells have low PTEN, high levels of c-Met & p-AKT. HGF stimulation of RH30 cells results in increased p-Met, p-Akt & p-Erk1/2 levels, correlating with enhanced migration and proliferation (<.001). SMI of PI3K (LY294002) controls RH30 proliferation (p<.01), not migration; c-Met (PHA665752) & MAPK (PD98059) SMIs stop HGF-directed migration through control of p-Erk levels (p<.01). PTEN induction in RH30 cells via PPAR-gamma agonist, rosiglitazone, results in decreased basal p-Akt levels. RH30 cells with stable, retroviral-infected PTEN have significantly reduced migration& proliferation as compared to cells with vector alone (p<.001). In nude mice xenograft models, PTEN & novel PI3K SMI, SF1126 at 50mg/kg, control RH30 tumoriginesis. SF1126 also controls spontaneous RH30Luc metastasis to the lungs. Conclusions: High c-Met-expressing RH30 cells are sensitive to HGF-stimulated migration through MAPK & proliferation via PI3K. PTEN’s control of aRMS migration, proliferation & tumorigenesis suggests that PTEN controls both PI3K & MAPK. Novel PI3K inhibitor, SF1126, controls tumor growth in vivo & prevents spontaneous lung metastasis. Recapitulating PTEN TS function with SF1126 alone or in combination with SMIs of the HGF/c-Met or MAPK may benefit patients with aRMS & deserves further pre-clinical study. [Table: see text]
A comparison of BRCA1 and BRCA2 risk assessment models
Authors: Panchal S. , Ennis M. , Yee H. , Contiga V. , Bordeleau L. J. 
Published: March 2020

10034 Background: A number of models of varying complexity are available to calculate the risk of carrying a BRCA1 or BRCA2 mutation causing hereditary breast and ovarian cancer. A >10% risk of carrying a BRCA1 or BRCA2 mutation is commonly used to establish testing eligibility in North America (testing threshold). We have compared these risk assessment models to ascertain their utility in patients from a large breast cancer program in our tertiary referral center. Methods: Risk assessment calculations were performed using the BRCAPRO, Myriad, Manchester, and UPennII models for all new probands referred to our clinic at Mount Sinai Hospital, Toronto (Canada), between May and October 2005. Individuals with a known familial mutation were excluded. Pearson correlation coefficients and pairwise scatterplots were performed for each pair of models. Regression analyses were developed to explore how well the BRCAPRO model can be predicted by other models. Results: 103 probands were included in our analyses (97% female, mean age: 50 yrs, 22% of Ashkenazi Jewish descent, 52.4% affected with breast cancer, 67% with ≥ one 1st degree relative affected with breast or ovarian cancer). The proportion of probands meeting the testing threshold based on each model was: BRCAPRO (34.0%), Myriad (33.0%), Manchester (55.3%), and UPennII (46.6%). Correlations calculated for each pair of models were large (range: 0.48–0.86). In comparing two of the most clinically relevant models (BRCAPRO and UPennII), the proportion of probands meeting the testing threshold was significantly higher using the UPennII model (p=0.0036). Between these two models, a higher correlation was observed for BRCA1 than for BRCA2 (R=0.76, R=0.58, respectively). The UPennII model was the strongest univariate predictor of the BRCAPRO results. Conclusions: All risk assessment models predicted a substantial proportion of patients referred to our clinic to be eligible for testing (≥ 33% of probands). A significantly higher proportion of probands were eligible for testing when using the UPennII model compared to the BRCAPRO model. This difference is in part due to the differential inclusion of prostate/pancreatic cancers and of third degree relatives with cancer in these models. An exploration of the sensitivity and specificity of these models will be presented. No significant financial relationships to disclose.
Serum antibodies specific for tumor antigens in colorectal cancer may be useful diagnostic biomarkers
Authors: Lu H. , Goodell V. , Disis M. L. 
Published: March 2020

10041 Background: Colorectal cancer is immunogenic as evidenced by the presence of antibodies specific to tumor antigens in patient serum and T cell infiltration at the tumor site predicting favorable disease outcome. We questioned whether antibody immunity to tumor associated antigens (TAA) in patients with colorectal cancer could be used as a biomarker to predict disease. Methods: We evaluated serum samples for the presence of antibody immunity to six tumor antigens, cyclin D1, HER-2/neu, insulin-like growth factor binding protein 2 (IGFBP2), NY-ESO-1, p53, and topoisomerase-IIα (TOPO2α), in colorectal cancer patients (n=40) and normal donors (n=200) using ELISA. We then evaluated the diagnostic value of these potential biomarkers by measuring antibody levels to these TAA in an independent sample set which included 30 colorectal cancer patients and 135 normal donors. The samples were judged as positive or negative for colorectal cancer using measurements derived either from a single marker or a combination of the markers. Receiver operating characteristic (ROC) plots were generated to determine the diagnostic accuracy of each test. Results: Colorectal cancer patients had increased levels of antibodies to p53 (p=0.002), TOPO2α (p<0.001), and IGFBP2 (p<0.001) compared to controls. By using a combination of just two antibody measurements, TOPO2α and IGFBP2, we could discriminate colorectal cancer patients from controls with a diagnostic power of 0.775 as estimated by the area under ROC curve. At a cutoff point of 0.03 mcg/ml TAA specific IgG, the sensitivity was 100% and the specificity was 58%. Conclusions: Serum antibodies to colorectal cancer related antigens may serve as useful biomarkers for colorectal cancer diagnosis. No significant financial relationships to disclose.
Therapy prediction in a breast cancer primary systemic chemotherapy (PST) study applying docetaxel/epirubicin/cyclophosphamide (TEC) by gene expression profiling
Authors: Vogt U. , Brandt B. , Bosse U. , Bonk U. , Adigüzel H. , Ergoenenc Y. , Kemming D. , Schlotter C. 
Published: March 2020

10049 Background: Currently there are no tests to assist in selecting the optimal PST regimen for breast cancer patients. Primary study goals of this prospective, single-armed multicentric investigation are pathologically confirmed tumor response and the rate of breast conserving therapy (BCT). Secondary goals are to find histopathologic and gene profiling patterns best correlating with tumor remission in a taxane- anthracycline based neoadjuvant setting as well as to evaluate cytostatic toxicity and quality of life. Methods: In this phase II study of totally 40 eligible patients with invasive breast cancer Human Genome Survey Microarray (HGSM) expression profiling is performed on jet-biopsy sample basis. The protocol was elaborated for the treatment of patients suffering from a primary tumor with 6 cycles of TEC (3-weekly) prior to the surgical treatment. The selection of predictor genes was done with BRB-ArrayTools Version 3.3 using a model based on the Compound Covariate Predictor, Diagonal Linear Discriminant Analysis, Nearest Neighbor Classification, and Support Vector Machines with linear kernel.We estimated the prediction error of each model using leave-one-out cross-validation (LOOCV) as described by Simon R. 2000 random permutations were used. Clustering was done using Cluster 3.0 and Java TreeView 1.0.12. Results: Tumor response (pCR, pPR) of more than 70% can be achieved using neoadjuvant TEC-regimen. 22% pCR (ypT0; ypN0) and 90% BCT in this study are comparable with data of other published PST trials. Preliminary expression profiling results reveal a subset of 148 genes that classifies all patients with a complete remission (pCR), in one cluster with a very closely related gene expression pattern (n=5; PPV = 100%). Furthermore 10 patients defined as responders due to selected MIB1-expression based criteria (expressing cells in the residual tumor ≤ 5% and a Δ MIB1-expression ≥ 20%) can be correctly classified in 9 of 10 cases. Comparable separation of the groups could not be achieved by established tumor factors. Conclusions: HGSM expression profiling is promising to have the potential to figure out genes that are related to chemotherapy response, especially in PST. No significant financial relationships to disclose.
Gene and surface-antigen expression profilings concordantly identify alpha4-integrin/CD49d as a marker for unmutated (UM) bad prognosis B-cell chronic lymphocytic leukemia (B-CLL)
Authors: Gattei V. , Benedetti D. , Marconi D. , Dal Bo M. , Zucchetto A. , Del Poeta G. , Steffan A. , Bomben R. , Campanini R. , Degan M. 
Published: March 2020

10076 Background: The highly heterogeneous clinical courses of B-CLL can be foreseen by investigating IgVH gene mutations or expression of specific prognosticators. Gene and surface-antigen expression profilings (GEP and SEP) have been both employed for identifying molecules of prognostic relevance in B-CLL. Methods: i) GEP - Purified B-CLL cells from 19 UM and 38 mutated (M) cases were investigated for differential GEP by using a two-color Operon Human Genome Oligo Set 2.1 platform with normal B cells as common reference and by applying, after data pre-processing, the LIMMA (Linear Model for MicroArray) package with two combined cutoffs (Bayesian log-odds>1; adjusted p value for false discovery rate <10e−4); ii) SEP - B-CLL cells from 60 UM and 101 M cases were investigated for the expression of 36 surface markers by flow cytometry. Results: i) GEP - 77 probes (32 duplicates) were overexpressed in M B-CLLs (UM/M log-ratio range −0.79/−3.62; p range 6.72e−5/3.6e−10) and 81 probes (46 duplicates) in UM B-CLLs (UM/M log-ratio range 0.87/4.57; p range 9.49e−5/3.01e−12); the CD49d gene was overexpressed in UM cases with UM/M log-ratio of 3.21 (p=8.3e-10). ii) SEP - Six markers significantly discriminated UM to M B-CLLs (t-test, p<10ed-3) and separated most UM (49/60) from M B-CLLs by hierarchical clustering; among them, CD49d was significantly overexpressed in UM cases (median % positive cells 71.2±36 vs. 10.0±31; p=2.1e−10). By applying standardized log-rank statistics in 95 pts, all with CD49d expression and survival data, 30% of positive cells was judged optimal cutoff for identifying two groups with different survivals, 41 CD49dhigh pts showing worse prognosis than 54 CD49dlow cases (p=7.4×10e−5). Similarly, 46 UM B-CLLs had shorter survival than 77 M cases (p=1.4×10e−5). By combining IgVH mutations and CD49d expression, 42 concordant M/CD49dlow pts had better prognosis than 25 concordant UM/CD49dhigh cases (p=1.8×10e−5); noteworthy, among 28 discordant cases, 16 with a M/CD49dhigh phenotype had survival similar to bad prognosis cases. Conclusions: CD49d is a novel prognosticator for B-CLL. Given its high expression level in bad prognosis subsets, CD49d may be a promising therapeutic target. No significant financial relationships to disclose.
Serum levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) as prognostic factors in malignant pleural mesothelioma (MPM)
Authors: Betta P. , Filiberti R. , Marroni P. , Neri M. , Orecchia S. , Libener R. , Bottero G. , Paganuzzi M. , Puntoni R. 
Published: March 2020

10080 Background: MPM is an uncommon but extremely aggressive tumor of the serosal surfaces, which has been closely linked to asbestos exposure. Several in-vitro studies have demonstrated that HGF enhances MPM cell proliferation, migration, and invasiveness and the presence of EGF is closely related to the process of cell differentiation and the synthesis of glycosaminoglycans in MPM cells. Few studies have measured the blood levels of these growth factors in tumor patients and assessed their correlation with clinical outcome. This pilot study was designed to investigate the potential value of serum EGF and HGF measurements for the diagnosis and the prediction of survival in MPM patients. Methods: Baseline serum EGF and HGF levels (ng/ml) were determined using an ELISA method in 81 newly diagnosed MPM patients (mean age 67.5±11.0 years) and 48 patients with benign respiratory diseases (BRD; mean age 64.3±13.5 years). Results: HGF and EGF median concentrations in MPM (1.6 ng/ml and 0.5 ng/ml, respectively) were not statistically different from concentrations in BRD (1.2 ng/ml and 0.4 ng/ml). Median follow-up for MPM patients was 27 months, while overall median survival was 11.8 months. At univariate analysis, only high EGF serum levels were associated with an unfavorable survival outcome. Using a cut-off point for EGF of 0.5 ng/ml (corresponding to the median of marker concentration in MPM), the survival rate in patients with higher serum EGF was significantly worse than that in patients with lower levels (median 10.7 vs. 13.0 months, p=0.01). Multivariate analysis, after adjusting for age, sex, histology and platelet count, confirmed the independent predictive value of serum EGF concentration as a negative prognostic factor (p=0.01). Conclusions: High pre-treatment levels of serum EGF are associated with an adverse prognostic impact on survival in MPM patients. No significant financial relationships to disclose.
Preoperative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer
Authors: Reinthaller A. , Sevelda P. , Hefler L. A. 
Published: March 2020

10093 Objective: Serum vascular endothelial growth factor (VEGF) levels have been shown to be associated with an adverse outcome in patients with ovarian cancer. We studied the clinical value of serum VEGF as an independent prognostic parameter. Methods: In the present study, we ascertained preoperative serum VEGF in a series of 314 patients with ovarian cancer. VEGF serum were evaluated in 45 new cases. Serum VEGF was evaluated prior to primary surgery in all patients. The re-analysis of previously published data comprised a total of 269 cases. Patients were treated between 1990 and 2003. Mean duration of follow-up was 38.9 (32.4) months. Patients with epithelial ovarian cancer were included into the present study, patients with other malignant ovarian tumors, borderline tumors, and benign adnexal masses were excluded. Serum VEGF was evaluated prior to primary surgery using an enzyme linked immunosorbent assay (Quantikine Human VEGF Immunoassay; R&D Systems, Minneapolis, MN) in all studies. Results were correlated with clinical data. Results: Median serum VEGF was 407 (238–746) pg/mL. Serum VEGF was associated with serum CA 125 (p=0.003) and residual tumor mass (p=0.02; residual tumor mass < 1cm: 375.5 [209.5–608.9] pg/mL vs. residual tumor mass ≥ 1cm: 625.2 [320.7–1046.7] pg/mL). Serum VEGF was not associated with FIGO stage (p=0.5), lymph node involvement (p=0.2), tumor grade (p=0.2), and patients’ age (p=0.08). In a univariate Kaplan-Meier analysis, FIGO stage, residual tumor mass, tumor grade, patients’ age, serum CA 125, and preoperative serum VEGF were associated with overall survival. In a multivariate Cox regression model, higher FIGO stage, presence of residual tumor mass after primary surgery, and higher serum VEGF were independently associated with a shortened overall survival. Planned subgroup analysis was performed for patients with ovarian cancer FIGO stage I. In a multivariate Cox regression model, higher tumor grade and higher serum VEGF were the only independent prognosticators for overall survival. Patients with FIGO stage I ovarian cancer and a serum VEGF ≥ 380 pg/mL had a 8-fold increased risk for experiencing cancer related death. Conclusion: Serum VEGF is an independent prognostic parameter in patients with all stages of ovarian cancer. No significant financial relationships to disclose.
Engaging human tumor microvascular endothelium to improve ionizing radiation outcomes in solid tumor treatment
Authors: Lewin S. N. , Barakat R. R. , Haimovitz-Friedman A. , Kolesnick R. , Fuks Z. , Poynor E. A. 
Published: March 2020

10097 Background: Recent genetic and pharmacologic mouse model studies have shown tumor microvascular endothelium is a primary target in single-dose radiotherapy, required for induction of tumor cell death. The goal of this study is to establish the human tumor microvascular response to ionizing radiation (IR), and to determine whether targeting this response with IR might improve solid tumor treatment. Methods: Fresh epithelial ovarian cancer (EOC) tissue was obtained and irradiated within 30 minutes from patients undergoing surgical resection. Tumors were sliced into 0.5cm fragments, bathed in Dulbecco’s Modification of Eagle’s Medium (DMEM) and irradiated ex vivo at 0, 7, 13, 17, 20, 25 Gy. Specimens were incubated at 37°C post-irradiation for 0, 2, 3, 4 hours, fixed in formalin and paraffin embedded. Immunohistochemistry using TUNEL-CD34 double staining was subsequently performed to detect apoptotic tumor endothelial cells. Results: 10 EOC specimens were initially studied. Tumor microvascular endothelium underwent a linear dose and time dependent apoptotic response mirroring the range reported in mouse models. Three to four hours post irradiation, 60% of endothelial cells underwent apoptosis at 17–25 Gy compared to a baseline rate of 5% in unirradiated controls. Response heterogeneity among the tumor samples was not seen. Of interest is our observation that a maximal apoptotic response obtained in glioblastoma, classically considered radioresistant, was only 30%. Conclusion: The endothelial compartment is an important target in EOC radiation response at the clinically-relevant dose range. Studies assessing endothelial cell radiosensitivity of human EOC and the impact of endothelial cell radiosensitizing agents may provide opportunities to improve radiation responsiveness of EOC. No significant financial relationships to disclose.
Androgen-dependent regulation of Her-2/neu in prostate cancer cells
Authors: Berger R. , Lin D. I. , Nieto M. , Signoretti S. , Hahn W. C. , Loda M. 
Published: March 2020

10099 Background: The mechanisms underlying the progression of prostate cancer to androgen independence remain poorly understood. Overexpression of Her-2/neu (c-ErbB2) activates the androgen receptor pathway and confers a survival and growth advantage to prostate cancer cells in an androgen-deficient milieu. Methods: Androgen-sensitive prostate cancer cell line LNCaP was used as a model system in vitro and in vivo. Experiments in mice were undertaken by injecting cells orthotopically into the ventral lobe of the mice prostate. Results: Here, we report that androgen receptor (AR) and Her-2/neu reciprocally regulate each other in LNCaP human prostate cancer cells. Absence of androgens, AR blockade with Casodex (bicalutamide) or suppression of AR with RNAi induced Her-2/neu protein expression and phosphorylation in vitro and in vivo. Similarly, suppression of Her-2-neu expression resulted in AR upregulation. In contrast, upon re-administration of androgens, Her-2/neu mRNA, protein and phosphorylation levels decreased linearly with increasing concentrations of androgens as LNCaP cells re-entered the cell cycle. Conclusions: Thus, induction and activation of Her-2/neu occurs in an androgen-depleted environment or as a result of AR inactivation, promoting androgen-independent survival of prostate cancer cells. No significant financial relationships to disclose.