bluuebunny/crossref_metadata_2025_split huggingface dataset:
High throughput, highly multiplexed transcriptional profiling of cytologic preparations from buccal mucosa
Authors: Everson R. B. , Bangsi D. , Darga L. L. , Bell M. R. , Pidlaoan V. P. , Kanakapalli D. 
Published: March 2020

14104 Background: Alterations in gene expression can be sensitive and informative indicators that a biologically effective exposure occurred. For example, serial specimens could provide evidence that a dose with a biological effect was reached in Phase I testing. Sampling buccal mucosal can provide epithelial cell specimens rapidly with little discomfort. However, ribonucleases in saliva rapidly degrade epithelial cell RNA, prohibiting analysis by standard array techniques. Using buccal cells, we conducted a pilot study to optimize procedures for RNA isolation and analysis and determined influences of gender, race, and cigarette smoking on gene expression. Methods: Buccal cells were collected by scraping the inner cheek with a previously described standardized plastic tool (BioTechniques. 2004;36:484–487) made available Avrum Spira of Boston University. Preliminary experiments compared RNA extraction procedures, including methods based on trizol (Invitrogen, Carlsbad, CA), RNeasy columns (Qiagen, Valencia, CA), and the High Pure RNA Paraffin Kit (Roche, Indiana, USA). After standardization of the method, specimens were obtained from 64 subjects using a blocked design sampling equal numbers of subjects by gender, African American and white race, and smoking status. Gene expression levels were determined using the cDNA-mediated annealing, selection, extension, and ligation assay (Illumina, Inc.), which measures expression of over 500 genes per analysis. Results: The Roche extraction method provided the highest yield of RNA and was used for subsequent assays. Technical replicates were highly reproducible. Preliminary analyses revealed that using P=0.05, 38 genes were expressed differentially by gender, 20 by race, and 10 by smoking status. The genes most differentially expressed by gender included IRF1, MET, STAT1, RAP1GDS1; race CD9, CCNA2, CEACAM1, FVT1; smoking CD44, NQO1, SKI, SRC. Conclusions: Highly multiplexed gene expression analysis of buccal cells are feasible. Demographic characteristics of study subjects can be important, but they do not heavily influence levels for many genes. Results indicate the assays could be provide useful information in cross-sectional or serial studies of the impact of molecular therapeutics. No significant financial relationships to disclose.
Growth inhibitory effect of ceramide-incorporated nanoliposomes in human pancreatic cancer cells
Authors: Jiang Y. , Kaiser J. , Heakal Y. , Cheng H. , Loughran T. , Kester M. 
Published: March 2020

14105 Background: In cancer therapy, it is a challenging task to develop an optimal therapeutic regimen with an improved drug delivery vehicle and a cancer targeting strategy. Liposome-based drug delivery vehicles have been proven feasible and effective in clinical applications. We have recently developed a novel 80 nanometer diameter liposomal formulation that incorporates 30 molar percent C6-ceramide, a lipid-derived second messenger that is proapoptotic to cancer cells, but not to normal cells. Methods: MTT assay was used to evaluate cell proliferation and viability. In vitro soft agar colony forming assay was utilized to assess the transforming activity of pancreatic cancer cell lines. For apoptosis, caspase 3/7 assay was applied. Results: We assessed the biological effect of C6-ceramide nanoliposomes (C6 liposome) in two human pancreatic cancer cell lines, L3.6p1 and Panc1 cells. We demonstrated in L3.6p1 cells as well as Panc1 cells that C6 liposomes, but not control liposomes, increased cytotoxicity, as measured by MTT assay. Moreover, the C6 liposome synergized with low dose gemcitabine, a first line pancreatic cancer neoplastic agent, to dramatically enhance apoptosis, as measured by caspase 3/7 activities. Further, in vitro transforming assays (soft agar colony forming assay) indicated that L3.6p1 cells treated with C6 liposome formed much smaller colonies than that of control cells, suggesting that the C6 liposome alone can inhibit the in vitro transforming ability of the L3.6p1 cells. Conclusions: Collectively, we have developed a novel nanotechnology-based liposomal drug delivery system for pancreatic tumors. Our data suggest that the C6 liposomal formulation is able to enhance the efficacy of gemcitabine to suppress the proliferation and in vitro transforming activity of pancreatic tumor cells. Acknowlegements: Penn State Research Foundation has licensed ceramide liposomes to Tracon Pharmaceutical, Inc. San Diego, CA. No significant financial relationships to disclose.
A phase I trial of lapatinib in combination with carboplatin in patients with platinum sensitive recurrent epithelial ovarian cancer
Authors: Kimball K. J. , Numnum T. M. , Estes J. M. , Kirby T. O. , Barnes M. N. , Alvarez R. D. 
Published: March 2020

14106 Objective: Lapatinib is an inhibitor of EGFR and ErBb-2 tyrosine kinase. It has demonstrated anti-tumor activity in preclinical trials. Early trials evaluated toxicities and doses in several tumors types, however very few ovarian cancer patients have been included in lapatanib trials. The primary objective of this study was to determine the nature and degree of toxicity as well as the maximum tolerated dose (MTD) of Lapatinib in combination with carboplatin when used as second line therapy for platinum sensitive, recurrent ovarian or primary peritoneal carcinoma. The secondary outcome includes preliminary evaluation of response to therapy. Methods: After obtaining IRB approval, patients with measurable, recurrent, platinum sensitive epithelial ovarian or primary peritoneal carcinoma were eligible for enrollment. Patient cohorts were treated with intravenous (IV) carboplatin (AUC 6) every 21 days in combination with escalating dosages of daily oral lapatinib for 6 planned cycles. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events. Response and time to documented progression were also monitored. Results: Nine patients have been enrolled in 2 cohorts to date. Six women with recurrent cancer were administered eighteen cumulative cycles of IV carboplatin and 750 mg of oral lapatinib and were evaluable for toxicity data. The most common toxicity was hematologic with 8 (44%) cycles effected by grade 3 or 4 neutropenia or thrombocytopenia. Two patients were taken off the study secondary to excessive delay for hematologic depression. The dose of carboplatin was reduced to an AUC 5 in the second cohort due to excessive hematologic toxicity and treatment delay. Grade 3 nonhematologic toxicities consisted of abdominal pain (38%), indigestion (6%), fatigue (6%), and urinary frequency (11%). One patient withdrew due to abdominal pain not related to the study drug. Two subjects were evaluable for response. As indicated by biochemical and radiographic examination, both had a complete response and have no evidence of disease. Conclusions: Lapatinib, in combination with IV carboplatin at an AUC 5, portrays an acceptable toxicity profile and antitumor activity. Accrual to cohorts of escalating lapatinib doses is ongoing. No significant financial relationships to disclose.
Dynamic contrast enhanced MRI (DCE MRI) for assessment of effects of anti-angiogenic therapy: Comparison of the transfer constant (Ktrans) to blood flow and permeability derived by a distributed parameters model
Authors: Thng C. H. , Koh T. S. , Rumpel H. , Khoo J. B. , Ong A. B. , Sukri N. , Tai B. C. , Soo R. A. , Humerickhouse R. , Goh B. C. 
Published: March 2020

14109 Background: Transfer constant (Ktrans) and IAUC60 normalized with arterial input function are commonly used dynamic contrast enhanced magnetic resonance imaging (DCE MRI) parameters. The distributed parameters model (DP) is a DCE MRI model that enables derivation of blood flow and capillary permeability-surface area product (PS). We aim to study the distributed parameters model as an alternative method of angiogenesis assessment and correlate the above parameters to drug exposure and patient outcome in a Phase I anti- angiogenic trial. Methods: Fifteen evaluable patients from an on-going Phase I trial (ABT 869) with 3 dose escalations formed the study population. Pharmacokinetic study was performed on Day 1 and the area under the concentration time curve extrapolated to infinity (AUCinfinity) was used as an indicator of drug exposure. All patients underwent DCE MRI at baseline, Day 3 and Day 15 with temporal resolution of 4 seconds. Gadolinium concentrations were estimated using a dual flip angle method. Patients demonstrating progressive disease in first 2 evaluation scans (cycle 2 or 4) based on RECIST criteria were considered progressors and all other patients non-progressors. Receiver operating curve (ROC) analysis was performed. Correlation with AUCinfinity was analyzed. Results: There is good correlation (Spearman’s coefficient -0.67, p = 0.008) between AUCinfinity and DP derived PS and less strong correlation with normalized IAUC60 (Spearman’s coefficient -0.57, p = 0.03). There is no correlation for Ktrans (Spearman’s coefficient 0.04). ROC analysis for predicting progressors versus non-progressors showed a higher ROC area for PS compared to Ktrans (0.83 versus 0.47, p = 0.037). Normalized IAUC60 showed a slightly lower area compared to PS (0.77 versus 0.83) but the difference is not significant (p = 0.58). Conclusions: PS derived from DP model shows better correlation with drug exposure and may predict patient outcome better than Ktrans. [Table: see text]
Effective treatment of 4T1 mammary adenocarcinoma by direct tumor injection and continuous systemic infusion of transferrin receptor antisense in mice
Authors: Head J. F. , Jiang X. , Fort K. A. , Dye V. D. , Elliott R. L. 
Published: March 2020

14113 Background: Transferrin receptors (TfR) on the cell surface are the major transporters of iron into cells. Tumor cells often have increased expression of TfR, compared to normal cells. TfR antibodies have been shown to inhibit the growth of tumor cells. We previously reported that human TfR antisense inhibited the proliferation of human breast cancer cell lines in vitro. Methods: In the present study, we used antisense oligonucleotides targeted to the mouse TfR gene to treat the 4T1 mammary adenocarcinoma mouse model. The antisense was either directly injected one time into the tumors or continuously infused systemically for 14 days through subcutaneous implantation of Alzet osmotic minipumps. The control group of mice received Hank’s balanced salt solution. Tumor sizes were measured twice a week. Tumor necrosis and metastasis were examined grossly at autopsy and by microscopy. Results: At 4, 7 and 10 days post- treatment, tumor volumes of treated groups, including direct injection and continuous infusion, were significantly smaller than the control group. At 14 days post-treatment, gross and microscopic pathology showed that the continuously systemically treated mice had significantly less lung metastases than the control group (p<0.001 and p<0.01, respectively). Although the group of mice treated with direct injection received an equal total dosage of TfR antisense as the continuously systemic treated mice, direct tumor injection of TfR antisense did not suppress lung metastasis. Primary tumors had varying degrees of necrosis in the treated and control groups, but there was no statistical difference between groups. Summary: TfR antisense effectively inhibited tumor growth and metastasis of 4T1 mammary adenocarcinoma in mice. Furthermore, continuously systemic administration of antisense was more effective than direct tumor injection. No significant financial relationships to disclose.
Angiotensin II type 1 receptor antagonist candesartan is an angiogenic inhibitor in MDA-MB 468 human breast cancer cells
Authors: Herr D. , Rodewald M. , Hack G. , Konrad R. , Kreienberg R. , Wulff C. 
Published: March 2020

14114 Background: The present study examined the effect of angiotensin II on the regulation of different angiogenesis associated genes in human breast cancer cells and attempted to determine whether administration of At1R blocker candesartan could suppress the angiotensin II dependent gene regulation. Methods: Angiotensin II dependent expression of vascular endothelial growth factor (VEGF), tissue inhibitor of matrix metalloproteinases 1 (TIMP-1), and hypoxia inducible transcription factor 2alpha (HIF-2alpha) as well as administration of angiotensin II and At1R blocker candesartan was analyzed in MDA-MB 468 human breast cancer cells using immunofluorescence and TaqMan-Real-Time PCR analysis. Results: VEGF, TIMP-1, HIF-2alpha and the At1R were expressed in MDA-MB 468 human breast cancer cells. Angiotensin II significantly increased gene expression of VEGF, TIMP-1, and HIF-2alpha in these cells. This effect was completely inhibited by candesartan. Conclusion: It is hypothesized that angiotensin II is involved in regulation of tumor angiogenesis in breast cancer by regulation of angiogenesis associated genes via At1R. These findings are the first evidence for targeting tumor angiogenesis by inhibition of At1R in human breast cancer cells and may lead to new therapeutical anticancer strategies proposing administration of candesartan. No significant financial relationships to disclose.
Gene expressions of TS and MDR-1 are predictive factors for chemosensitivity and survival in esophageal cancer with fluoropyrimidine-based chemotherapy
Authors: Uchida K. , Hayashi K. , Kudo K. , Kuramochi H. , Yamamoto M. 
Published: March 2020

14120 Background: Fluoropyrimidines are widely used in chemotherapy regimens for esophageal cancer. To test the hypotheses of whether the relative mRNA expression of the enzyme TS, DPD and MDR-1 were associated with response to in esophageal cancer. We investigated the associations reported between intratumoral TS, DPD and MDR-1 gene expressions and the response with 5-FU based chemotherapy for patients with esophageal cancer. Methods: Twenty six pts with esophageal cancer were treated with 5-FU based chemotherapy (14 pts were treated with chemotherapy only, and 12 pts were chemoradiotherapy). mRNA was isolated from frozen tumor specimens, and relative expression levels of each gene/β-actin were measured using a quantitative reverse transcription polymerase chain reaction (RT-PCR) (Taqman®) system. Results: The overall response rate was 50.0%. Each mRNA expression was detectable in 26 patients. TS expressions were significantly lower in the responding tumors compared to the non-responders respectively (P=0.009). There were no significant associations between MDR-1 expression and the response. By setting up a cut-off level for TS and MDR-1 of Median, combining the two gene expression two-dimensionally revealed a relationship with the response (P=0.037). Additionally, MDR-1 expressions were statistically significant predictors of prolonged survival (P=0.0084). Conclusions: These results suggest that intratumoral TS and MDR-1 expressions are prognostic factors for survival after 5-FU based chemotherapy in esophageal cancer. No significant financial relationships to disclose.
Expression and secretion of VEGF in solid tumor cells is mediated by the mammalian target of rapamycin (mTOR)
Authors: Lackner E. M. , Krauth M. T. , Kondo R. , Rebuzzi L. , Eigenberger K. , Vales A. , Kornek G. V. , Zielinski C. C. , Valent P. 
Published: March 2020

14123 Background: Tumor progression and metastasis formation are often associated with enhanced angiogenesis and with the formation of malignant effusions. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and a mediator of vascular permeability. We here describe that VEGF is produced and secreted by neoplastic cells in various solid tumors and its production mediated through mTOR. Methods and Results: As assessed by ELISA, the VEGF protein was detected in supernatants of cell lines derived from breast cancer (MDA-MB231), pancreatic carcinoma (BxPC-3), lung cancer (A-427), colon carcinoma (HCT8), and cholangiocellular carcinoma (EGI-1). In addition, VEGF was detected in supernatants of primary tumor cells obtained from malignant effusions in various malignancies (breast cancer, n=4; pancreatic cancer, n=1; ovarial cancer, n=1; parotic carcinoma, n=1; oesophageal carcinoma, n=1). In each case, VEGF protein was detectable in neoplastic cells by immunocytochemistry, and was found to accumulate in supernatants of cultured tumor cells over time, suggesting constant production and secretion. Correspondingly, as assessed by RT-PCR, primary tumor cells as well as the cell lines tested were found to express VEGF mRNA in a constitutive manner. Since mTOR is a well known regulator of VEGF synthesis, we applied rapamycin on primary neoplastic cells and on tumor cell lines. Rapamycin (20–200 nM) was found to counteract the production and secretion of VEGF in all tumor cells tested (VEGF in supernatants in cultures supplemented with rapamycin at 100 nM compared to control=100% on day 6: MDA-MB231: 11.8±0.2%; BxPC-3: 23.6±18.8%; A-427: 30.1±3.4%; HCT8 17.2±0.5%; EGI-1 28.4±1.1%; p<0.05). By contrast, neither rapamycin nor VEGF were found to modulate growth of primary tumor cells or the growth of the tumor cell lines tested. Conclusions: Various human tumor cells express and secrete VEGF. VEGF production is mediated through mTOR. These observations may have implications for the design of new treatment approaches attempting to counteract VEGF production/secretion and thus VEGF-dependent angiogenesis and effusion- formation in solid tumors. No significant financial relationships to disclose.
Prevention of chemotherapy-induced delayed nausea and vomiting with aprepitant in patients recieving highly emetogenic-five day cisplatin regimens
Authors: Joshi A. J. , Singh H. , Chawla S. 
Published: March 2020

14125 Background: It has been shown that addition of the NK1 receptor antagonist aprepitant to 5HT3 antagonist plus dexamethasone is more effective than just the 5HT3 antagonist plus dexamethasone for prevention of acute and delayed emesis due to high dose cisplatin and also that this effect lasts for multiple cycles. This study evaluated whether the antiemetic efficacy of aprepitant could be sustained for 5 day cisplatin regimens. Methods: Patients receiving cisplatin 20mg/m2/day for 5 days (PEB and TCF regimens ) were randomized to one of the following two regimens: (1) aprepitant 125 mg 1 hour before cisplatin on day 1 and aprepitant 80 mg on days 2 and 3 (n = 17); (2) placebo before cisplatin on days 2 to 7 (n = 19). All groups received ondansetron 32 mg and dexamethasone 20 mg before cisplatin, and dexamethasone 8 mg on days 2 to 7. The primary end point was complete response (no emesis and no rescue therapy) over 7 days following cisplatin in up to six cycles analyzed by a modified intent-to-treat approach. Secondary end point was evaluated using Functional Living Index-Emesis questionnaire. Treatment comparisons were made using logistic regression models and P value calculated using the chi square test due to small sample size. Results: In the acute period, 83% and 56% of patients were without emesis in groups I and II, respectively (P < .01 for group I v group II). In the delayed period upto day 5, the proportion of patients without emesis in groups I and II, was 59% and 32%, respectively (P < .01 for groups I v group II). In the extended period day 6 and 7 the proportion of patients without emesis in groups I and II was 50% and 38% respectively (P< .01 for groups I v II). The distribution of nausea scores in the delayed period beyond day 5 was lower when comparing group I with group II (P < .05 for days 6 and 7). Two serious adverse events of diarrhea were probably attributed to aprepitant. Conclusions: Once daily oral administration of aprepitant was effective and superior in reducing delayed emesis and nausea after 5 days cisplatinum regimen when added to 5HT3 antagonist plus dexamethasone. This benefit persists upto day 7. Confirming and extending previous results aprepitant should be used in triple combination in patients receiving 5 day cisplatin regimens. No significant financial relationships to disclose.
Genistein combined polysaccharide (GCP) is highly active in both human and canine lymphoma models
Authors: Mack P. C. , Burich R. A. , McCall J. L. , Kent M. S. , Hackman R. M. , Tuscano J. M. , deVere White R. W. 
Published: March 2020

14126 Background: The soy isoflavones genistein and daidzein have demonstrated anticancer activity in vitro in multiple tumor types including leukemia/lymphoma, with evidence for a role in chemoprevention. GCP (Amino Up Chemical Co.) is a fermentation product of soy extract and the mycelium of Basidiomycetes, a process which converts soy isoflavones to their aglycone form, greatly increasing intestinal absorption. In humans, GCP has negligible toxicity at potentially active concentrations. We hypothesized that GCP would have significant anticancer activity in hematologic malignancies. Methods: Three human lymphoma cell lines (Jurkat, Raji, and Ramos), a leukemia line (HL60), and four canine lymphoid cell lines (GL-1, CLGL-90, CL1, and CLL-1390) were treated with GCP at doses ranging from 25 to 200 μg/ml. Growth effects were assessed by trypan blue exclusion 5–7 days following a single treatment. Flow cytometry and Westerns were used to measure changes in cell cycling, protein expression and apoptosis. We are conducting a single-agent dose escalation clinical trial in chemo-naïve canines with lymphoma. Results: GCP had striking cytotoxic effects in both canine and human lymphoma cell lines. In all human lines, the 50% inhibitory concentrations (IC50s) were less than 25μg/ml. At 100μg/ml, a concentration achievable in patient plasma, virtually no viable cells remained. Three of four canine lines were sensitive with IC50s in the range of 15–50μg/ml. Substantial G2 cell cycle accumulation was observed, apparent within two hours and maintained for at least 48h. GCP treatment induced apoptosis, as shown by an increase in sub-G1 DNA content and cleavage of PARP and caspase 3. At higher doses, elevated Bcl-2 levels were observed, suggesting a potential mechanism of resistance. These results provided the rationale for a clinical trial in canine patients at UC Davis. One patient with aggressive diffuse large B-cell lymphoma treated at 93 mg/kg/day (dose level 2) had a confirmed partial response. Conclusions: GCP has potent anticancer activity in vitro against lymphoid cell lines, with almost complete cell kill at doses achievable in patient plasma with minimal toxicity. A phase I clinical trial in canine lymphoma will determine whether testing in human lymphoma patients is warranted. No significant financial relationships to disclose.