bluuebunny/crossref_metadata_2025_split huggingface dataset:
The inhibition of p21 on irradiation-induced apoptosis in EL-4 cells.
Authors: Yan Feng-qin , Wang Jian-qiu , Fu Shi-bo , Wang Fang-zheng , Fu Zhen-fu , Ju Gui-zhi 
Published: March 2020

e13558 Background: To elucidate the effect of p21 on ionizing radiation-induced apoptosis in EL-4 cells. Methods: In EL-4 cells, RT-PCR, immunocytochemistry and flow cytometry (FCM) were used to analyze the changes in the expression of p21 with time and doses caused by ionizing radiation; RNAi was used to silence the expression of p21 in EL-4 cells; FCM was applied to analyze the distribution of cell cycle,the number of the chromosome and the apoptosis in wild or p21-silencing EL-4 cells exposed to X-rays. Results: In EL-4 cells, p21 protein level was markedly increased at 8 ~ 72 h after exposure in 4.0 Gy of X-ray in vitro (p<0.01), as well as exposed in 1.0 ~ 4.0 Gy of X-ray at 24 h in vitro (p<0.05). Results of time-course experiments showed that, in EL-4 cells exposed to 4.0 Gy X-rays, the percentage in G0/G1 phase increased while that in S phase decreased, significantly different with the sham-irradiated groups (p<0.05), during 8-48h after exposure; the percentage of diploid cells increased significantly during 8-48 h (p<0.01), and the percentage of tetraploid and octoploid cells decreased significantly at 2 h and 8 h (p<0.05); the percentage of apoptosis during 2-72 h increased significantly (p<0.05-p<0.01). Compared with wild EL-4 cells, in p21-silencing EL-4 cells, the distribution of cell cycle had no apparent difference; the percentage of diploid cells decreased significantly and the percentage of octoploid cells increased significantly (p<0.01); the percentage of apoptosis increased significantly (p<0.05). Conclusions: p21 inhibited the apoptosis induced by ionizing radiation in EL-4 cells.
Phase I clinical, pharmacokinetic, and pharmacodynamic study of CG200745, a histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumors.
Authors: Kim Kyu-Pyo , Hong Yong Sang , Ahn Jin-Hee , Lee Jae-Lyun , Bae Kyun-Seop , Kim Tae Won 
Published: March 2020

e13560 Background: The aim of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single dose of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Methods: Two to six patients received Intravenous CG200745 every 3 weeks according to the single dose-escalating 2+4 method. Acetylated histone H4 (Acetyl-H4) was measured in peripheral blood mononuclear cells (PBMCs). Results: Ten patients were treated at one of five doses (1.8-24.0 mg/m2) and received 3 (1-7) cycles of CG200745 (median, range). No dose-limiting toxic effects or QTc prolongations were noted. Dose proportionality was observed for both Cmax and AUC. The elimination half-life and mean residual time was 5.43±0.37(mean±SD) and 4.15±0.50 hrs. An increase in Acetyl-H4 was observed at hour 1 and correlated with dose and Cmax. Acetyl-H4 persisted for 8 hrs in 3 pts and 24 hrs in another 3 pts. Stable disease was seen in 2 pts with colorectal cancer at levels 7.2 and 24 mg/m2. Conclusions: CG200745 can be safely administered at the effective dose levels that inhibit HDAC in PBMCs. As MTD was not reached, this agent is under further investigation for multiple ascending doses.
Expression of eIF4E relevant biomarkers detected in circulating tumor cells from metastatic NSCLC and prostate cancer patients using antibody-independent ApoStream technology.
Authors: Wu Weiguo , Woo Jacky , Melnikova Vladislava O. , Pace Margaret , Gupta Vishal , Jouravleva Elena , Anderes Kenna Lynn , Ackermann Elizabeth J. , Kwoh T. Jesse , Davis Darren W. 
Published: March 2020

e13562 Background: Enumeration of circulating tumor cells (CTCs) is used clinically to monitor disease progression and has previously been shown to be an independent biomarker for predicting survival of metastatic breast, prostate, and colorectal cancer patients. Molecular characterization of CTCs is rapidly emerging as a minimally invasive approach to interrogate the genotype and phenotype of cancers. However, the use of EpCAM-based enrichment platforms relies on the expression of EpCAM thus limiting the type of tumor cells that can be recovered. ApoStream, is a novel, antibody-independent, dielectrophoretic field-flow fractionation based technology that recovers CTCs from cancer patient blood samples. Methods: A side-by-side comparison of EpCAM dependent CellSearch and ApoStream was performed for CTC enumeration in NSCLC and prostate cancer patients. A multiplexed immunofluorescent assay was developed for CTC (cytokeratin+/CD45-/DAPI+ cells) enumeration. CTCs recovered by ApoStream were evaluated for the expression of multiple eIF4E pathway biomarkers using quantitative laser scanning cytometry (LSC). Results: ApoStream isolated a significantly greater number of CTCs in both NSCLC and prostate cancer patients (NSCLC: range 9-1037, mean=407 by ApoStream versus a range of 30-340, mean=118 by CellSearch , p<0.05; prostate cancer: range 12-3490, mean=1472 by ApoStream versus a range of 16-2155, mean=502 by CellSearch , p<0.05). The eIF4E protein expression in CTCs was positively correlated with the CTC count. A trend toward correlation between the eIF4E protein expression level and the expression levels of Cyclin D1, Survivin and Bcl-2 was observed. Conclusions: The ApoStream platform recovers higher numbers of CTCs from the blood of metastatic NSCLC and prostate cancer patients compared to the EpCAM-dependent CellSearch platform. CTCs recovered by ApoStream are suitable for downstream molecular analyses paving the way for broader applications in translational cancer research.
ERCC1, p16, and Ki-67 immunohistochemichal expression as predictive and prognostic markers in head and neck squamous cell carcinoma treated with platin-based induction chemotherapy: Staining with the two anti-ERCC1 antibodies (8F1 and FL-297) was compared.
Authors: Roussel Helene , Housset Martin , Tournat Helene , Ravel Patrice , Hans Stephane , Bruneval Patrick , Badoual Cecile 
Published: March 2020

e13578 Background: Head and neck squamous cell carcinoma (HNSCC) treatment had undergone important changes, in particular due to the organ preservation and the advent of chemotherapy, particularly using platinum. The excision repair cross-complementation group 1 (ERCC1) enzyme plays a rate-limiting role in the nucleotide excision repair pathway and has been associated with resistance to platinum-based chemotherapy. The purpose of this study was to evaluate the role of ERCC1expression with p16 and Ki-67 as predictive markers in the response to platin-based induction chemotherapy and as prognostic markers in patients with HNSCC. Methods: 208 patients treated from 2000 to 2006 by an induction chemotherapy regimen for HNSCC were included retrospectively. ERCC1 (8F1 and FL297 clone), p16 and Ki-67 staining were performed on paraffin-embedded tumor tissue collected before chemotherapy. We assessed response to treatment, progression-free survival (PFS) and overall survival (OS). Results: Respectively, 68% (142/208 patients) and 81.5% (163/200 patients) of HNSCC showed low expression of 8F1 and FL297 ERCC1. No correlation was found between the two clones (p=0.1). There was no correlation between the expression of 8F1 ERCC1, FL297 ERCC1 and Ki-67 and the response to induction chemotherapy, OS or PFS. However, in the subgroup of 129 patients treated with induction cisplatin-5FU chemotherapy, a low expression of 8F1 ERCC1 was significantly associated with a better response (p=0.027). Over expression of p16, found in 34.5% of cancers of the oropharynx was significantly correlated with a better OS (p=0.0007) and a better PFS (p = 0.01). Conclusions: These results suggest that ERCC1 expression might be a useful predictive marker of HNSCC in patients treated by cisplatin-based chemotherapy. The 8F1 ERCC1 clone appears to be the best for immunohistochemical analysis; clone FL297 did not show any association with treatment response and survival. Independently, our study confirms the prognostic value of the over expression of p16 in carcinoma of the oropharynx.
Comprehensive preclinical testing for neuroblastoma using orthotopic xenografts of a patient tumor.
Authors: Federico Sara Michele , Stewart Elizabeth , Brennan Rachel Christine , Bradley Cori , Wang Fan , Freeman Burgess B. , Stewart Clinton F. , Wu Jianrong , Dyer Michael A. 
Published: March 2020

e13584 Background: Neuroblastoma is an aggressive malignancy that accounts for 15% of pediatric cancer deaths. There are limited well characterized neuroblastoma models for use in preclinical trials. We characterized a human neuroblastoma orthotopic xenograft, performed comprehensive preclinical studies, and evaluated the pharmacokinetics of drugs targeting the PI3K pathway. Methods: Tumor tissue (MAST3) was obtained from a 2 year old with stage IV metastatic MYCN amplified neuroblastoma. Using ultrasound guidance, MAST3 cells were injected into the para-adrenal space of nod-scid mice. Tumors were monitored for growth with routine ultrasound and passaged. The initial patient tumor (MAST3) and tumor from each passage were extensively analyzed including: histology, electron microscopy (EM), gene expression profiling, single nucleotide polymorphism (SNP ) microarrays, whole genome sequencing (WGS), and spectral karyotyping (SKY). Using this orthotopic xenograft model, a randomized preclinical trial was conducted to evaluate the response to standard chemotherapeutic agents. Pharmacokinetic studies of oral BEZ-235, BKM-120, OSI-906 and everolimus were conducted. Results: Analysis of the histology, EM, gene expression profiling, SNP microarrays, WGS, and SKY showed minimal variability between the MAST3 tumor and the passaged tumors in the orthotopic xenografts. Notably, MAST3 metastasized to the liver, lung and spleen in vivo. Administering standard chemotherapeutic agents every 3 weeks for a total of 6 courses, we observed a significant response in 40% of treated mice. Further ongoing preclinical trials will evaluate the comparative efficacy of IGFR/PI3K/mTOR molecular targeted therapies. Conclusions: We developed the first well characterized neuroblastoma orthotopic xenograft. Our comprehensive characterization of this xenograft indicates that it retains many of the molecular, cellular and genetic properties of the primary lesion. A preclinical trial using standard chemotherapeutic agents has provided a valuable baseline for comparison with novel therapeutics and will inform our selection of the most promising agents to move into clinical trials.
Phase I study of everolimus in combination with fluvastatin and zoledronic acid in patients with solid tumours.
Authors: Lemech Charlotte Rose , Fontela Antoinette , Arkenau Hendrik-Tobias , Chin Melvin T.M. , Li Sandra , Liauw Winston S. , Thomas David , De Souza Paul L. 
Published: March 2020

e13585 Background: Everolimus (E) is an mTOR inhibitor with broad anti-tumour clinical activity. There is preclinical evidence of synergistic activity through the combination of E with fluvastatin (F) and zoledronic acid (ZA). F, an HMG CoA reductase inhibitor, and ZA, a bisphosphonate, have both been shown preclinically to inhibit isoprenylation (addition of hydrophobic molecules) of key signalling proteins with subsequent inhibition of the Ras pathway. We investigate their potential activity further in this open-label phase I trial. Methods: Patients (pts) with advanced solid tumours were treated with escalating doses of E, F and ZA to evaluate safety, clinical activity, pharmacokinetics (PK), pharmacodynamics (PD) and the recommended dose for further study. PK samples were obtained over 24 hrs on day 1 and 8 of cycle 1 and day 1 of cycle 2. Pre- and post-dose PBMCs were analysed for markers of MAPK and PI3K-AKT-mTOR pathways (pERK, pAKT and pS6). Results: Maximum doses of each drug in combination (DL 4) were feasible and no DLTs were observed. Of the 16 pts evaluable [median age=63yrs (range 47-81)], the median number of cycles was 3.8 (range 1-8), with 44% of pts receiving ≥ 4 cycles. Drug related toxicities were mainly G1/2, many within the expected toxicity profile of E, including fatigue (12 pts, 75%), myalgias (9 pts, 56%), anorexia (8 pts, 50%), infection (8pts, 50%), dyspnoea (7pts, 44%), diarrhoea (7 pts, 44%), nausea (7 pts, 44%), peripheral oedema (5 pts, 31%) and mucositis (4 pts, 25%). G3 adverse events were predominantly due to symptoms of disease progression. G1/2 anemia and thrombocytopaenia were the most common haematological toxicities, particularly in DL 3 and 4. 44% of pts achieved stable disease as best response (mean 4.5m [range 3-6m]); including 2 CRC pts (DL 4) and 2 CRPC pts (DL 3 and 4). PK and PD results will be presented in further detail. Conclusions: The combination of E/F/ZA is feasible without any added or overlapping toxicities in this phase 1 study. [Table: see text]
Use of DNA repair proteins translated from biomarker screening to predict overall survival in patients with esophageal cancer treated with oxaliplatin chemotherapy.
Authors: Sharma Ricky A , Macgregor Tom , Gillies Richard , Hatch Stephanie , Swift Lonnie , Humphrey TIM , Chetty Runjan , McHugh Peter J , Middleton Mark R. 
Published: March 2020

e13587 Background: Oxaliplatin is first-line chemotherapy for colorectal, gastric, and esophageal cancers. Aim was to identify key determinants of oxaliplatin sensitivity and optimise these biomarkers to select patients for chemotherapy. Methods: High-throughput screening of oxaliplatin sensitivity was performed in a Schizosaccharomyces pombe deletion library of 229 DNA repair strains and Chinese Hamster Ovary (CHO) cell lines with mutations in specific proteins. Biopsies were taken from 50 patients with esophageal cancer, who then received two cycles of oxaliplatin and fluorouracil chemotherapy prior to surgery. Levels of DNA repair proteins were quantified by immunohistochemistry and by qRT-PCR. Results: Twelve lead biomarkers were identified from the preclinical models. In CHO cells, XPF and ERCC1 mutants were approximately 30 times more sensitive than the WT cells (p<0.01). In comparison to WT CHO cells, XPF-deficient cells had prolonged delay in mid-late S-phase after oxaliplatin treatment, and persistence of double strand breaks for at least 48 hours. Modified Comet assay confirmed persistence of inter-strand crosslinks created by oxaliplatin. Cells deficient in DNA polymerase eta (pol eta) also accumulated in S-phase and were 3-fold more sensitive (p<0.01) to oxaliplatin treatment than pol eta-complemented cells. Knockdown of XPF, ERCC1 or pol eta sensitised both oxaliplatin-resistant and oxaliplatin-sensitive HCT116 cells to oxaliplatin. In patients with esophageal cancer, low or absent XPF protein expression predicted complete pathological response to chemotherapy with a sensitivity of 58% and specificity of 72%. Cyclin A protein levels (univariate analysis, p<0.005) and pol eta mRNA levels (multivariate analysis, P<0.005) in pre-treatment esophageal biopsies correlated with overall survival. Conclusions: Results suggest that inter-strand DNA cross-links are the principal cytotoxic lesions created by oxaliplatin. Homologous recombination and damage checkpoint proteins are leading biomarkers for patient selection. In patients with esophageal cancer, XPF and pol eta predict response to oxaliplatin chemotherapy.
Modulation of pharmacodynamic (PD) biomarkers in dermal biopsies from patients treated on a phase I study of bevacizumab (Bev) in combination with everolimus (Ev) and erlotinib (Erl) for advanced solid tumors.
Authors: Jia Jingquan , Li Haiyan , Dellinger Andrew , Pang Herbert , Russell Karen Bullock , Hurwitz Herbert , Nixon Andrew B. 
Published: March 2020

e13589 Background: Tumor growth and angiogenesis are regulated by multiple cellular pathways, including the VEGF, mTOR, and EGFR pathways. We have previously reported our clinical experience combining Bev, Ev and Erl therapies. Taking advantage of the similarities between tumor growth and wound healing, we conducted a PD analysis of these agents using novel dermal wound angiogenesis assays. Methods: Patients with advanced solid tumors received either 1) Bev-Ev doublet therapy; 2) Bev-Ev-Erl triplet therapy; 3) Ev monotherapy for 14 days followed by addition of Bev-Erl; 4) Erl monotherapy for 14 days followed by addition of Bev-Ev. Full-thickness dermal granulation biopsies were harvested; the phospho (p) and total (t) levels of VEGFR2, EGFR, and S6RP were measured at baseline, end of the monotherapy lead-in period (day 14), and 35 days post doublet or triplet therapy. A dermal wound angiogenesis assay, which quantifies peripheral wound vascularization was also incorporated in the study. Results: 38 pts were evaluable for biomarker analysis. Wilcoxon signed rank tests indicated that both VEGFR2 and S6RP were significantly down-regulated after Bev-Ev-Erl triplet therapy: tVEGFR2 (q=5.1E-05), pVEGFR2 (q=0.01), tS6RP (q=0.007), pS6RP (q=9.7E-04). Levels of tVEGFR2 (q=5.5E-04) and pS6RP (q=6.9E-04) were also found to be significantly down-regulated after Bev-Ev doublet therapy. Ev monotherapy for 14 days led to significant tVEGFR2 down-regulation (q=0.035). No significant changes in EGFR levels were observed in any cohort. Additionally, Bev-Ev-Erl triplet therapy led to a slight decrease in dermal wound vascularization (p=0.098), which positively correlated with changes in tVEGFR2 levels (q=0.008). Conclusions: This is the first investigation evaluating the PD effects of VEGF, mTOR, and EGFR inhibition in a clinical wound-healing model. Our results indicate that targeting of all three pathways is associated with overall down-regulation of both VEGF and mTOR pathways. These data suggest that this dermal wound model can be used to quantify PD markers in evaluating multiple classes of targeted therapies.
Antimetastatic activity of Atu027, a liposomal small interfering RNA formulation, targeting protein kinase N3 (PKN3): Final results of a phase I study in patients with advanced solid tumors.
Authors: Strumberg Dirk , Schultheis Beate , Meyer-Sabellek W , Vank C. , Gebhardt F , Santel A. , Keil O. , Giese K. , Kaufmann J. , Drevs Joachim 
Published: March 2020

e13597 Background: Atu027 contains siRNA-lipoplexes, which elicits RNAi mediated suppression on PKN3 in vascular endothelial cells. In various xenograft mouse models, silencing of PKN3 expression and significant inhibition of invasive growth, lymph node and pulmonary metastasis formation was shown. Methods: Atu027 was applied to patients (pts) as a single 4h-infusion with subsequent follow-up for 3 wks. Thereafter pts were treated twice weekly for 4 weeks. In case of SD, pts were treated until PD. Dose escalation was associated with assessment of toxicity, pharmacokinetics (PK), and multiplex biomarker analyses in plasma from treated pts. Results: A total of 33 pts have received Atu027 of 11 dose levels (DL) up to 0.336 mg/kg. No pre-medication was required. No cytokine activation (TNF-α, IL-1β, IFN-γ, IL-6) was observed. In some subjects transient activation of the complement system (C3a, Bb, sC5b-9) was found, but without any clinical relevance. PK-data showed dose-dependent increase in plasma siRNA as well as lipid levels. Among various biomarkers tested, sVEGFR-1 plasma levels decreased significantly upon treatment. Across all dose levels, Atu027 was well-tolerated. Adverse events possibly related to Atu027 were fatigue grade G1 (6pts), hair loss G1 (2pts), sweating G1 (1pt), and abdominal pain G2 (1pt). G3 AEs not considered as DLTs were elevated lipase (2 pts, DL2+DL10) and diarrhea (1 pt, DL5). So far, no DLTs were seen in the last DL. Stable disease after 3 and 6 months was observed in 10 and 3 pts, respectively. Two pts with neuroendocrine cancer had disease stabilization for 9 and 12 months, respectively, including partial regression of pulmonary metastases in 1 pt. Another patient with breast cancer had regression of liver metastases. Conclusions: Atu027 is well-tolerated and anti-metastatic activity has been observed. Soluble VEGFR-1 might serve as a biomarker. So far, 0,336 mg/kg is the recommended dose for further phase II trials.
MLN9708, an investigational proteasome inhibitor, in patients (pts) with solid tumors: Updated phase I results.
Authors: Smith David C. , Sullivan Daniel , Infante Jeffrey R. , Kauh John S. , Siu Lillian L. , Vlahovic Gordana , Thompson John A. , Gupta Neeraj , Di Bacco Alessandra , Liu Guohui , Kalebic Thea 
Published: March 2020

e13603 Background: MLN9708 is a potent, reversible, orally bioavailable, and specific 20S proteasome inhibitor. This study (NCT00830869) assessed the safety, MTD, PK, PD, and antitumor activity of intravenous (IV) MLN9708 in pts with solid tumors. Methods: Pts aged ≥18 yrs (ECOG PS 0–2) received increasing doses of IV MLN9708 (starting at 0.125 mg/m2) on days 1, 4, 8, and 11 of 21-day cycles, for up to 12 cycles. MTD expansion cohorts included head and neck (H&N) cancer, non-small cell lung cancer, soft tissue sarcoma, prostate cancer, and a tumor PD expansion cohort. Plasma PK and blood PD data were analyzed by a non-compartmental method using WinNonlin software v5.3. The candidate PD biomarker ATF-3 was assessed using IHC. Results: 113 pts were enrolled; 23 in dose escalation and 96 in MTD expansion (includes 6 from dose escalation) cohorts. Median age of these heavily pretreated pts was 58 yrs (range 29–80). MTD was established as 1.76 mg/m2. Pts have received a median of 2 cycles (range 1–12) to date (data cut-off Dec 1, 2011); 22 received ≥4 cycles. 88% had ≥1 drug-related AE; most common drug-related AEs included fatigue (40%), thrombocytopenia (39%), rash (high level term) (33%), and nausea (32%). 52% of pts experienced grade ≥3 drug-related AEs, including thrombocytopenia (20%) and rash (9%). Drug-related peripheral neuropathy (PN) was seen in 13% of pts; 2 pts had grade 3 PN. 25% had drug-related SAEs, 15% discontinued due to AEs; 7 pts died, all unrelated to treatment. Of 75 response-evaluable pts, 26 achieved SD. A partial response (PR) was observed in a pt in the H&N cohort; response was achieved after 4 cycles and maintained through 8 cycles. Change in ATF-3 levels in tumor tissue post treatment was seen in 6 patients with tumor biopsy samples, indicating proteasome inhibition. PK data showed three-exponential plasma disposition, half-life of ~4–8 days, and dose linearity from 0.5–2.34 mg/m2. At MTD, maximal 20S proteasome inhibition in blood was approximately 60% at 0.08 hours. Whole blood PD effect was immediate and dose dependent. Conclusions: These data suggest that twice-weekly IV MLN9708 has a generally manageable safety profile and potential clinical utility; updated results will be presented.