In this paper, an efficient computational approach is developed to investigate the free-vibration behavior of functionally graded plates. The problem is developed based on a three-dimensional elasticity theory, which is expected to capture the structural response accurately. Isogeometric analysis is employed as a discretion tool to solve the problems. The accuracy of the proposed approach is verified by comparing the obtained results with those available in the literature. In addition, various examples are also presented to illustrate the efficiency of the proposed approach. There are five types of plates with different configurations of material gradations. The benchmark results for those are also given for future investigations.
 Keywords: multi-directional functionally graded materials; 3D elasticity; isogeometric analysis; free-vibration.
3102 Background: MK4827 is an orally active, PARP 1/2 inhibitor with nanomolar potency. It induces selective synthetic lethality in homologous recombination (HR) repair deficient tumors with BRCA1/2 loss and in tumor cell lines with non-BRCA-related HR defects, supporting broad clinical application. A phase I study was undertaken to determine the toxicity and tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and preliminary anti-tumor activity. Methods: Patients (p) with advanced solid tumors enriched for BRCA-mutation carriers (BRCA-MC) and non-BRCA HR defects received once daily, escalating doses of MK4827 in cohorts of 3-6 p. Dose escalation was guided by toxicity, PK and PD data. Results: 60 p (M13, F47; median age 56 yr; 21 BRCA-MC) were treated at 10 dose levels from 30mg to 400mg on days 1-21 of a 28 day cycle (C) in C1, followed by continuous dosing. 20 additional p with soc were enrolled at the MTD. Prior systemic treatments were ≤2 (23p), ≥3 (17p), and ≥4 (40p). Overall, DLT was observed in 4p: grade (G) 3 fatigue in 1/6p at 30mg, reversible G3 pneumonitis in 1/6p at 60mg, and reversible G4 thrombocytopenia in 2/6p treated at 400mg. The MTD was established at 300mg. Other MK4827 related G1-2 reversible adverse events included fatigue, anorexia, nausea and myelosuppression. Dose proportional PK was observed with a mean t1/2 of 40 hours (range 37-42 hr). PD studies confirmed PARP inhibition in peripheral blood mononuclear cells at doses of ≥80 mg. Antitumor activity was observed in both sporadic and BRCA-MC cancers. In total, there have been 12p with partial responses (PR) (10 ovarian [7 BRCA-MC; 3 soc], 2 breast, 10/12 BRCA-MC cancers, 4/12 with ongoing treatment), and 8p with stable disease (SD) (4 ovarian [2 BRMC-MC], 2 NSCLC, 2/4 BRCA-MC) ≥120 days. PRs have ranged from 86(+)-483 days and SD from 18(+)-354 days. Conclusions: MK-4827 was well tolerated, had linear PKs, evidence of target modulation, and promising antitumor activity in both BRCA-MC and sporadic cancer. Specific cohort expansions in other nonhereditary tumors enriched for HR defects is ongoing. Updated safety and response data will be provided.
Abstract Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.
OBJECTIVE:To establish the quality standard of Liuwei dihuang pill (concentrated pill). METHODS:Radix Rehmanniae Preparata,Dioscorea opposita,Poria cocos and Alisma orientalis in Liuwei dihuang pill (concentrated pill) were identified by TLC and the contents of paeonolum and loganin were determined by HPLC.RESULTS:The TLC spots were clear and well-separated yet free of interference of negative sample.The linear ranges of paeonolum and laganin were 0.100 6～1.006 μg (r=0.999 9) and 0.309 6～2.322 μg(r=0.999 6),respectively,and their recovery rates were 98.2%(RSD=2.3%,n=6) and 95.3%(RSD=0.42%,n=6),respectively.CONCLUSION:The established standard is applicable for the quality control of Liuwei dihuang pill.
445 Background: Monoclonal antibodies (mAb) against programmed cell death-1 (PD-1) have demonstrated antitumor activity across multiple malignancies. BGB-A317 is a humanized IgG4 mAb with high affinity and binding specificity for PD-1. Previous reports from an ongoing Phase 1A/1B study (NCT02407990) in patients with advanced solid tumors suggested that BGB-A317 was generally well tolerated and had antitumor activity in multiple tumor types. Here, we present the preliminary results from a subset of patients with UC enrolled in this study. Methods: Patients with UC received intravenous BGB-A317 at doses of 2, 5, 10 mg/kg Q2W or Q3W and 200 mg Q3W. Tumor cell (TC) and immune cell (IC) PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Safety and tolerability was assessed by monitoring adverse events (AEs) and antitumor effects were assessed by RECIST v1.1 criteria. Results: As of 8 June 2017, 15 patients with UC (median age, 72 yr [range: 39–79]) received BGB-A317 during phases 1A (n = 8) and 1B (n = 7). All patients were Caucasian and 13 patients were male; the median number of prior systemic anticancer therapies was 1 (range: 0–4). Median duration of treatment was 115 d (range: 27–476); 6 patients remain on treatment. The most common treatment-related AEs (TRAEs) were fatigue (n = 5) and rash (n = 3); grade ≥3 TRAEs included fatigue (n = 1), and hyperglycemia and type 1 diabetes mellitus (T1DM; n = 1). Serious TRAEs occurred in 2 patients (infusion-related reaction [n = 1]; hyperglycemia and T1DM [n = 1]). All patients were evaluable for response assessment. Confirmed complete and partial responses occurred in 1 and 3 patients, respectively, for a response rate of 27%; the disease control rate (CR+PR+SD) was 53%. Nine samples were available for PD-L1 evaluation. Responses were observed in 3 of 6 patients with PD-L1 + tumors (defined as ≥25% TC or IC expressing PD-L1 by IHC) while 1 in 3 patients with PD-L1 – tumors responded. Conclusions: BGB-A317 was generally well tolerated in patients with UC and objective responses were observed in both PD-L1 + and PD-L1 – diseases. BGB-A317 is currently being investigated in China as monotherapy for patients with PD-L1 + UC (CTR20170071). Clinical trial information: NCT02407990.
Abstract We herein show that Artemin (ARTN), one of the glial cell line–derived neurotrophic factor family of ligands, promotes progression of human non–small cell lung carcinoma (NSCLC). Oncomine data indicate that expression of components of the ARTN signaling pathway (ARTN, GFRA3, and RET) is increased in neoplastic compared with normal lung tissues; increased expression of ARTN in NSCLC also predicted metastasis to lymph nodes and a higher grade in certain NSCLC subtypes. Forced expression of ARTN stimulated survival, anchorage-independent, and three-dimensional Matrigel growth of NSCLC cell lines. ARTN increased BCL2 expression by transcriptional upregulation, and inhibition of BCL2 abrogated the oncogenic properties of ARTN in NSCLC cells. Forced expression of ARTN also enhanced migration and invasion of NSCLC cells. Forced expression of ARTN in H1299 cells additionally resulted in larger xenograft tumors, which were highly proliferative, invasive, and metastatic. Concordantly, either small interfering RNA–mediated depletion or functional inhibition of endogenous ARTN with antibodies reduced oncogenicity and invasiveness of NSCLC cells. ARTN therefore mediates progression of NSCLC and may be a potential therapeutic target for NSCLC. Mol Cancer Ther; 9(6); 1697–708. ©2010 AACR.
