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e14526 Background: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Cell free DNA (cfDNA) is a non-invasive mechanism for monitoring malignancy in UM patients. BET proteins activate transcription of oncogenic genes, and mivebresib (ABBV-075) is a potent pan-BET inhibitor. In the first-in-human phase 1 study, safety and pharmacokinetics of mivebresib were assessed in patients with advanced cancer (NCT02391480). We compared cfDNA mutational dynamics with the survival of UM patients treated with mivebresib. Methods: Adult patients with metastatic solid tumors and ≥1 line of prior treatment were treated with mivebresib on a schedule of daily; 3 days/week; or 4 days on, 3 days off. Two mL of plasma cfDNA (≥10ng) in 5 patients (3 progressive disease [PD], 2 stable disease [SD]) were sequenced with a targeted 63-gene panel (68 Kb) to ≥800X unique depth after barcode-based error-suppression and genomic alterations discovered in all patients. Results: As of May 2018, 10 UM patients received ≥1 dose of mivebresib with median 8.1 weeks (range, 3.6–39.6) of treatment. The median age was 55 years (range, 37–73). 9 patients experienced a treatment-emergent adverse event (TEAE), most commonly (≥40% patient incidence), dysgeusia (60%), thrombocytopenia and nausea (40%, each). 9 patients were evaluable, 4 achieved a best response of SD and 5 PD (RECIST v1.1). The mean pretreatment cfDNA concentration was 21.0 ng/mL (N = 5 with plasma available). cfDNA levels increased in two patients by 0.6% (SD) and 64.4% (PD). In PD patients, elevated cfDNA concentration (32.7 ng/mL [PD] vs 3.5 ng/mL [SD]) was associated with shorter progression-free survival and overall survival. At baseline, the cfDNA mutational load (median mutant molecules/mL plasma) of pathogenic (COSMIC) mutations with AF ≥1% was highest in PD (893.9; range, 78-4951.5) vs SD patients (53.1; range, 9.3-606.2) and negatively correlated with the patient’s survival (R2= 0.531). In 1 PD patient, multiple TP53 (C23G, V203M) and CDKN2A (A148T, L63P) mutations were acquired by the time of progression. Conclusions: These data suggest cfDNA as a potential marker for survival of UM patients. Further investigation of BET inhibition in this population is warranted. Clinical trial information: NCT02391480.

7030 Background: Bromodomain and extra-terminal (BET) proteins bind to acetyllysines and upregulate oncogenic target genes. Mivebresib (ABBV-075) is a pan-BET inhibitor with antitumor activity in vitro and xenograft models of AML. This 2-part phase 1 study evaluates the safety and pharmacokinetics of mivebresib at monotherapy or combination dosing schedules in patients with solid tumors (part 1) and acute myeloid leukemia (AML; part 2) (NCT02391480). Here, we report preliminary data from part 2 in patients with relapsed/refractory (RR) AML. Methods: Mivebresib monotherapy (MIV-mono), or combined with venetoclax (MIV-VEN), were administered daily to adult patients with AML. The dose-limiting toxicity (DLT) period was 28 d. Results: As of Dec 2018, 41 patients (median age: 69 y [range, 29–84]; 19 patients had > 2 prior therapies) were enrolled: 19 in MIV-mono (5 of whom switched to MIV-combo) and 22 who began treatment in MIV-VEN cohorts. 23 patients had high cytogenetic risk. Median time on treatment was 28 d (range, 8–562). There were no DLTs. All patients experienced a treatment-emergent adverse event (AE), most commonly (≥40% patient incidence), fatigue (56%), dysgeusia (46%), decreased appetite (44%), diarrhoea (42%), nausea (42%), vomiting (42%). 40 patients had grade ≥3 AEs (febrile neutropenia (37%), anemia (34%) and thrombocytopenia (32%). 33 patients had serious AEs, most commonly febrile neutropenia (19%). 25 deaths were reported; 15 patients died of causes unrelated to mivebresib and 10 patients due to AML progression. The median best % bone marrow blast change for 26 evaluable patients was -20% (range, -98% to +300%). Gene expression analysis in pre- and post-treatment peripheral blood samples showed that HEXIM1, DCXR and CD93 genes were reliable PD biomarkers of ABBV-075 which were consistently modulated in a dose-dependent manner. At the cutoff date, median overall survival for all patients was 2.6 m. Conclusions: Mivebresib was well tolerated and showed antileukemic effects in patients with RR AML. Clinical trial information: NCT02391480.

8510 Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a potent oral PARP1/2 inhibitor, interferes with repair of chemotherapy- or radiation-induced DNA damage. In a phase 2 study, Vel showed favorable efficacy vs placebo when added to C/P in stage IV NSCLC. The reported phase 1 trial assessed the safety and efficacy of Vel + C/P-based CRT in Tx of stage III NSCLC (NCT02412371). Methods: Eligible pts (≥18 yr, unresectable stage III NSCLC, no prior NSCLC therapy) received Vel + CRT of weekly C area under the curve (AUC) 2 + P 45 mg/m2 weekly + 60 Gy (2 Gy/day) RT over 6–9 weeks (wk). Vel was dose escalated from 60 mg twice daily (BID) to 240 mg BID followed by Vel 120 mg BID added to consolidation therapy (CON) once every 3 wk of C AUC 6 + P 200 mg/m2 for 2 cycles (cohort 1–5). Cohort 6 received Vel 240 mg BID + CRT followed by Vel 240 mg BID + CON. Samples for pharmacokinetic (PK) analysis were collected on wk 4 day –3. The primary endpoint was to establish the recommended phase 2 dose (RP2D) of Vel + CRT/Vel + CON. Results: As of Sep 2018, 48 pts enrolled into cohorts 1–6 at Vel 60 mg/120 mg (n = 7), 80 mg/120 mg (n = 9), 120 mg/120 mg (n = 7), 200 mg/120 mg (n = 8), 240 mg/120 mg (n = 12), and 240 mg/240 mg (n = 5) added to CRT/CON; median age 65 yr (range, 48–81). Vel PK was dose proportional; 39 (81.3%) pts completed therapy. Grade ≥3 Tx-emergent adverse events (AEs) were reported in 37 (77.1%) pts; anemia and febrile neutropenia (10.4% each) were the most common. Serious AEs were observed in 19 (39.6%) pts. Dose-limiting toxicities occurred at 200 mg/120 mg (n = 1; influenza and pneumonia), 240 mg/120 mg (n = 1; insomnia), and 240 mg/240 mg (n = 2; febrile neutropenia, neutropenia, thrombocytopenia, esophagitis, suprapubic pain, sepsis); Vel 240 mg BID + CRT/Vel 120 mg + CON was chosen as the maximum tolerated dose/RP2D. Of 41 pts evaluable for tumor assessment, 26 (63.4%) had a confirmed response. Interim median progression-free survival was 24.1 mo (range, 8.9 – not reached); updated results will be reported. Conclusions: Vel 240 + CRT/Vel 120 mg BID + CON was well tolerated with promising antitumor activity in stage III NSCLC and was determined as RP2D. Clinical trial information: NCT02412371.

With the rapid development of information technology, the travel mode of " Internet + Transportation " has brought convenience to residents while causing a series of urban traffic problems. Based on GPS data from Didi Chuxing, this paper relates the residents' travel behaviour to their daily activities, and studies the regularity of the pick-up and drop-off activities of residents from the dimensions of time and space. The results are as follows: Firstly, the daily variation trend of residents' travel is unbalanced. At the same time, the travel volume of residents is at a higher level during night. Secondly, the travel of urban residents is closely related to urban areas and urban functional structures. On the administrative scale, the distribution of residents' travel is concentric, and the farther the distance from the downtown area is, the smaller the number of orders is. On the functional scale, the hot functional areas of residents' travel are related to residents' needs. At last, mastering the distribution of residents' travel hot spots and time will help to understand the residents' travel mode and the current situation of urban traffic, and provide new ideas for solving traffic problems in big cities.

Methane (CH4) and nitrous oxide (N2O) concentration, saturation and fluxes in river network of Shanghai city (Yangtze Delta) and Tianjin city (Haihe watershed) were investigated in winter. Results showed that CH4 and N2O concentration were high in river network and supersaturated. The average of CH4 concentration was 0.86 μmol/L (saturation: 758%), and ranged from 0.043±0.001 to 25.3±9.32 μmol/L. The average of N2O concentration was 86.8 nmol/L (saturation: 488%), and ranged from 9.71±0.41 to 691±35.2 nmol/L. CH4 and N2O concentration in two sewage draining rivers of Tianjin city were clearly higher than other rivers (Average CH4 and N2O concentration were 38.4 μmol/L and 88.9 nmol/L, respectively). There is significant spatial variation of CH4 and N2O concentration and saturation, data of concentration and saturation in Shanghai river network was significant higher than in Tianjin city. Air-water interface fluxes of CH4 and N2O widely varied from -1.35±0.22 to 665±246 μmol/m2 h (Average was 24.1 μmol/m2 h), and from -0.19±0.02 to 22.6±5.05 μmol/m2 h (Average was 2.28 μmol/m2 h), respectively. CH4 concentration had significant negative correlation with dissolved oxygen (DO), but positive with ammonium (NH4+), and N2O concentration had significant positive correlation with NH4+ and nitrate and nitrite (NO3-+NO2-). Air-water interface fluxes of CH4 and N2O in urban area were evidently higher than in suburban and rural area, implicating that seriously polluted river is a potential source of atmospheric CH4 and N2O.

The aim of the study was to investigate heavy metals concentrations in wheat field soils of Tianjin sewage irrigation region, and evaluate the potential ecological risk of heavy metals pollution. ICP-OES was employed to analyze the heavy metals concentrations in wheat field soils of Tianjin sewage-irrigation region. The grading standard of Tianjin soil environmental quality was used as the assessment foundation for soils and Lars Hakanson’s potential ecological hazards index method was used to evaluate the heavy metals pollution potential ecological risk in soils. The results showed that: Cd concentrations in soils ranged from 0.03 mg•kg-1 to 1.17 mg•kg-1, with an average value of 0.46 mg•kg-1; Zn concentrations in the soils ranged from 62 mg•kg-1 to 307 mg•kg-1, with an average value of 129.08 mg•kg-1. The concentrations of Cd and Zn in the soils exceeded second grade standards of Tianjin soil environment quality, so the soil was polluted. The other heavy metal elements, such as Cu, Pb, Cr and Ni, were all lower than second level of Tianjin soil environment quality standards, meaning that the soil was not contaminated by these heavy metals. The heavy metal concentrations were relatively rich in saline wet fluvo-aquic soil and clayification fluvo-aquic soil. Based on Lars Hakanson’s potential ecological hazards index method, Cd had heavily ecological risk in soils and was the main pollutant, while the other heavy metals had lightly ecological risk. Ecological risk of total heavy metals pollution was moderate. The heavy metals were most likely from wastewater irrigation. The pollutants in the soils came mainly from sewage irrigation. The waste water treatment technology should involve steps to remove heavy metals causing risk to human health.

A series of empirical studies involving typhoon rainstorm and flood risk scenario analysis were carried out on a medium spatial scale, covering Pingyang County. Considering a rainstorm/water-logging conversion process, active flooding submergence and per unit area values (million yuan/km2), two typical risk scenarios (50- and 100-year frequency) were simulated and analyzed. The study revealed that high-risk areas distributed across the towns of Aojiang, Qiancang and Xiaojiang, with a maximum submerged depth of 4.61 m for a 100-year flood hazard. In the case of a disaster loss rate >65 %, the potential maximum loss could be more than 10 million yuan/km2. For medium-scale disaster risk, more attention must be paid to catastrophic events, which have a low probability of occurrence but would induce great losses. An amended risk formula could determine the degree of priority for responses to hazards of equal risk value better. In Pingyang County, the 50-year flood risk for Kunyang, Aojiang, Qiancang and Xiaojiang is greater than that of 100-year events for the next 50 years. However, these areas should give priority to their responses to 100-year disaster events during the next 100 years. In addition, the attention of disaster risk should vary in different spatial regions.

Land subsidence, a major geological hazard in Tianjin, has caused serious losses. In this research, we established a numerical model to predict potential land subsidence caused by groundwater overdraft in the next decades. The model set three groundwater extraction scenarios, corresponding to (1) current rate, (2) 2 % decrease, and (3) South-to-North Water Transfer Project. Economic losses induced by land subsidence were calculated based on the three land subsidence scenarios. The results showed that with a better management plan (e.g., 2 % decrease in groundwater extraction) or with the success of the water transfer project, the economic loss could be reduced by 36 % or even 74 %. The results of this research provide a scientific basis for the sustainable development planning as well as disaster prevention policy-making of Tianjin Binhai New Area.

The design and calibration of high current with high-stability has been a problem in metrology, a current calibration system with high-stability is introduced, which includes a novel DC current comparator, an original sampling method for high-precision current source, an adaptive control method for air enclosure. The stabilities of major components are analyzed and measured individually. The measurement results show that when the current is 300 A, the stability in one hour can be up to 5.7×10−7, and the uncertainty of measurement is 1.8×10−6.

The in vitro degradation behavior of organogel with different gelators based on amino acid was investigated in detail. Two methods were applied in this research: weighting method and high-performance liquid chromatography with evaporative light scattering detection (HPLC-ELSD) method, which was established for the first time. Their degradation behaviors in vivo were investigated by varying the kind and concentration of gelators via subcutaneous implantation. The results showed that the stronger the gelation ability or the higher the gelator concentration, the slower the degradation rate of organogel. Moreover, the organogel prepared by oils with longer alkyl length degraded slower than that of the shorter ones, which also decreased in thermal stability and mechanical strength. The investigation on degradation process showed that the degradation rate was mainly controlled by the collapse of network structure formed by gelators. In conclusion, organogel had a tunable degradation rate through altering the gelator type, oil type and the gelator concentration. It remains a promising candidate for subcutaneous in-situ implant as drug delivery vehicle.

We construct a complete-connective regular network based on Self-replication Space and the structural principles of cantor set and Koch curve. A new definition of dimension is proposed in the paper, and we also investigate a simplified method to calculate the dimension of two regular networks. By the study results, we can get a extension: the formation of Euclidean space may be built by the process of the Big Bang's continuously growing at a constant rate of three times.

This paper reviewed and analyzed the development of our nation’s loan loss provision system, then studied the relations of commercial bank loan loss provision and earnings management and capital management through empirical study. This paper selected 14 domestic commercial banks of year 2001-2009 as data sample, using Kanagaretnam et al.’s (2003) research method, dividing the loan loss provision into two parts that is discretionary and nondiscretionary part, and empirically studied the relationship of discretionary part of loan loss provision and earnings before taxes and provisions (EBTP) and capital adequacy ratio (CAR). Empirical results show that: there is significant positive correlation between the discretionary loan loss provisions and earnings before taxes and provisions (EBTP), and there is significant negative correlation between the discretionary loan loss provisions and capital adequacy ratio (CAR). That provides evidence for the relation of bank loan loss provision and earnings management and capital management. In the last, combining with empirical research findings and the status of the loan loss provision system of China’s commercial banks, this paper made several suggestions to improve the system of loan loss provision.

Based on the analysis and calculation of the hazard intensity of typhoon rainstorms and floods as well as the vulnerability of flood receptors and the possibility of great losses, risk scenarios are proposed and presented in Wenzhou City, Zhejiang Province, China, using the Pearson-III model and ArcGIS spatial analyst tools. Results indicate that the elements of risk scenarios include time–space scenarios, disaster scenarios, and man-made scenarios. Ten-year and 100-year typhoon rainstorms and flood hazard areas are mainly concentrated in the coastal areas of Wenzhou City. The average rainfall across a 100-year frequency is 450 mm. The extreme water depth of a 100-year flood is 600 mm. High-vulnerability areas are located in Yueqing, Pingyang, Cangnan, and Wencheng counties. The average loss rate of a 100-year flood is more than 50%. The greatest possible loss of floods shows an obvious concentration-diffusion situation. There is an area of about 20–25% flood loss of 6–24 million Yuan RMB/km2 in the Lucheng, Longwan and Ouhai districts. The average loss of a 100-year flood is 12 million Yuan RMB/km2, and extreme loss reaches 49.33 million Yuan RMB/km2. The classification of risk scenario may be used for the choice of risk response priorities. For the next 50 years, the 10-year typhoon rainstorm-flood disaster is the biggest risk scenario faced by most regions of Wenzhou City. For the Yueqing, Ruian, and Ouhai districts, it is best to cope with a 100-year disaster risk scenario and the accompanying losses.

The fiber coupling efficiency between the turbulent ocean to fiber of a partially coherent Gaussian beam propagating through the weak to strong anisotropic oceanic turbulence is studied. We derive the expression of new model of the fiber coupling efficiency for the partially coherent Gaussian beam. The numerical analyses reveal that larger inner scale and anisotropic factor, weaker oceanic turbulence strength, and smaller temperature-salinity contribution ratio will lead to a higher coupling efficiency; a longer wavelength, an suitable aperture diameter of the coupling lens, an optimum focal length and beam size, and a higher coherent degree will improve the fiber coupling efficiency. Our fiber coupling efficiency is higher than the previous fiber coupling efficiency.

7019Background: Pts with RR AML have a poor prognosis. BET proteins bind acetylated histone tails, leading to the upregulation of oncogenic target genes; their inhibition can block aberrant transcr...

2570Background: ABBV-075 is an oral small molecule inhibitor of the BET family of bromodomain-containing proteins that function as regulators controlling many transcriptional programs required for ...

2510Background: BDs are protein domains that bind to acetylated histone tails, leading to upregulation of target genes driving oncogenesis. Inhibition of the BET family prevents assembly of the macromolecular complex and its transcriptional response. ABBV-075 is a pan-BET inhibitor that induces death in cell lines and tumor growth inhibition in xenograft models. This first-in-human, phase 1, two-part study (NCT02391480) assessed the safety and pharmacokinetics of ABBV-075 in pts with advanced tumors. Results from the dose escalation part in pts with solid tumors are reported. Methods: The dose escalation part of this open-label study enrolled adult pts with R/R solid tumors in a 3+3 fashion. Endpoints included maximum tolerated dose, recommended phase 2 dose (RP2D) at different ABBV-075 dosing schedules (daily, Monday/Wednesday/Friday [MWF], or 4 days on/3 off [4/7]), safety and preliminary efficacy. Results: As of Dec 2017, 72 pts with solid tumors enrolled in the dose escalation cohort. Most common tumo...

Based on daily, monthly, seasonal and annual precipitation, monthly duration and flood-affected area data from 1954 to 2007, we examined the absolute and relative change trends of rainfall and their effects on hazard intensity in Wenzhou city, China. The long-term trend of precipitation was studied by linear regression, moving average, cumulative anomaly and Z index methods, respectively. Our results show that there was no significant downward trend of annual precipitation. In contrast, there was significant decrease in autumn, July, mid-January and early June and significant increase in early January and late May, especially in late June. During 1954 and 2007, although significant fluctuation existed in the absolute value of precipitation, the relative changes of wet and dry were not significant compared with the average. The 10-year decrease in precipitation was 23.37 mm in autumn, 14.85 mm in July, 0.33 mm in mid-January and 6.87 mm in early June; while the 10-year increase was 0.35 mm in early January, 3.05 mm in late May and 8.57 mm in late June, respectively. Moreover, we found that 1964, 1966, 1977 and 1995 were the transition periods when the rainfall Z index was at peaks, the flood intensity was high, and the drought intensity was relatively low. On the other hand, 1958, 1968, 1971, 1980, 1989 and 1992 were the periods when the rainfall Z index was at valleys, the flood intensity was low, and the drought intensity was relatively high. Taken together, we demonstrated the obvious effects of precipitation changes on flood and drought intensities.

Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. A single-dose and multiple-dose rifampin study was conducted to evaluate the effect of CYP3A induction and transporter inhibition on the pharmacokinetics of venetoclax. Subjects received a single dose of venetoclax 200 mg on day 1 of period 1 and days 1 and 14 of period 2, a single dose of rifampin 600 mg on day 1 of period 2, and rifampin 600 mg once daily on days 5 through 17 of period 2. Blood samples were collected up to 96 hours after each venetoclax dose on day 1 of period 1 and days 1 and 14 of period 2. Compared with venetoclax alone, coadministration with a single dose of rifampin increased venetoclax C

Yongyuan Guo,1,* Beibei Hu,2,* Chu Tang,1 Yunpeng Wu,1 Pengfei Sun,1 Xianlong Zhang,3 YuhuaJia1 1Orthopaedic Department, 2Medical Examination Center, Qilu Hospital of Shandong University, Jinan, 3Orthopaedic Department, The Sixth Affiliated People’s Hospital, Medical School ofShanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally tothis work Abstract: Surface topography has significant influence on good and fast osseointegration of biomedical implants. In this work, ultrasonic shot peening was conducted to modify titanium to produce nanograined (NG) surface. Its ability to induce new bone formation was evaluated using an in vivo animal model. We demonstrated that the NG surface enhanced osteoblast adhesion, proliferation, differentiation, and mineralization in in vitro experiments compared to coarse-grained titanium surface. Push-out test, histological observations, fluorescent labeling, and histomorphometrical analysis consistently indicated that the NG surfaces developed have the higher osseointegration than coarse-grained surfaces. Those results suggest that ultrasonic shot peening has the potential for future use as a surface modification method in biomedical application. Keywords: ultrasonic shot peening, titanium, in vivo, osseointegeration

Paritaprevir (administered with low-dose ritonavir), ombitasvir, and dasabuvir are direct-acting antiviral agents administered as combination regimens for the treatment of chronic hepatitis C virus infection. Drug-drug interactions between 2D (ombitasvir/paritaprevir/ritonavir) or 3D (ombitasvir/paritaprevir/ritonavir and dasabuvir) regimens and omeprazole, a CYP2C19 substrate and acid-reducing agent, were evaluated in 24 healthy volunteers. Subjects received omeprazole (40 mg once daily) on day 1 and days 20-24 and the 2D or 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily) on days 6-24. Compared with omeprazole alone, coadministration with the 2D or 3D regimen decreased omeprazole geometric mean Cmax and AUCt values by 40% to 50%. Ombitasvir, dasabuvir, and ritonavir mean exposures showed

Background: Aberrant EGFR plays a vital role in the oncogenesis of multiple tumor types. ABBV-221 is a 2nd-generation antibody-drug conjugate (ADC) targeting EGFR, based on the 1st-generation ADC depatuxizumab mafodotin (depatux-m, formerly ABT-414). Depatux-m demonstrates efficacy in glioblastoma (GBM) patients (pts) with EGFR amplification in ongoing studies. ABBV-221 is an affinity matured monoclonal antibody against EGFR linked to the microtubule toxin monomethylauristatin E. ABBV-221 has higher affinity for EGFR than depatux-m, potentially allowing it to target a broader range of tumor types. To understand the population most suitable for ABBV-221, molecular assays characterizing EGFR pathway status, including EGFR protein, EGFR mRNA, and EGFR ligand mRNA expression, were evaluated from available tumor tissue of enrolled patients. The results of each assay were correlated with patient outcome to determine which marker may be best associated with prognosis. Methods: In this phase 1, multicenter study of ABBV-221, eligible pts have solid tumors that are likely to overexpress EGFR. EGFR protein expression in tumor tissue samples was analyzed with immunohistochemistry (IHC) using the Dako pharmDx IHC assay. EGFR and mRNA expression from the EGFR ligands epiregulin (EREG) and amphiregulin (AREG) were measured using next-generation RNA sequencing (RNAseq). Results: As of 29 March 2017, 42 pts were treated (13 colon, 5 head & neck [H&N] cancer, 5 non-small cell lung cancer, 5 GBM, 2 breast, 12 other). Ten dose escalation cohorts have been completed with the last cleared dose 4.5 mg/kg per cycle. The most common adverse events were infusion reactions in 19/42 pts (45%) and fatigue in 17/42 pts (41%). Sixteen pts (38%) had stable disease (SD), including 4 pts who remained on study longer than 6 months. All markers are expressed in a wide range across enrolled pts. The pts with response had high EGFR and EGFR ligand. One pt with head and neck cancer who received 5 cycles of ABBV-221 had a partial response and elevated levels of both EGFR (3-fold higher than median for all pts) and EGFR ligand (8-fold higher AREG and 19-fold higher EREG than median for all pts). One colorectal cancer pt with durable SD >6 months had high levels of ligand (EREG) but not receptor, and one H&N pt with SD >6 months had high levels of EGFR receptor but not ligand. Conclusions: Multiple EGFR pathway status biomarkers were evaluated and correlated with clinical outcomes observed in this phase 1 trial of ABBV-221. Patients who observed clinical benefit had high levels of EGFR pathway markers. The duration of SD in pts with refractory solid tumors is encouraging. Clinical trial information: NCT02365662 Citation Format: Emiliano Calvo, James M. Cleary, Victor Moreno, Maryella Gifford, Lisa Roberts-Rapp, Peter J. Ansell, Ho-Jin Lee, Beibei Hu, David Barch, Christopher Ocampo, Anthony W. Tolcher. Biomarker analysis in a phase 1 study of the antibody-drug conjugate ABBV-221 in patients with solid tumors likely to overexpress the epidermal growth factor receptor (EGFR) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A028.

8530 Background: The majority of SCLC cases are diagnosed as ED, for which there is a poor prognosis and no curative treatment (Tx). V, a potent PARP inhibitor, has been shown in preclinical studies to enhance the antitumor activity of platinum-based agents and E against SCLC. The presented phase 1 dose-escalation (NCT02289690) evaluated V combined with Cb/E. Methods: Pts (≥18 years) with ED SCLC or other advanced/metastatic solid tumors with ≤1 line of prior cytotoxic therapy and ECOG performance score 0/1 were included. This study followed a 3+3 design. V starting dose and schedule were 80 mg BID PO administered on days (D) –2 to 5 in combination with Cb AUC 5 mg/mL•min administered on D 1 and E 100 mg/m2 administered on D 1 to 3 via intravenous infusion in 21-D cycles. V schedules of D –2 to 12 and continuous dosing were also explored. Primary objectives were to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for V combined with Cb/E, and to evaluate the pharmacokinetic (PK) interaction between V and E. Results: Thirty-nine pts (n = 24 ED SCLC; n = 15 other solid tumors) with median age of 62 years (range 43–79) received study Tx. Most common adverse events (AEs; ≥40%) were nausea (54%), fatigue (51%), alopecia (46%), and anemia (44%); grade 3/4 AEs (≥30%) were decreased neutrophil count, neutropenia (31% each), and anemia (26%). Dose-limiting toxicity occurred in 1 pt (n = 1 grade 3 fatigue) at V 240 mg BID D –2 to 5. The MTD was not reached; RP2D for V was set at 240 mg BID on D –2 to 12 based on long-term tolerability. Continuous dosing of V 240 mg BID with Cb/E resulted in unacceptable Cb/E dose delays due to hematologic toxicity. Coadministration of V (80 to 240 mg BID) with Cb/E exhibited dose-proportional kinetics with no impact on the E PK. Confirmed responses: ED SCLC 63% (15/24 pts) across all dose levels and in 83% (5/6) at RP2D; other tumor types: 13% (2/15) across all dose levels. Conclusions: V + Cb/E had an acceptable safety profile in pts with ED SCLC, with an RP2D of 240 mg BID D –2 to 12. Coadministration of V with Cb/E had no effect on E PK. Responses were seen across all dose levels. A phase 2 study of V with Cb/E in ED SCLC is ongoing. Clinical trial information: NCT02289690.

8546 Background: CRT is a standard for patients with Stage III NSCLC. V is a potent, orally bioavailable PARP1/2 inhibitor that can delay DNA repair following chemotherapy or radiation induced damage. A Phase 2 study indicated favorable efficacy of V vs placebo when added to C/P in advanced NSCLC (Ramalingam et al. Clin Cancer Res. 2016). Based on these results, a Phase 1/2 trial was initiated to study the safety and efficacy of V/C/P-based CRT in the treatment of Stage III NSCLC. Methods: Subjects without prior NSCLC therapy suitable for definitive CRT received V plus C AUC 2 + P 45 mg/m2 weekly + 60 Gy over 6-9 weeks. V was escalated from 60 mg BID to a maximum planned dose based on prior studies of 240 mg BID via 3+3 design with allowed over-enrollment followed by consolidation therapy of V 120 mg BID + C AUC 6 + P 200 mg/m2 for up to two 21-day cycles. Results: Thirty-one subjects (median age 64; 10 male) have been enrolled to date into dosing cohorts at 60 mg (7), 80 mg (9), 120 mg (7) and 200 mg (8). PK of V was dose proportional. CRT or V required dose reduction for 0 or 1 subject, respectively. Four (13%) subjects discontinued study during CRT. No DLTs have been observed and an MTD has not yet been identified. The most common any grade AEs were fatigue (16), esophagitis (15), nausea (13), neutropenia (12), thrombocytopenia (12), constipation (10) and decreased appetite (10). 21 SAEs were observed including 8 with reasonable attribution to V but outside the DLT window including G3/4 febrile neutropenia (2), G3 dehydration (1), G3 vomiting (1), G3 radiation esophagitis (1), G3 esophageal stricture (1), G3 intractable N/V (1) and G5 sepsis during consolidation (1). Of 21 subjects evaluable for tumor assessment, best response was CR (1), PR (11), SD (6), and PD (3). Conclusions: V/C/P-based CRT followed by V/C/P consolidation therapy is a tractable regimen for the treatment of Stage III NSCLC. A randomized placebo-controlled Phase 2 extension of this study is planned. Clinical trial information: NCT02412371.

2510 Background: ABBV-221 is a 2nd-generation antibody-drug conjugate (ADC) targeting EGFR based on the 1st-generation ADC ABT-414. ABT-414 shows efficacy in glioblastoma (GBM) patients (pts) with EGFR amplification in ongoing studies. ABBV-221 is an affinity matured monoclonal antibody against EGFR linked to the toxin MMAE. ABBV-221 has higher affinity for overexpressed EGFR than ABT-414, potentially allowing it to target a broader range of tumor types. Methods: This is a Phase 1, multicenter study to determine maximum tolerated dose (MTD) and recommended Phase 2 dose (RPTD) of ABBV-221. Pts are required to have an EGFR-dependent cancer to be eligible. Starting dose of ABBV-221: 0.3 mg/kg IV infused over 3 hrs for each 21-day cycle, with alternate dosing schedules utilized (2 wks on, 1 wk off or weekly) to mitigate infusion reactions. Results: As of 11 January 2017, 42 pts were treated (13 colon, 5 head & neck (H&N) cancer, 5 non-small cell lung cancer, 5 GBM, 2 breast, 12 other). Ten dose escalation cohorts have been completed with the last cleared dose 4.5 mg/kg per cycle. Tumor tissue samples were evaluated for EGFR protein expression by IHC, EGFR and EGFR ligand mRNA expression by RNAseq, and the results compared to outcome. The most common adverse event (AE) was infusion reaction in 18/42 pts (43%); 3 pts experienced severe infusion reactions. Several mitigation strategies were used to permit continued dose escalation. The other most common AE was fatigue in 17/42 pts (41%). Only 1 pt had keratitis (Grade 4). Sixteen pts (38%) had stable disease (SD), including 4 pts who remained on study longer than 6 months. One H&N pt who has received 2 cycles of ABBV-221 had an unconfirmed partial response and continues to be treated. This pt had high levels of both EGFR and EGFR ligand. Preliminary pharmacokinetics (PK) analysis suggests ABBV-221 exposures are approximately dose-proportional. Conclusions: Safety, PK, pharmacodynamics, and preliminary efficacy data of ABBV-221 warrant further study in this population. Infusion reactions have been manageable and primarily a first dose phenomenon. The duration of SD in pts with refractory solid tumors is encouraging. Clinical trial information: NCT02365662.

We present Durchblick, a conference assistance system for Augmented Reality devices. We demonstrate a prototype which can deliver context-sensitive event information and recommendations via Google Glass. This prototype incorporates semantic data from user-specific and public sources to build user profiles, maintains rich context information and employs event processing as well as recommender systems to proactively select and present relevant information.

In this paper, it’s research hard on the normalization algorithm of image preprocessing. It proposes that normalize the size of a single character at first, and then thin this character, make an amendment to the framework image at last. Experimental results indicate that this method is validate and lays a solid foundation for consequence processing of the Chinese character recognition.

Current spoken dialogue systems (SDS) for mobile search are mostly domainspecific and make use of static knowledge. Consequently they do not take into account the interests, location and contextual situation of the concrete user. We propose PARLANCE, which is a more dynamic and personalized SDS that incorporates 1) a dynamic knowledge base consisting of modular ontologies that are enriched incrementally with information extracted from the Web; 2) and an evolving user profile. This allows the system to provide answers that are more tailored to the concrete user and to exploit the Web as a source of information, which can improve the quality of experience for the user. The PARLANCE SDS aims to guide the user in his search for information by providing answers that are: (1) Hyperlocal: The current geographical location of the user is taken into account to provide points of interest (POIs) in the neighborhood; (2) Dynamic: New concepts and entities are learned at runtime and included in the appropriate modular ontologies; (3) Personalized: Potential relevant answers adapted to user’s queries are selected and ranked according to user preferences. Complementary, a form of social search is performed by looking at interests of similar user in the neighborhood (i.e. collaborative filtering). The central component in the PARLANCE architecture is the Interaction Manager (IM) which probabilistically decides on the most appropriate next answer to be provided to the user. The IM exploits information from the Semantic Web by interacting with the Knowledge Base (KB), the Web Content Analyzer (WCA) and the Local Search (LS) components, which will be detailed in the next section.

Li, Y.; Wang, Y.; Xu, S.; Hu, B., and Wang, Z.-L., 2017. Effects of mariculture and solar-salt production on sediment microbial community structure in a coastal wetland. Mariculture and solar-salt production are two pervasive anthropogenic activities in worldwide coastal areas; however, their effects on sediment microbial biomass, community composition, and diversity have received less attention. Here, this question was investigated using the phospholipid fatty acids (PLFAs) analysis and 16S rRNA gene sequencing in Bohai Rim, northern China. Both mariculture and salt production increased bacterial (+135% and +84%), fungal (+45% and +20%), and total PLFAs contents (+72% and +39%) compared with intertidal wetlands. Furthermore, mariculture and salt production shifted microbial PLFAs compositions. The ratio of fungi:bacteria-PLFAs decreased in mariculture ponds (−40%) and salt fields (−37%) relative to the undisturbed wetland, and the ratio of Gram-positive:Gram-negative bacteria decreased in the sa...

This paper presents a rule-based architecture that enables causal and temporal reasoning of events and supports their relevance assessment given the user's situation, in order to provide contextualized services for citizens inhabiting a smart city. Our approach for context reasoning and assessment is illustrated by emergency scenarios.

We proposed a new algorithm for automatic identification of fluorescent signal. Based on the features of chromatographic chips, mathematic morphology in RGB color space was used to filter and enhance the images, pyramid connection was used to segment the areas of fluorescent signal, and then the method of Gaussian Mixture Model was used to detect the fluorescent signal. Finally we calculated the average fluorescent intensity in obtained fluorescent areas. Our results show that the algorithm has a good efficacy to segment the fluorescent areas, can detect the fluorescent signal quickly and accurately, and finally realize the quantitative detection of fluorescent signal in chromatographic chip.

The detection of fluorescent signal in chromatographic chip is the key of disease diagnosis by immunochromatographic assay. We propose a new algorithm for the automatic identification of fluorescent signal. Based on the features of chromatographic chips, mathematic morphology in RGB color space is used to filter and enhance the images, pyramid connection is used to segment the areas of fluorescent signal and then the method of Gaussian Mixture Model is available to detect the fluorescent signal. At last we calculate the average fluorescence intensity in obtained fluorescent areas. It can be proved that the algorithm has a good effect to segment the fluorescent areas and it can detect the fluorescent signal quickly and accurately to achieve the quantitative detection of chromatographic chip through experimental data analysis.

The article made an empirical econometric analysis on the fluctuation of China’s total Energy Consumption and then estimated GARCH model, TARCH model and EGARCH model by the way of maximum-likehood estimation. Empirical studies showed GARCH model made the best estimation in statistics and the fluctuation rate was altering. And the fluctuation’s impact on China’s energy consumption was very high. The TGARCH and EGARCH models also showed that it had asymmetrical relation with the fluctuation of China’s total energy consumption. The authors summarized the features of volatility from empirical results and put forward some suggestions for further development and improvement.

A novel design of physical format coding system (PFCS) is presented based on Multi-level read-only memory disc (ML ROM) in order to solve the problem of low efficiency and long period of disc testing during system development. The PFCS is composed of four units, which are 'Encode', 'Add Noise', 'Decode', 'Error Rate', and 'Information'. It is developed with MFC under the environment of VC++ 6.0, and capable to visually simulate the procedure of data processing for ML ROM. This system can also be used for developing other optical disc storage system or similar channel coding system.

Disc scratches, dusts and noise corruption et al. will cause data sequence errors including random errors and burst errors. With the recording density of multilevel (ML) optical storage system increasing, the same length of scratches on the surface of optical disc will bring more burst errors in ML DVD than conventional optical recording systems, e.g., digital versatile disc (DVD) and compact disc (CD). A new interleaving scheme based on Reed-Solomon code (RS) is proposed to solve this problem. In DVD system, the burden of the Parity of Outer-code (PO) is huge, while the Parity of Innercode (PI) has more correcting ability than needed. The new interleaving algorithm adjusts the structure of data frame and block and improves the interleaving depth of ECC block to reduce the burden of PO. The results of numerical simulations are presented to verify the performance of the new interleaving algorithm compared with RSPC. The new proposed scheme can correct maximum burst error length of the proposed code is 6912 bytes. Burst error correcting capacity of the proposed scheme is improved up to137.4% more than that of the RSPC.

This article introduces DVD Download specification and Manufacturing On Demand (MOD) system firstly. Then it will show a designed MOD system and analyze the function of each part in it. In this system, we need to combine two DVD's files into one disc automatically, so in the last part, the article shows work on this problem and achievement up to now.