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Organophosphate esters (OPEs) are normally used as flame retardants, plasticizers and lubricants, but have become environmental pollutants. Because OPEs are normally present alongside heavy metals in soils, the effects of interactions between OPEs and heavy metals on plant uptake of OPEs need to be determined. In this study, we investigated the effects of OPEs chemical structure, plant cultivar and copper (Cu) on the uptake and translocation of OPEs by plants. The bioaccumulation of OPEs varied among plant cultivars. They were preferentially enriched in carrot, with the lowest concentrations observed in maize. OPEs with electron-ring substituents (ER-OPEs) exhibited a higher potential for root uptake than did OPEs with open-chain substituents (OC-OPEs), which could be attributed to the higher sorption of ER-OPEs onto root charged surfaces. This was explained by the stronger noncovalent interactions with the electron-rich structure of ER-OPEs. The presence of Cu slightly reduced the distinct difference in the ability of roots to take up OC-OPEs and ER-OPEs. This was explained by the interactions of Cu ions with the electron-rich structure of ER-OPEs, which suppressed the sorption of ER-OPEs on the root surface. A negative relationship between the logarithms of the translocation factor and octanol-water partition coefficient (Kow) was observed in treatments with either OPEs only or OPEs + Cu, implying the significant role of hydrophobicity in the OPEs acropetal translocation. The results will improve our understanding of the uptake and translocation of OPEs by plant cultivars as well as how the process is affected by the chemical structure of OPEs and Cu, leading to improvements in the ecological risk assessment of OPEs in the food chain.

Engineering ceramic has been widely used in various fields, especially in bearings, for its excellent characteristics, such as the outstanding tolerance to temperature and wear, good stiffness, high strength, and so on. Surface quality is vital for precision bearings. However, the machining of ceramic materials is difficult due to their high hardness and high brittleness. To investigate the effect of grinding parameters (grinding wheel speed, workpiece, and grinding depth) on the surface quality in internal grinding of Silicon Nitride (Si3N4) ceramics applied to bearing ring, an orthogonal experiment was carried out in this study. The surface roughness (SR), surface morphology, and subsurface damage of the ceramic material were analyzed based on a sequence of experimental results, respectively. Then, two prediction models on the SR in the internal grinding of Si3N4 ceramics were established combining the experimental results, internal grinding process, and empirical equation. This study provides a significant reference to obtain better surface quality in the internal grinding of ceramic material.

Toxic heavy metals and metalloids in agricultural ecosystems are crucial factors that limit global crop productivity and food safety. Industrial toxic heavy metals and metalloids such as cadmium, lead, and arsenic have contaminated large areas of arable land in the world and their accumulation in the edible parts of crops is causing serious health risks to humans and animals. Plants have co-evolved with various concentrations of these toxic metals and metalloids in soil and water. Some green plant species have significant innovations in key genes for the adaptation of abiotic stress tolerance pathways that are able to tolerate heavy metals and metalloids. Increasing evidence has demonstrated that phytohormone abscisic acid (ABA) plays a vital role in the alleviation of heavy metal and metalloid stresses in plants. Here, we trace the evolutionary origins of the key gene families connecting ABA signaling with tolerance to heavy metals and metalloids in green plants. We also summarize the molecular and physiological aspects of ABA in the uptake, root-to-shoot translocation, chelation, sequestration, reutilization, and accumulation of key heavy metals and metalloids in plants. The molecular evolution and interaction between the ABA signaling pathway and mechanisms for heavy metal and metalloid tolerance are highlighted in this review. Therefore, we propose that it is promising to manipulate ABA signaling in plant tissues to reduce the uptake and accumulation of toxic heavy metals and metalloids in crops through the application of ABA-producing bacteria or ABA analogues. This may lead to improvements in tolerance of major crops to heavy metals and metalloids.

Purpose: This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors. Patients and Methods: The 3 + 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m2 on days 1–3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity. Results: Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively. Conclusions: Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC.

The first umpolung strategy for the cycloacylation of fullerene using a N-heterocyclic carbene organocatalyst is reported. The coupling of [60]fullerene with different structural α,β-unsaturated aldehydes efficiently furnishes interesting [60]fullerene-fused cyclopentan-1-ones or cyclohex-2-en-1-ones in good to excellent yields. This new reaction displays a wide substrate scope and excellent functional-group tolerance, and diverse substituents such as aryl, heteroaryl, alkenyl, alkyl, and ester can be installed by using the corresponding enals.

Carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) concentration, saturation and fluxes in rivers (Beitang drainage river, Dagu drainage rive, Duliujianhe river, Yongdingxinhe river and Nanyunhe river) of Tianjin city (Haihe watershed) were investigated during July and October in 2014, and January and April in 2015 by static headspace gas chromatography method and the two-layer model of diffusive gas exchange. The influence of environmental variables on greenhouse gases (GHGs) concentration under the disturbance of anthropogenic activities was discussed by Spearman correlative analysis and multiple stepwise regression analysis. The results showed that the concentration and fluxes of CO2, CH4 and N2O were seasonally variable with >winter>fall>summer, spring>summer>winter>fall and summer>spring>winter>fall for concentrations and spring>summer>fall>winter, spring>summer>winter>fall and summer>spring>fall>winter for fluxes respectively. The GHGs concentration and saturation were higher in comprehensively polluted river sites and lower in lightly polluted river sites. The three GHGs emission fluxes in two sewage draining rivers of Tianjin were clearly higher than those of other rivers (natural rivers) and the spatial variation of CH4 was more obvious than the others. CO2 and N2O air-water interface emission fluxes of the sewage draining rivers in four seasons were about 1.20-2.41 times and 1.13-3.12 times of those in the natural rivers. The CH4 emission fluxes of the sewage draining rivers were 3.09 times in fall to 10.87 times in spring of those in the natural rivers in different season. The wind speed, water temperature and air temperature were related to GHGs concentrations. Nitrate and nitrite (NO3-+NO2--N) and ammonia (NH4+-N) were positively correlated with CO2 concentration and CH4 concentration; and dissolved oxygen (DO) concentration was negatively correlated with CH4 concentration and N2O concentration. The effect of human activities on carbon and nitrogen cycling in river is great.

Evasion of carbon dioxide (CO2) and methane (CH4) in streams and rivers play a critical role in global carbon (C) cycle, offsetting the C uptake by terrestrial ecosystems. However, little is known about CO2 and CH4 dynamics in lowland coastal rivers profoundly modified by anthropogenic perturbations. Here, we report results from a long-term, large-scale study of CO2 and CH4 partial pressures (pCO2 and pCH4) and evasion rates in the Shanghai river network. The spatiotemporal variability of pCO2 and pCH4 were examined along a land-use gradient and the annual CO2 and CH4 evasion were estimated to assess its role in regional C budget. During the study period (August 2009 – October 2011), the overall mean pCO2 and median pCH4 from 87 surveyed rivers were 5846±2773 μatm and 241 μatm, respectively. Internal metabolic CO2 production and DIC input via upstream runoff were the major sources sustaining the widespread CO2 supersaturation, coupling pCO2 to biogeochemical and hydrological controls, respectively. While CH4 was oversaturated throughout the river network, CH4 hotpots were concentrated in the small urban rivers and highly discharge-dependent. The Shanghai river network played a disproportionately important role in regional C budget, offsetting up to 40% of the regional terrestrial net ecosystem production (NEP) and 10% of net C uptake in the river-dominated East China Sea fueled by anthropogenic nutrient input. Given the rapid urbanization in global coastal areas, more research is needed to quantify the role of lowland coastal rivers as a major landscape C source in global C budget.

Losatuxizumab vedotin (formerly ABBV-221) is a second-generation antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). In this multicenter phase 1 study, eligible patients with EGFR-dependent solid tumors received losatuxizumab vedotin (3 + 3 design) intravenously at starting dose of 0.3 mg/kg over 3 h per 21-day cycle, with alternate dosing schedules utilized (2 weeks on/1 week off or weekly) to mitigate infusion reactions. Forty-five patients received ≥1 doses of losatuxizumab vedotin (13 colon, 6 non-small cell lung cancer, 5 head and neck [HNC], 5 glioblastoma multiforme, 2 breast, 14 other). Tumor samples were evaluated for EGFR protein expression by immunohistochemistry, EGFR and EGFR ligand mRNA expression by RNAseq, and results compared with outcome. Most common adverse events were infusion-related reaction (22/45; 49%) and fatigue (20/45; 44%). While most infusion reactions were grade ≤ 2, four patients experienced grade ≥3 infusion reactions. Several infusion reaction mitigation strategies were explored. Because of the high incidence of infusion reactions, the trial was stopped and the maximum tolerated dose was not reached. The last cleared dose: 6 mg/kg/cycle. Nineteen patients (42%) had stable disease; 4 remained on study >6 months. One HNC patient with increased levels of EGFR and EGFR ligands (amphiregulin, epiregulin) achieved a confirmed partial response. Pharmacokinetic analysis of losatuxizumab vedotin showed exposures appeared to be approximately dose-proportional. The high frequency of infusion reactions necessitated early closure of this trial. The detailed mitigation strategies used in this protocol for infusion-related reactions may provide beneficial information for trial design of agents with high infusion reaction rates.

Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child–Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.

BackgroundTreatment of patients coinfected with hepatitis C and human immunodeficiency viruses (HCV; HIV) requires careful consideration of potential drug-drug interactions between HCV direct-acting antiviral agents (DAA) and HIV antiretrovirals. Glecaprevir/pibrentasvir is a fixed-dose combination of an NS3/4A protease inhibitor and an NS5A inhibitor approved for the treatment of chronic HCV genotype 1–6 infection, including patients with HIV coinfection.MethodsA series of phase 1 studies was conducted to evaluate potential interactions of glecaprevir and pibrentasvir with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, abacavir/dolutegravir/lamivudine, raltegravir, rilpivirine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, or efavirenz/emtricitabine/tenofovir disoproxil fumarate. Pharmacokinetics of the antiretrovirals and DAAs were characterized when administered alone and in combination to quantify changes in systemic drug exposure.ResultsGlecaprevir area under the curve increased >4-fold in the presence of ritonavir-boosted HIV protease inhibitors, while pibrentasvir concentrations were not significantly affected; elevations in alanine transaminase occurred in combination with atazanavir/ritonavir only. Exposures of glecaprevir and pibrentasvir may be significantly decreased by efavirenz. Coadministration with glecaprevir and pibrentasvir did not result in clinically significant changes in the exposure of any antiretroviral agents.ConclusionsAtazanavir is contraindicated with glecaprevir/pibrentasvir and use of boosted protease inhibitors or efavirenz is not recommended. No clinically significant interactions were observed with other studied antiretrovirals.

Aims To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. Methods Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5–11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. Results Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to infinity (AUC∞) by 2.3-fold (90% confidence interval [CI]: 2.0–2.7) and 6.4-fold (90% CI: 4.5–9.2; range: 2- to 12-fold), respectively. Conclusions Coadministration of venetoclax with multiple doses of ketoconazole resulted in a significant increase of venetoclax exposures, strongly suggesting that CYP3A plays a major role in elimination of venetoclax in patients. These results suggest the need to avoid concomitant use with strong and moderate inhibitors or inducers of CYP3A during the venetoclax ramp-up phase in chronic lymphocytic leukaemia (CLL) patients. For patients who have completed the ramp-up phase, a modification in venetoclax dose for use with strong and moderate inhibitors or inducers of CYP3A is recommended.

Venetoclax is a selective, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. In vitro data indicated weak cytochrome P450 (CYP) 2C9 inhibition by venetoclax; however, it is not predicted to cause clinically relevant inhibition due to high plasma protein binding. A Phase 1 study was conducted in healthy volunteers to evaluate the effect of venetoclax on warfarin pharmacokinetics. Subjects received a single oral dose of 5 mg warfarin on day 1 of both periods 1 and 2, separated by a 14 days washout. On day 1 of period 2, subjects concomitantly received a single 400 mg oral dose of venetoclax. Blood samples for warfarin concentration determination were collected after each dose administration for up to 9 days. Modest increases of 18 to 28% were observed in the maximum observed plasma concentration (C max) and area under the curve from time zero to infinity (AUC∞) of both R- and S-warfarin. Due to the narrow therapeutic window of warfarin, it is recommended that the international normalized ratio (INR) be monitored closely in patients receiving venetoclax and warfarin. Since similar increases in exposure were observed for both enantiomers, even though CYP2C9 is only involved in the metabolism of the S-enantiomer, and the half-life of both enantiomers remained the same, the interaction does not appear to be mediated via CYP2C9.

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 Cmax and AUC∞ by 106% (90%CI, 73%-145%) and 78% (90%CI, 50%-111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax Cmax and AUC∞ by 42% (90%CI, 31%-52%) and 71% (90%CI, 66%-76%), respectively. It was possible to isolate the net effect of chronic CYP3A induction from acute P-glycoprotein (P-gp) inhibition by comparing venetoclax exposures following coadministration with multiple doses of rifampin versus a single dose of rifampin, which showed that CYP3A induction decreased venetoclax Cmax and AUC by 72% and 84%, respectively. These results are consistent with venetoclax being a P-gp substrate and indicate that CYP3A plays a major role in venetoclax metabolism. Prescribers should consider agents with little or no CYP3A induction during treatment with venetoclax.

To enhance the osteointegration and antibacterial property of titanium (Ti) implant, zinc calcium phosphate chemical conversion (Zn-Ca-PCC) was fabricated on pure Ti by phosphate chemical conversion technique. The surface of the coating was verified by combined techniques of scanning electron microscopy, energy-dispersive X-ray spectrometry, atomic force microscopy and water contact angle measurements. Plate-like Zn-Ca-PCC coatings are built up on the surface of Ti. The results obtained from the antibacterial studies suggest that the Zn-Ca-PCC coatings can greatly inhibit the growth of both Gram-positive ( Staphylococcus aureus ) and Gram-negative ( Pseudomonas aeruginosa ) bacteria. Moreover, the in vitro evaluations demonstrate that the adhesion, proliferation and differentiation of osteoblasts on Zn-Ca-PCC coatings were significantly enhanced compared with pure Ti. In conclusion, innovative Zn-Ca-PCC coatings on Ti with excellent antibacterial activity and biocompatibility are promising candidates for orthopedic and dental implants.

Nitrous oxide (N2O) is one of the main greenhouse gases, which contributes to the global warming and ozone destruction. Sediment cores and river water were collected from an urban and a suburban river for N2O efflux measurement at the sediment-water interface and the factor-controlled incubations to investigating the N2O effluxes under varying conditions of dissolved oxygen (DO), ammonium (NH4 +), nitrate (NO3 −) and sulfate (SO4 2−). Vertical profiles of dissolved N2O concentrations in pore water were also acquired at eight depths. Results show that N2O effluxes were higher at the urban site (13.01 ± 6.51 μg N m−2 h−1) than the suburban site (4.02 ± 2.01 μg N m−2 h−1). Oxygen consumption rates were optimal under high DO and NH4 + amendment incubation, highlighting the strong nitrification potential in the sediment surface. Although N2O effluxes at the urban site increased with the NO3 − concentration under low DO condition, DO and NH4 + concentrations in overlying water were the principal factors controlling N2O effluxes (R = −0.415, p = 0.000 and R = 0.512, p

Background & AimsParitaprevir (administered with ritonavir, PTV/r), ombitasvir (OBV), and dasabuvir (DSV) are direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection. Thirteen studies were conducted to characterize drug-drug interactions for the 3D regimen of OBV, PTV/r, and DSV and various medications in healthy volunteers to inform dosing recommendations in HCV-infected patients.MethodsMechanism-based drug-drug interactions were evaluated for gemfibrozil, ketoconazole, carbamazepine, warfarin, omeprazole, digoxin, pravastatin, and rosuvastatin. Drug-drug interactions with medications commonly used in HCV-infected patients were evaluated for amlodipine, furosemide, alprazolam, zolpidem, duloxetine, escitalopram, methadone, buprenorphine/naloxone, and oral contraceptives. Ratios of geometric means with 90% confidence intervals for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were used to determine the magnitude of interaction.ResultsCoadministration with the 3D regimen of OBV, PTV/r, and DSV resulted in a

The addition of surfactant in tablet was a well-defined approach to improve drug dissolution rate. While the selected surfactant played a vital role in improving the wettability of tablet by medium, it was equally important to improve the dissolution rate by permeation effect due to production of pores or the reduced inter-particle adhesion. Furthermore, understanding the mechanism of dissolution rate increased was significant. In this work, contact angle measurement was taken up as an alternative approach for understanding the dissolution rate enhancement for tablet containing surfactant. Ethylcellulose, as a substrate, was used to prepare tablet. Four surfactants, sodium dodecyl sulfate (SDS), sodium dodecylbenzenesulfonate (SDBS), dodecyltrimethylammonium bromide (DTAB), and sodium lauryl sulfonate (SLS), were used. Berberine hydrochloride, metformin hydrochloride, and rutin were selected as model drugs. The contact angle of tablet in the absence and presence of surfactant was measured to explore the mechanism. The dissolution test was investigated to verify the mechanism and to establish a correlation with the contact angle. The result showed that the mechanism was the penetration effect rather than the wetting effect. The dissolution increased with a reduction in the contact angle. DTAB was found to obtain the highest level of dissolution enhancement and the lowest contact angle, while SDS, SDBS, and SLS were found to be the less effective in both dissolution enhancement and contact angle decrease. Therefore, contact angle was a good indicator for dissolution behavior besides exploring the mechanism of increased dissolution, which shows great potential in formula screening.

Venetoclax is a selective BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). It is predominately metabolized by cytochrome P450 (CYP) 3A. The study objective was to determine the effect of different dosage regimens of ritonavir, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax in 20 healthy subjects. In cohorts 1 and 2, subjects received single 10 mg doses of venetoclax in periods 1 and 2 and a single 50- or 100-mg dose of ritonavir in period 2. In cohort 3, subjects received 10-mg venetoclax doses on day 1 of period 1 and days 1 and 11 of period 2, and 50 mg ritonavir daily on days 1 to 14 of period 2. Single doses of 50 and 100 mg ritonavir increased the venetoclax maximum concentration (Cmax) 2.3- to 2.4-fold compared to venetoclax alone and the area under the curve (AUC) 6.1- and 8.1-fold, respectively. Daily 50 mg ritonavir resulted in a 2.4- and 7.9-fold increase in venetoclax Cmax and AUC, respectively. Administration of 50 mg ritonavir daily saturated CYP3A inhibition and completely inhibited the formation of the major venetoclax metabolite M27. Time-dependent CYP3A inhibition with daily 50 mg ritonavir was offset by ritonavir CYP3A induction, resulting in a limited net increase in CYP3A inhibition with multiple doses. After completion of the dose ramp-up, venetoclax dose reductions of at least 75% are recommended when administered concomitantly with strong CYP3A inhibitors to maintain venetoclax exposures within the established therapeutic window for CLL treatment.

Background: The bromodomain and extra terminal (BET) family of proteins bind acetylated histone tails, leading to the regulation of oncogenic target genes. Mivebresib (ABBV-075; MIV) is a pan-BET inhibitor that has demonstrated antitumor activity in vitro and in xenograft models of acute myeloid leukemia (AML). This phase 1, first-in-human, 2-part study (NCT02391480) assessed the safety and pharmacokinetics (PK) of MIV at various monotherapy (MIV-mono) or combination dosing schedules with venetoclax (MIV-VEN). Here we report PK and pharmacodynamic (PD) data in correlation to biological activity in patients with relapsed/refractory AML. Methods: Gene expression analysis was performed on RNA extracted from whole blood samples collected at multiple time points (pre-and post-MIV-mono treatment). mRNA expression was analyzed from total RNA and sequenced on HiSeq 3000 (Illumina, San Diego, CA). Soluble cytokine modulation was evaluated in serum samples (pre- and post-MIV-mono treatment) on Myriad Rules-Based Medicine's ExplorerMAP® Panel (145 analytes; Myriad RBM, Austin, TX). Cytogenetic analysis was performed at each site using institutional guidelines. Molecular profiling was performed at the site and by AbbVie using targeted next-generation sequencing (myeloid-specific panel). PK sampling was done on cycle 1 day 1 (C1D1), C1D8 and C2D1. PK analyses were completed using non-compartmental analysis methods. A linear regression analysis was performed to determine association between drug exposure and percentage change in gene modulation from baseline at 6 hours on C1D1. Biologic activity was defined as measurable reduction in bone marrow (BM) blasts from baseline. Results: As of Jan 2019, 44 patients (median age: 68 y [range, 29-84]; 35 patients >2 prior therapies) were enrolled: 19 in MIV-mono (5 of whom switched to MIV-VEN) and 25 who began treatment in MIV-VEN cohorts. MIV (1-2.5 mg) exposures were dose proportional and MIV was rapidly absorbed with a Tmax of 2-6 hours and terminal half-life of ~15-20 hours. Concomitant administration of VEN did not show any clinically significant effect on MIV plasma PK at steady state. At 6 hours post-MIV-mono treatment, a significant correlation was observed between drug exposure and PD biomarker modulation, with a dose-dependent gene expression increase in DCXR and HEXIM1 and decrease in CD93 (p In patients treated with MIV-mono, measurable reduction in BM blast counts was observed in 7/19 (37%) patients (Figure): complete remission (CR) with incomplete blood count recovery (n=1), ≥50% blast reduction (n=4), modest blast reduction of The majority of patients (30/44; 68%) were classified as adverse risk per ELN 2017 criteria. At baseline, 6/19 (32%) MIV-mono and 17/30 (57%) MIV-VEN patients had mutations in signaling genes; FLT3-ITD/TKD were the most commonly mutated in MIV-VEN population (10/17, 59%). In the MIV-VEN group, 4/10 (40%) patients with FLT3-ITD/TKD mutations and 4/6 (67%) patients with PTPN11 mutations had reduction in BM blasts following treatment. At baseline, 12/30 (40%) patients had mutations in either SF3B1/U2AF1 or PTPN11; 8 (67%) of these patients had reduction in BM blasts, including 1 CR and 1 MLFS. Conclusions: MIV exposure was dose proportional and a significant correlation was identified between multiple biomarkers (HEXIM1, DCXR, CD93 gene modulation) and drug exposure at 6 hours post-MIV treatment. MIV treatment inhibited BCL-2, VEGF and Myc gene expression, while inducing expression of pro-apoptotic genes. Biologic activity was observed particularly in patients treated with MIV-VEN who had SF3B1/U2AF1 or PTPN11 mutations. Disclosures Borthakur: Arvinas: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cantargia AB: Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Merck: Research Funding; Janssen: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; PTC Therapeutics: Consultancy; Incyte: Research Funding; GSK: Research Funding. Odenike:Agios: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; NS Pharma: Research Funding; Oncotherapy: Research Funding; Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI/Baxalta: Research Funding; Astex Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Research Funding. Aldoss:Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria; AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses. Rizzieri:AbbVie: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Kite Pharma: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy; TEVA: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Amgen: Consultancy; Jazz Pharmaceuticals: Speakers Bureau; Millennium: Speakers Bureau. Prebet:Boehringer Ingelheim: Research Funding; pfizer: Honoraria; Tetraphase: Consultancy; Genentech: Consultancy; novartis: Honoraria; Boehringer Ingelheim: Research Funding; novartis: Honoraria; novartis: Honoraria; novartis: Honoraria; Agios: Consultancy, Research Funding; pfizer: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; novartis: Honoraria; Boehringer Ingelheim: Research Funding; pfizer: Honoraria; pfizer: Honoraria; pfizer: Honoraria. Modi:AbbVie: Employment, Other: Stock/stock options. Joshi:AbbVie: Employment, Other: Stock/stock options. Hu:AbbVie: Employment, Other: Stock/stock options. Sun:AbbVie: Employment, Other: Stock/stock options. Wolff:AbbVie Inc: Employment, Other: Stock/stock options. Jonas:AbbVie, Amgen, GlycoMimetics: Other: Travel expenses; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding.

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.

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.

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

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.