CF6 jet engine performance deterioration results

The use of the performance baseline from the flight planning manual as a reference to measure changes in cruise fuel flow rates was discussed. For the CF6-6D engine, the introduction of design changes for performance and durability reasons was seen to introduce an average increment relative to this baseline of 3.2% WFM increase at Nl, 2.5% Fn increase at Nl, 0.8% specific fuel consumption (SFC) increase at Fn, and 7 C EGT increase at Nl, while maintaining sufficient SFC margin of the delivered airplane. The effect of revenue service deterioration and performance restoration relative to the reference was shown to be an adder on top of these design effects. A schematic of typical CF6-6D performance through revenue service and airline maintenance is presented in terms of percent cruise SFC relative to an airline datum point (average level upon entering revenue service). The typical changes in SFC margin are shown for airline revenue service through for installations and refurbishments

Productivity and quality of smooth brome pastures under continuous, rotational, and mob grazing by sheep

Master of ScienceDepartment of AgronomyPeter J. TomlinsonIn recent years, an alternative grazing method to continuous and rotational methods has gained popularity among producers and has been termed mob grazing. Mob grazing uses high animal densities grazing for a short period of time. The objectives of this study were to determine the impact of continuous, rotational, and mob grazing on forage production and the quality of smooth bromegrass (Bromus inermis Leyss), along with soil dissolved organic carbon (DOC), microbial biomass carbon (MBC), and dehydrogenase enzyme activity. Twelve paddocks, 4 continuous (40 X 10 m), 4 rotational and 4 mob (15 X 10 m), were designated at the Kansas State University Sheep and Meat Goat Center in Manhattan, KS. Forage quality samples were collected by hand clipping randomly throughout the paddock. Neutral detergent fiber (NDF) and acid detergent fiber (ADF) were determined using ANKOM technology and crude protein (CP) content was calculated by multiplying total nitrogen determined by combustion by 6.25. Soil samples were extracted with 0.5 M K2SO4 and analyzed for DOC and MBC using the chloroform-fumigation-extraction method and soil dehydrogenase activity using the colorimetric method. Forage quality declined as the spring grazing season progressed in all treatments. Sheep grazed higher quality forage in the continuous and rotational treatments in the period prior to the spring mob grazing event. No treatment differences were found for DOC, MBC, dehydrogenase, or total forage biomass accumulation. Dissolved organic carbon and soil biological parameters have not been altered by the grazing management. Forage quality was found to be poorest in the mob treatment at the time of grazing. The mob treatment accumulated the greatest amount of aboveground biomass prior to grazing, however season-long total biomass accumulation was not different from the other treatments. Based on this research, in the short-term, there are no advantages of mob grazing over rotational grazing

Adenoviral vector-mediated expression of a gene encoding secreted, EpCAM-targeted carboxylesterase-2 sensitises colon cancer spheroids to CPT-11

CPT-11 (irinotecan or 7-ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) is an anticancer agent in use for the treatment of colon cancer. In order to be fully active, CPT-11 needs to be converted into SN-38 (7-ethyl-10-hydroxycamptothecin) by the enzyme carboxylesterase (CE). In humans, only a minority of CPT-11 is converted to SN-38. To increase the antitumour effect of CPT-11 by gene-directed enzyme prodrug therapy, we constructed a replication-deficient adenoviral vector Ad.C28-sCE2 containing a fusion gene encoding a secreted form of human liver CE2 targeted to the surface antigen epithelial cell adhesion molecule (EpCAM) that is highly expressed on most colon carcinoma cells. By targeting CE2 to EpCAM, the enzyme should accumulate specifically in tumours and leakage into the circulation should be minimised. Ad.C28-sCE2-transduced colon carcinoma cells expressed and secreted active CE that bound specifically to EpCAM-expressing cells. In sections of three-dimensional colon carcinoma spheroids transduced with Ad.C28-sCE2, it was shown that C28-sCE2 was capable of binding untransduced cells. Most importantly, treatment of these spheroids with nontoxic concentrations of CPT-11 resulted in growth inhibition comparable to treatment with SN-38. Therefore, Ad.C28-sCE2 holds promise in gene therapy approaches for the treatment of colon carcinoma

Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38

We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500 h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC500 h) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC500 h using only two timed samples: AUC500 h=(6.588×C2.5 h)+(146.4×C49.5 h)+15.53, where C2.5 h and C49.5 h are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan

Secreted and tumour targeted human carboxylesterase for activation of irinotecan

Irinotecan (CPT-11) is an anticancer agent for the treatment of colon cancer. CPT-11 can be considered as a prodrug, since it needs to be activated into the toxic drug SN-38 by the enzyme carboxylesterase. An approach to achieve tumour specific activation of CPT-11 is to transduce the cDNA encoding carboxylesterase into tumour cells. A secreted form of carboxylesterase may diffuse through a tumour mass and may activate CPT-11 extracellularly. This could enhance the antitumour efficacy by exerting a bystander effect on untransduced cells. In addition a secreted tumour-targeted form of carboxylesterase should prevent leakage of the enzyme from the site of the tumour into the circulation. We have constructed a secreted form of human liver carboxylesterase-2 by deletion of the cellular retention signal and by cloning the cDNA downstream of an Ig kappa leader sequence. The protein was secreted by transfected cells and showed both enzyme activity and efficient CPT-11 activation. To obtain a secreted, tumour-targeted form of carboxylesterase-2 the cDNA encoding the human scFv antibody C28 directed against the epithelial cell adhesion molecule EpCAM, was inserted between the leader sequence and carboxylesterase-2. This fusion protein showed CPT-11 activation and specific binding to EpCAM expressing cells. Importantly, in combination with CPT-11 both recombinant carboxylesterase proteins exerted strong antiproliferative effects on human colon cancer cells. They are, therefore, promising new tools for gene directed enzyme prodrug therapy approaches for the treatment of colon carcinoma with CPT-11

Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a Phase Ib/II study

Purpose: Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML. Patients and Methods: Adults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m2 per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS). Results: Median age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months). Conclusion: Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.Andrew H. Wei, Stephen A. Strickland Jr, Jing-Zhou Hou, Walter Fiedler, Tara L. Lin, Roland B. Walter, Anoop Enjeti, Ing Soo Tiong, Michael Savona, Sangmin Lee, Brenda Chyla, Relja Popovic, Ahmed Hamed Salem, Suresh Agarwal, Tu Xu, Kaffa M. Fakouhi, Rod Humerickhouse, Wan-Jen Hong, John Hayslip and Gail J. Robo