Development of Novel Interspecific Fertile Cytotype (4X) Of \u3cem\u3ePennisetum glaucum\u3c/em\u3e X \u3cem\u3ePennisetum purpureum\u3c/em\u3e Utilizing Modified Ploidy Coupled With Embryo Rescue Technique

Interspecific hybrids of genus Pennisetum (P. glaucum x P. purpureum) is the one of the most popular manmade hybrid. It combines the unique features of both P. glaucum (Pearl millet; Bajra) and P. purpureum (Napier; Elephant grass) species, which makes it more resilient to harsh environments with superior fodder quality. Due to ploidy level variation among the parents, these hybrids are sterile and propagated vegetatively only. To overcome this, attempts were made in the present study by exploring the feasibility of novel tetraploid pearl millet (2n=4x=28; Tetra 1; INGR 09047) developed at IGFRI, as a female parent in crossing program involving different Napier genotypes as male parent. Due to limited crossability and hybrid necrosis issues among countless crosses (\u3e 1000), only 1% seed set was initially recorded that too in shriveled state and the developing embryos were aborted after 10-14 days of pollination and fertilization. To save these, embryo rescue technique was standardized and the developing embryos were dissected out aseptically and rescued after 8-10 days of pollination. Continuous crossing programme along with screening of large tissue culture raised nurseries resulted in development of a novel tetraploid seed producing BN hybrid (TBN-20-15) along with 14 novel sterile tetraploid BN hybrids. Presence of univalent chromosomes leads to sterility while proper pairing between parents of TBN-20-15 hybrid have significant effect on fertility. The fertile hybrid is able to produce \u3e15,000-20,000 seeds throughout the year with 80-90% seed germination ability. Their hybridity was confirmed by morphology, molecular and cytogenetic studies. This fertile tetraploid BN hybrid (TBN-20-15) reported for the first time globally will be very helpful in easy and cost-effective dissemination of this highly potential forage crop to the farmer’s field. It has the potential to be the game changer in biofuel production, grassland rejuvenation programs besides bridging the fodder demand supply deficit

Modeling the 5-Fluorouracil Area Under the Curve Versus Dose Relationship to Develop a Pharmacokinetic Dosing Algorithm for Colorectal Cancer Patients Receiving FOLFOX6

5-Fluorouracil (5-FU) is administered based on standard body surface area (BSA) dosing. BSA administration results in highly variable exposure, measured as the area under the concentration-time curve (AUC). An immunoassay (OnDose®; Myriad Genetic Laboratories, Inc., Salt Lake City, UT) that measures plasma 5-FU concentration and reports an AUC in mg · h/L has been developed to optimize therapy using pharmacokinetic (PK) dosing. The results of an analysis to model the 5-FU AUC-dose relationship are presented

Serum Alpha-fetoprotein Levels and Clinical Outcomes in the Phase III CELESTIAL Study of Cabozantinib versus Placebo in Patients with Advanced Hepatocellular Carcinoma

PURPOSE: The phase III CELESTIAL study demonstrated improved overall survival (OS) and progression-free survival (PFS) with cabozantinib versus placebo in patients with previously treated, advanced hepatocellular carcinoma (HCC). We analyzed outcomes by baseline alpha-fetoprotein (AFP) and on-treatment AFP changes. PATIENTS AND METHODS: Serum AFP was measured every 8 weeks by blinded, centralized testing. Outcomes were analyzed by baseline AFP bifurcated at 400 ng/mL and by on-treatment AFP response (≥20% decrease from baseline at Week 8). The optimal cutoff for change in AFP at Week 8 was evaluated using maximally selected rank statistics. RESULTS: Median OS for cabozantinib versus placebo was 13.9 versus 10.3 months [HR, 0.81; 95% confidence interval (CI), 0.62-1.04] for patients with baseline AFP <400 ng/mL, and 8.5 versus 5.2 months (HR, 0.71; 95% CI, 0.54-0.94) for patients with baseline AFP ≥400 ng/mL. Week 8 AFP response rate was 50% for cabozantinib versus 13% for placebo. In the cabozantinib arm, median OS for patients with and without AFP response was 16.1 versus 9.1 months (HR, 0.61; 95% CI, 0.45-0.84). AFP response was independently associated with longer OS. The optimal cutoff for association with OS in the cabozantinib arm was ≤0% change in AFP at Week 8 [AFP control; HR 0.50 (95% CI, 0.35-0.71)]. HRs for PFS were consistent with those for OS. CONCLUSIONS: Cabozantinib improved outcomes versus placebo across a range of baseline AFP levels. On-treatment AFP response and control rates were higher with cabozantinib than placebo, and were associated with longer OS and PFS with cabozantinib

Modeling the 5‐Fluorouracil Area Under the Curve Versus Dose Relationship to Develop a Pharmacokinetic Dosing Algorithm for Colorectal Cancer Patients Receiving FOLFOX6

BACKGROUND. 5-Fluorouracil (5-FU) is administered based on standard body surface area (BSA) dosing. BSA administration results in highly variable exposure, measured as the area under the concentration-time curve (AUC). An immunoassay (OnDose®; Myriad Genetic Laboratories, Inc., Salt Lake City, UT) that measures plasma 5-FU concentration and reports an AUC in mg · h/L has been developed to optimize therapy using pharmacokinetic (PK) dosing. The results of an analysis to model the 5-FU AUC-dose relationship are presented. METHODS. A set of 589 sequential patients from a clinical database receiving 5-FU, leucovorin, and oxaliplatin (the FOLFOX6 regimen) for colorectal cancer (CRC) treatment was analyzed. A subset including only patients who had at least two consecutive cycles tested, received 1,600–3,600 mg/m(2) of continuous infusion 5-FU during the initial test cycle, and had a blood sample collected after ≥18 hours, was used to conduct regression modeling of the change in AUC versus change in dose. RESULTS. A simple regression model with R(2) = 0.51 developed over n = 307 cycle-pair observations characterizes the AUC-Dose relationship as: change in AUC = 0.02063 * dose change. The model suggests that dose changes in the range of 145–727 mg/m(2) would be sufficient to adjust the AUC to a potential therapeutic threshold of >20 mg · h/L for most patients. CONCLUSIONS. 5-FU is an ideal candidate for PK dose optimization. Because individual factors other than dose change may also affect the change in AUC, longitudinal PK monitoring in all cycles and dose adjustment to ensure AUC in the desired range of 20–30 mg · h/L are recommended