A phase I study with MAG-camptothecin intravenously administered weekly for 3 weeks in a 4-week cycle in adult patients with solid tumours

In MAG-camptothecin (MAG-CPT), the topoisomerase inhibitor camptothecin is linked to a water-soluble polymer. Preclinical experiments showed enhanced antitumour efficacy and limited toxicity compared to camptothecin alone. Prior phase I trials guided the regimen used in this study. The objectives were to determine the maximum tolerated dose, dose-limiting toxicities, safety profile, and pharmacokinetics of weekly MAG-CPT. Patients with solid tumours received MAG-CPT intravenously administered weekly for 3 weeks in 4-week cycles. At the starting dose level ( 80 mg m(-2) week(-1)), no dose-limiting toxicities occurred during the first cycle (n = 3). Subsequently, three patients were enrolled at the second dose level ( 120 mg m(-2) week(-1)). Two of three patients at the 80 mg m(-2) week(-1) cohort developed haemorrhagic cystitis ( grade 1/3 dysuria and grade 2/3 haematuria) during the second and third cycles. Next, the 80 mg m(-2) week(-1) cohort was enlarged to a total of six patients. One other patient at this dose level experienced grade 1 haematuria. At 120 mg m(-2) week(-1), grade 1 bladder toxicity occurred in two of three patients. Dose escalation was stopped at 120 mg m(-2) week(-1). Cumulative bladder toxicity was dose-limiting toxicity at 80 mg m(-2) week(-1). Pharmacokinetics revealed highly variable urinary camptothecin excretion, associated with bladder toxicity. Due to cumulative bladder toxicity, weekly MAG-CPT is not a suitable regimen for treatment of patients with solid tumours

Mathematical Modeling and Simulation of Ventricular Activation Sequences: Implications for Cardiac Resynchronization Therapy

Next to clinical and experimental research, mathematical modeling plays a crucial role in medicine. Biomedical research takes place on many different levels, from molecules to the whole organism. Due to the complexity of biological systems, the interactions between components are often difficult or impossible to understand without the help of mathematical models. Mathematical models of cardiac electrophysiology have made a tremendous progress since the first numerical ECG simulations in the 1960s. This paper briefly reviews the development of this field and discusses some example cases where models have helped us forward, emphasizing applications that are relevant for the study of heart failure and cardiac resynchronization therapy

Genomic Approaches to Enhance Stress Tolerance for Productivity Improvements in Pearl Millet

Pearl millet [Pennisetum glaucum (L.) R. Br.], the sixth most important cereal crop (after rice, wheat, maize, barley, and sorghum), is grown as a grain and stover crop by the small holder farmers in the harshest cropping environments of the arid and semiarid tropical regions of sub-Saharan Africa and South Asia. Millet is grown on ~31 million hectares globally with India in South Asia; Nigeria, Niger, Burkina Faso, and Mali in western and central Africa; and Sudan, Uganda, and Tanzania in Eastern Africa as the major producers. Pearl millet provides food and nutritional security to more than 500 million of the world’s poorest and most nutritionally insecure people. Global pearl millet production has increased over the past 15 years, primarily due to availability of improved genetics and adoption of hybrids in India and expanding area under pearl millet production in West Africa. Pearl millet production is challenged by various biotic and abiotic stresses resulting in a significant reduction in yields. The genomics research in pearl millet lagged behind because of multiple reasons in the past. However, in the recent past, several efforts were initiated in genomic research resulting into a generation of large amounts of genomic resources and information including recently published sequence of the reference genome and re-sequencing of almost 1000 lines representing the global diversity. This chapter reviews the advances made in generating the genetic and genomics resources in pearl millet and their interventions in improving the stress tolerance to improve the productivity of this very important climate-smart nutri-cereal

Critical and minimum N contents for development and growth of grain sorghum

This paper quantifies the effects of N-stress on development and growth of sorghum by identifying critical values for stover N% (SNC) and specific leaf nitrogen (SLN) for a range of physiological processes (rates of leaf appearance, leaf expansion, leaf area increase, and biomass accumulation). It also compares the merits of the SNC and SLN approach for implementation in the N-routines of crop growth simulation models. Data from experiments covering a range of nitrogen treatments, grown at three contrasting locations in Australia, were used in the analyses. For the rate of biomass accumulation, the critical and minimum SLN were constant for most of the growing season, except for early stages prior to approximately panicle initiation. For SNC, however, the critical and minimum values continued to decline throughout the growing season, although the decline was limited at later development stages. During the stage of leaf growth, the critical N content was similar for all processes considered. Although critical SLN was less sensitive to development stage than SNC, identification of a critical SLN was hampered if environmental effects on specific leaf area were present. The merit of each approach in simulation models will depend upon their ability to capture genotypic differences in N-dynamics. (C) 2001 Elsevier Science B.V. All rights reserved

Genetic variation in potential kernel size affects kernel growth and yield of Sorghum

Large-seededness can increase grain yield in sorghum [Sorghum bicolor (L.) Moench] if larger kernel size more than compensates for the associated reduction in kernel number. The aim of this research was to investigate kernel filling characteristics associated with the high kernel weight of KS115 germplasm and consider implications for grain yield improvement. Germplasm with a twofold range in potential kernel size was grown in two field experiments. In both experiments, a large-seeded hybrid based on KS115 yielded significantly more grain than a normal-seeded hybrid with the same female parent. Genotypic differences in final kernel weight were associated with both an increased rate and extended duration of kernel filling. A high kernel filling rate was associated with a high rate of increase in kernel water content and kernel volume, which resulted in large maximum water content and volume per kernel. The long kernel filling duration of KS115-based germplasm was associated with an extended duration of the period of rapid water uptake into the kernel following the onset of rapid dry mass accumulation in the grains. For this particular germplasm, this was likely due to the presence of large ovaries before fertilization. Because of a trade-off between potential kernel weight and number, prolonged duration, rather than an increased rate of kernel filling, appeared to be the main mechanism through which large-seededness of KS115 could increase grain yield

Functional dynamics of the nitrogen balance of sorghum. II. Grain filling period

Maintenance of green leaf area during grain filling can increase grain yield of sorghum grown under terminal water limitation. This ‘stay-green’ trait has been related to the nitrogen (N) supply–demand balance during grain filling. This study quantifies the N demand of grain and N translocation rates from leaves and stem and explores effects of genotype and N stress on onset and rate of leaf senescence during the grain filling period. Three hybrids differing in potential height were grown at three levels of N supply under well-watered conditions. Vertical profiles of biomass, leaf area, and N% of leaves, stem and grain were measured at regular intervals. Weekly SPAD chlorophyll readings on main shoot leaves were correlated with observed specific leaf nitrogen (SLN) to derive seasonal patterns of leaf N content. For all hybrids, individual grain N demand was sink determined and was initially met through N translocation from the stem and rachis. Only if this was insufficient did leaf N translocation occur. Maximum N translocation rates from leaves and stem were dependent on their N status. However, the supply of N at canopy scale was also related to the amount of leaf area senescing at any one time. This supply–demand framework for N dynamics explained effects of N stress and genotype on the onset and rate of leaf senescence