Modulation of P-gp expression by lapatinib.

Chemotherapy drug resistance is a major obstacle in the treatment of cancer. It can result from an increase in levels of cellular drug efflux pumps, such as P-glycoprotein (P-gp). Lapatinib, a growth factor receptor tyrosine kinase inhibitor, is currently in clinical trials for treatment of breast cancer. We examined the impact of co-incubation of chemotherapy drugs in combination with lapatinib in P-gp over-expressing drug resistant cells. Unexpectedly, lapatinib treatment, at clinically relevant concentrations, increased levels of the P-gp drug transporter in a dose- and time-responsive manner. Conversely, exposure to the epidermal growth factor (EGF), an endogenous growth factor receptor ligand, resulted in a decrease in P-gp expression. Despite the lapatinib-induced alteration in P-gp expression, use of accumulation, efflux and toxicity assays demonstrated that the induced alteration in P-gp expression by lapatinib had little direct impact on drug resistance.

Genetics of bull semen characteristics in a multi-breed cattle population.

Little is known of the genetic variability in semen quality traits in cattle and their inter-relationships. The objective of the present study was to estimate genetic parameters for a range of semen quality measures. The data consisted of 35,573 ejaculates from 787 artificial insemination bulls of 16 breeds. Genetic parameters were estimated using a repeatability animal linear mixed model. Large breed differences were detected with Belgian Blue bulls, on average, producing lesser semen volume than all other breeds while the Charolais bulls, on average, produced semen with fewer live sperm and reduced motility. The within-breed coefficient of genetic variation for sperm concentration, semen volume and total number of sperm per ejaculate was 0.17, 0.15 and 0.19, respectively. The genetic standard deviation for percentage live sperm pre-cryopreservation was 5.6% units while the genetic standard deviation for progressive motility pre-cryopreservation (scale 0 to 5) was 0.25 units. The heritability of all traits was between 0.13 and 0.34. The repeatability of the semen quality traits varied from 0.22 to 0.45. Sperm concentration and volume were negatively genetically correlated (-0.40) although the phenotypic correlation was near zero (-0.01). The genetic correlations between percentage live sperm and sperm motility varied from 0.68 to 0.94 irrespective of whether the traits were measured pre- or post-cryopreservation or even the change in both traits during cryopreservation. A very strong genetic correlation existed between percentage live sperm pre- and post-cryopreservation (0.96) or sperm motility pre- or post-cryopreservation (0.92). Results highlight the large genetic variability in a range of semen quality traits, many of which are actually highly heritable, and therefore useful predictors of actual phenotypic measures.