Drug‐microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL

The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll‐like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL‐infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell‐extrinsic mechanisms of drug resistance and disease progression.     

Pregnancy rates in cows and heifers inseminated at predetermined times using progesterone-releasing intravaginal devices

The time of estrus and ovulation were controlled using a proges-terone-releasing intravaginal device constructed from silicone rubber. Pregnancy rates were determined in beef cows and heifers inseminated with frozen semen at predetermined times after removal of the device. Two experiments were conducted using two types of devices. In experiment I, a sleeve-covered device was inserted into the vagina and left for 21 days. Thirty-six hours after the devices were removed each animal received 100 μg of synthetic GnRH intramuscularly and was inseminatec 48 hours after coil removal. Five percent of the heifers lost coils during the 21-day treatment period compared to 25% of mature cows. First service pregnancy rate was 26%. In experiment II, a PRID^® was used for a 14-day treatment period. Animals were not treated with GnRH as in experiment I and were inseminated from 56 to 68 hours after PRID removal. Only 3.5% of the coils were lost during the 14 days. Pregnancy rates ranged from 13 to 60%.