Oral pre- and early postnatal cannabis exposure disinhibits ventral tegmental area dopamine neuron activity but does not influence cocaine preference in offspring in mice.

Cannabis consumption has increased from 1.5% to 2.5% in Canada between 2012 and 2019. Clinical studies have indicated effects of prenatal cannabis exposure on birth weight, substance use, and neurodevelopmental disorders, but are confounded by several difficult to control variables. Animal models allow for examination of the mechanism of cannabis-induced changes in neurodevelopment and behavior, while controlling dose and timing. Several animal models of prenatal cannabis exposure exist which provide varying levels of construct validity, control of dose, and exposure to maternal stress. Using a voluntary oral consumption model, mouse dams received 5 mg/kg Δ9-tetrahydrocannabinol (THC) whole cannabis oil in peanut butter daily from gestational day 1 (GD1) to postnatal day 10 (PD10). At GD1, GD18, PD1, PD10, and PD15, maternal plasma was collected; pup brains were collected from GD18 onward. Pup brains had higher levels of THC and cannabidiol at each time point, each of which persisted in maternal plasma and pup brains past the end of treatment (PD15). Male and female adolescent offspring were examined for changes to ventral tegmental area (VTA) dopamine neuron activity and cocaine-seeking behavior. Prenatal and early postnatal (GD1-PD10) cannabis-exposed male, but not female mice had decreased gamma-aminobutyric acid (GABAergic) input, depolarized resting membrane potential, and increased spontaneous firing of VTA dopamine neurons. Cannabis-exposed offspring showed faster decay of N-methyl-D-aspartate (NMDA) currents in both sexes. However, no differences in cocaine-seeking behavior were noted. These data characterize a voluntary prenatal cannabis exposure model and demonstrates VTA dopamine neuronal activity is disinhibited in offspring.

An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma.

BACKGROUND: Vismodegib is an oral hedgehog-pathway inhibitor approved for advanced basal cell carcinoma (BCC). Although most BCCs are amenable to surgery, excision of large tumors in aesthetically sensitive sites may compromise function or cosmesis. OBJECTIVE: We sought to evaluate the reduction in BCC surgical defect area after 3 to 6 months of neoadjuvant vismodegib. METHODS: This was an open-label, single-arm intervention trial with a primary outcome of change in target-tumor surgical defect area pre- and post-vismodegib (150 mg/d). Secondary outcomes were change in tumor area and tolerability. RESULTS: Eleven of 15 enrolled patients, aged 39 to 100 years, completed the trial. Thirteen target tumors were excised after a mean of 4±2 months of vismodegib. In all, 29% (4 of 14 patients) could not complete more than 3 months because of vismodegib-related side effects. The mean baseline target-tumor diameter was 3.2 cm, and 10 of 13 tumors occurred on the face. Overall, vismodegib reduced the surgical defect area by 27% (95% confidence interval -45.7% to -7.9%; P=.006) from baseline. Vismodegib was not effective in patients who received less than 3 months. Over a mean follow-up of 11.5 (range 4-21) months for all tumors, only 1 tumor recurred at 17 months post-Mohs micrographic surgery. LIMITATIONS: Short follow-up time and no placebo control are limitations. CONCLUSION: Neoadjuvant vismodegib appears to reduce surgical defect area when taken for 3 months or longer for nonrecurrent BCCs in functionally sensitive locations. Further studies with larger sample sizes and long-term follow-up are warranted.

The relationship between gene-specific DNA methylation in leukocytes and normal colorectal mucosa in subjects with and without colorectal tumors.

CpG island methylation in the promoter regions of tumor suppressor genes has been shown to occur in normal colonic tissue and can distinguish between subjects with and without colorectal neoplasms. It is unclear whether this relationship exists in other tissues such as blood. We report the relationship between estrogen receptor gene (estrogen receptor alpha) methylation in leukocyte and normal colonic tissue DNA in subjects with and without colorectal neoplasia. DNA was extracted from frozen stored whole blood samples of 27 subjects with cancer, 30 with adenoma, 16 with hyperplastic polyps, and 57 disease-free subjects. DNA methylation in seven CpG sites close to the transcription start of estrogen receptor alpha was quantitated using pyrosequencing and expressed as a methylation index (average methylation across all CpG sites analyzed). Estrogen receptor alpha methylation in leukocyte DNA was compared with estrogen receptor alpha methylation in normal colonic mucosa DNA that had been previously determined in the same subjects. Estrogen receptor alpha was partially methylated (median, 4.3%; range, 0.0-12.6%) in leukocyte DNA in all subjects, with no significant difference between disease groups (P>0.05). Estrogen receptor alpha methylation in leukocytes was 60% lower than estrogen receptor alpha methylation in normal colonic tissue (P<0.001). Estrogen receptor alpha methylation in colonic tissue (P<0.001) and smoking (P=0.016) were determinants of estrogen receptor alpha methylation in leukocytes, independent of age, body mass index, gender, and disease status. In conclusion, there was a positive relationship between estrogen receptor alpha methylation in leukocytes and colonic tissue in subjects with and without colorectal tumors. However, unlike in colonic tissue, estrogen receptor alpha methylation in leukocytes was unable to distinguish between disease groups.