Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of α5 subunit-containing γ-aminobutyric acid type A receptors: implications for treating cognitive deficits.

BACKGROUND: Multiple cognitive and psychiatric disorders are associated with an increased tonic inhibitory conductance that is generated by α5 subunit-containing γ-aminobutyric acid type A (α5 GABAA) receptors. Negative allosteric modulators that inhibit α5 GABAA receptors (α5-NAMs) are being developed as treatments for these disorders. The effects of α5-NAMs have been studied on recombinant GABAA receptors expressed in non-neuronal cells; however, no study has compared drug effects on the tonic conductance generated by native GABAA receptors in neurones, which was the goal of this study. METHODS: The effects of five α5-NAMs (basmisanil, Ono-160, L-655,708, α5IA, and MRK-016) on tonic current evoked by a low concentration of GABA were studied using whole-cell recordings in cultured mouse hippocampal neurones. Drug effects on current evoked by a saturating concentration of GABA and on miniature inhibitory postsynaptic currents (mIPSCs) were also examined. RESULTS: The α5-NAMs caused a concentration-dependent decrease in tonic current. The potencies varied as the inhibitory concentration for 50% inhibition (IC50) of basmisanil (127 nM) was significantly higher than those of the other compounds (0.4-0.8 nM). In contrast, the maximal efficacies of the drugs were similar (35.5-51.3% inhibition). The α5-NAMs did not modify current evoked by a saturating GABA concentration or mIPSCs. CONCLUSIONS: Basmisanil was markedly less potent than the other α5-NAMs, an unexpected result based on studies of recombinant α5 GABAA receptors. Studying the effects of α5 GABAA receptor-selective drugs on the tonic inhibitory current in neurones could inform the selection of compounds for future clinical trials.

Survival of Filipino women with breast cancer in the United States.

BACKGROUND: The survival of women with early-stage breast cancer varies by racial group. Filipino women with breast cancer are an understudied group and are often combined with other Asian groups. We compared clinical presentations and survival rates for Filipino and White women with breast cancer diagnosed in the United States. METHODS: We conducted a retrospective cohort study of women with breast cancer diagnosed between 2004 and 2015 in the SEER18 registries database. We compared crude survival between Filipino and White women. We then calculated adjusted hazard ratios (HR) in a propensity-matched design using the Cox proportional hazards model. RESULTS: There were 10,834 Filipino (2.5%) and 414,618 White women (97.5%) with Stage I-IV breast cancer in the SEER database. The mean age at diagnosis was 57.5 years for Filipino women and 60.8 years for White women (p < 0.0001). Filipino women had more high-grade and larger tumors than White women and were more likely to have node-positive disease. Among women with Stage I-IIIC breast cancer, the crude 10-year breast cancer-specific survival rate was 91.0% for Filipino and 88.9% for White women (HR 0.81, 95% CI 0.74-0.88, p < 0.01). In a propensity-matched analysis, the HR was 0.73 (95% CI 0.66-0.81). The survival advantage for Filipino women was present in subgroups defined by age of diagnosis, nodal status, estrogen receptor status, and HER2 receptor status. CONCLUSION: In the United States, Filipino women often present with more advanced breast cancers than White women, but experience better breast cancer-specific survival.