ARID1A‐deficient cells require HDAC6 for progression of endometrial carcinoma

AT‐rich interactive domain‐containing protein 1A (ARID1A) loss‐of‐function mutation accompanied by a loss of ARID1A protein expression is frequently observed in endometrial carcinomas. However, the molecular mechanisms linking these genetic changes to the altered pathways regulating tumour initiation, maintenance and/or progression remain poorly understood. Thus, the main aim of this study was to analyse the role of ARID1A loss of function in endometrial tumorigenesis. Here, using different endometrial in vitro and in vivo models, such as tumoral cell lines, 3D primary cultures and metastatic or genetically modified mouse models, we show that altered expression of ARID1A is not enough to initiate endometrial tumorigenesis. However, in an established endometrial cancer context, ARID1A loss of function accelerates tumoral progression and metastasis through the disruption of the G2/M cell cycle checkpoint and ATM/ATR‐mediated DNA damage checkpoints, increases epithelial cell proliferation rates and induces epithelial mesenchymal transition through the activation of histone deacetylase 6 (HDAC6). Next, we demonstrated that the inhibition of HDAC6 function, using the HDAC6‐specific inhibitor ACY1215 or by transfection with HDAC6 short hairpin RNA (shRNA), can reverse the migratory and invasive phenotype of ARID1A‐knockdown cells. Further, we also show that inhibition of HDAC6 activity causes an apoptotic vulnerability to etoposide treatments in ARID1A‐deficient cells. In summary, the findings exposed in this work indicate that the inhibition of HDAC6 activity is a potential therapeutic strategy for patients suffering from ARID1A‐mutant endometrial cancer diagnosed in advanced stages.     

CYP3A5*3 and CYP3A4*1B allele distribution and genotype combinations: differences between Spaniards and Central Americans

The aim of this study was to detect genotypic differences between three populations of healthy volunteers from Northern Spain (204 subjects), Nicaragua (120 subjects), and El Salvador (112 subjects) regarding CYP3A4*1B and CYP3A5*3 polymorphisms. No significant differences were found by comparing allelic frequencies between the two Central American populations. The CYP3A5*3 allele frequency was significantly different (P < 0.01) between Central Americans (76%) and Spaniards (91%). By contrast, CYP3A4*1B allele was more prevalent among Central Americans (12.5%) than among North Spaniards (4%) (P < 0.01). Analysis of CYP3A4-3A5 genotype combinations revealed that individuals carrying CYP3A4*1B/CYP3A5*1 were more represented in Central Americans (16.9%) than in Spaniards (5.4%), suggesting a marked linkage disequilibrium. These data are compatible with a higher CYP3A enzyme activity in Central Americans as opposed to Spaniards and other white groups, which could imply differences in dose requirements for drugs metabolized by CYP3A and should be considered in allele-disease association studies.     

Predictors of substance abuse treatment participation among homeless adults

The current study focuses on the relationships among a trauma history, a substance use history, chronic homelessness, and the mediating role of recent emotional distress in predicting drug treatment participation among adult homeless people. We explored the predictors of participation in substance abuse treatment because enrolling and retaining clients in substance abuse treatment programs is always a challenge particularly among homeless people. Participants were 853 homeless adults from Los Angeles, California. Using structural equation models, findings indicated that trauma history, substance use history and chronicity of homelessness were associated, and were significant predictors of greater recent emotional distress. The most notable result was that recent emotional distress predicted less participation in current substance abuse treatment (both formal and self-help) whereas a substance use history alone predicted significantly more participation in treatment. Implications concerning treatment engagement and difficulties in obtaining appropriate dual-diagnosis services for homeless mentally distressed individuals are discussed.     

Glutamate-like immunoreactivity in ascending spinofugal afferents to the rat periaqueductal grey

The midbrain periaqueductal gray is a key structure for the mediation of an integrated defence behaviour. Although a prominent role for glutamate in PAG mechanisms is supported by both behavioural and morphological studies, whether PAG afferents conveying somatosensory information constitute a source of glutamatergic input to the PAG remains unknown. Here, we have compared the projection pattern of orthogradely-labelled spinoannular fibres with the distribution of glutamate-like immunoreactivity in the PAG at the light microscopic level. Transaxonal labelling was observed throughout the whole rostrocaudal axis of the PAG except for the dorsolateral regions. Cell-processes and terminal-reminiscent puncta were strongly immunoreactive in all PAG regions, including the dorsolateral areas. To ascertain whether glutamate-immunoreactive puncta observed at light microscopy indeed constituted axon terminals of the spinoannular system, glutamate-like immunoreactivity was assessed in orthogradely-labelled synaptic terminals using a post-embedding immunogold procedure for electron microscopy. Quantitative analysis of gold particle densities revealed over twice as strong an immunoreactivity in anatomically-identified spinoannular axon terminals as in dendrites postsynaptic to them, perikarya and inhibitory Gray II synapses, as well as an over 5-fold heavier immunolabelling than in glial profiles. These findings reveal that glutamate is accumulated in synaptic terminals of the spinoannular system, supporting a neurotransmitter role for this acidic amino acid in spinofugal afferents to the PAG.