The FABP12/PPARγ pathway promotes metastatic transformation by inducing epithelial‐to‐mesenchymal transition and lipid‐derived energy production in prostate cancer cells

Early stage localized prostate cancer (PCa) has an excellent prognosis; however, patient survival drops dramatically when PCa metastasizes. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. Here, we examine the role of a new member of the fatty acid‐binding protein (FABP) family, FABP12, in PCa progression. FABP12 is preferentially amplified and/or overexpressed in metastatic compared to primary tumors from both PCa patients and xenograft animal models. We show that FABP12 concurrently triggers metastatic phenotypes (induced epithelial‐to‐mesenchymal transition (EMT) leading to increased cell motility and invasion) and lipid bioenergetics (increased fatty acid uptake and accumulation, increased ATP production from fatty acid β‐oxidation) in PCa cells, supporting increased reliance on fatty acids for energy production. Mechanistically, we show that FABP12 is a driver of PPARγ activation which, in turn, regulates FABP12''s role in lipid metabolism and PCa progression. Our results point to a novel role for a FABP‐PPAR pathway in promoting PCa metastasis through induction of EMT and lipid bioenergetics.

Abbreviations

AR

androgen receptor

ATP

adenosine triphosphate

CN

copy number

CPT1

carnitine palmitoyltransferase I

CS

citrate synthase

EMT

epithelial–mesenchymal transition

ET

electron transfer‐state

FABP

fatty acid‐binding protein

LD

lipid droplet

OA

oleic acid

PCa

prostate cancer

PPAR

peroxisome proliferator‐activated receptor

PPRE

peroxisome proliferator‐activated receptor response element

TZD

thiazolidinediones

     

Profiles of sleep changes during the COVID‐19 pandemic: Demographic,behavioural and psychological factors

This study aimed to evaluate changes in sleep during the COVID‐19 outbreak, and used data‐driven approaches to identify distinct profiles of changes in sleep‐related behaviours. Demographic, behavioural and psychological factors associated with sleep changes were also investigated. An online population survey assessing sleep and mental health was distributed between 3 April and 24 June 2020. Retrospective questions were used to estimate temporal changes from before to during the outbreak. In 5,525 Canadian respondents (67.1% females, 16–95 years old: Mean ± SD = 55.6 ± 16.3 years), wake‐up times were significantly delayed relative to pre‐outbreak estimates (p < .001,  = 0.04). Occurrences of clinically meaningful sleep difficulties significantly increased from 36.0% before the outbreak to 50.5% during the outbreak (all p < .001, g ≥ 0.27). Three subgroups with distinct profiles of changes in sleep behaviours were identified: “Reduced Time in Bed”, “Delayed Sleep” and “Extended Time in Bed”. The “Reduced Time in Bed” and “Delayed Sleep” subgroups had more adverse sleep outcomes and psychological changes during the outbreak. The emergence of new sleep difficulties was independently associated with female sex, chronic illnesses, being employed, family responsibilities, earlier wake‐up times, higher stress levels, as well as heavier alcohol use and television exposure. The heterogeneity of sleep changes in response to the pandemic highlights the need for tailored interventions to address sleep problems.     

Neurodevelopmental phenotype associated with CHD8-SUPT16H duplication

Microdeletions encompassing 14q11.2 locus, involving SUPT16H and CHD8, were shown to cause developmental delay, intellectual disability, autism spectrum disorders and macrocephaly. Variations leading to CHD8 haploinsufficiency or loss of function were also shown to lead to a similar phenotype. Recently, a 14q11.2 microduplication syndrome, encompassing CHD8 and SUPT16H, has been described, highlighting the importance of a tight control of at least CHD8 gene-dosage for a normal development. There have been only a few reports of 14q11.2 microduplications. Patients showed variable neurodevelopmental issues of variable severity. Breakpoints of the microduplications were non-recurrent, making interpretation of the CNV and determination of their clinical relevance difficult. Here, we report on two patients with 14q11.2 microduplication encompassing CHD8 and SUPT16H, one of whom had normal intelligence. Review of previous reports describing patients with comparable microduplications allowed for a more precise delineation of the condition and widening of the phenotypic spectrum.

     

Ultrasonic signs of pneumothorax: Preliminary work

Ultrasonography is considered to have limited application in respiratory diseases because air reflects sound waves. Twenty-four patients with radiologically confirmed pneumothorax and 100 healthy subjects underwent sonography. In all normal subjects, the hyperechoic pulmonary interface showed respiratory motions termed the “gliding sign” with some comet-tail artifacts. Sonographic signs were shown in all pneumothoraces: disappearance of the gliding sign and no comet tails. The extent of collapse cannot be evaluated, but it is possible to determine its area in partial pneumothorax (N = 5). The follow-up (N = 8) showed the reappearance of the gliding sign. Ultrasonography may be helpful in diagnosing pneumothorax in certain cases. © 1993 John Wiley & Sons, Inc.     

Inhibitory influence of the mesocortical dopaminergic neurons on their target cells: electrophysiological and pharmacological characterization

Both dopaminergic (DA) and noradrenergic (NA) systems exert an inhibitory influence on the activity of prefrontal cortical neurons (PFC). As NA-containing fibers run close to the dorsal ventral tegmental area (VTA), electrical stimulation of the VTA might coactivate both DA and NA systems. In the present study extracellular recordings and microiontophoresis were used in anesthetized rats to analyze first whether the inhibitory cortical responses to VTA stimulation and DA application were mediated by DA or adrenergic receptors. Inhibitory responses elicited by DA application or VTA stimulation were observed in PFC output neurons identified by antidromic activation from subcortical structures. Both types of inhibitory effects were reversed by the DA antagonist sulpiride, but not by the adrenergic antagonists prazosin (alpha-1), yohimbine (alpha-2) or propranolol (beta). NA and the beta agonist isoproterenol inhibited the activity of PFC cells and these effects were antagonized by propranolol, but neither by prazosin and yohimbine nor by the DA antagonist sulpiride. Thus, the inhibitory influence of the mesocortical DA system in the PFC involves DA, but not NA, recognition sites. The DA receptor subtype mediating the inhibitory effects of VTA stimulation and DA application in the PFC was analyzed further. VTA- and DA-evoked inhibitory responses were antagonized by the D2 selective antagonists (-)-sulpiride, LUR 2366 and RIV 2093, but not by the D1 selective antagonist SCH23390. In addition, the DA-induced inhibitory response was mimicked by the selective D2 agonist LY 171555 but not by the selective D1 agonist SKF 38393. Surprisingly, haloperidol, which is also a potent D2 antagonist, failed to consistently block DA- and VTA-induced inhibitory effects. The present results indicate that the inhibition of PFC cells by mesocortical DA neurons is mediated via a subtype of DA receptors which is particularly sensitive to benzamides.     

Development and validation of an algorithm for the study of sleep using a biometric shirt in young healthy adults

Portable polysomnography is often too complex and encumbering for recording sleep at home. We recorded sleep using a biometric shirt (electrocardiogram sensors, respiratory inductance plethysmography bands and an accelerometer) in 21 healthy young adults recorded in a sleep laboratory for two consecutive nights, together with standard polysomnography. Polysomnographic recordings were scored using standard methods. An algorithm was developed to classify the biometric shirt recordings into rapid eye movement sleep, non‐rapid eye movement sleep and wake. The algorithm was based on breathing rate and heart rate variability, body movement, and included a correction for sleep onset and offset. The overall mean percentage of agreement between the two sets of recordings was 77.4%; when non‐rapid eye movement and rapid eye movement sleep epochs were grouped together, it increased to 90.8%. The overall kappa coefficient was 0.53. Five of the seven sleep variables were significantly correlated. The findings of this pilot study indicate that this simple portable system could be used to estimate the general sleep pattern of young healthy adults.     

NREM sleep EEG slow waves in autistic and typically developing children: Morphological characteristics and scalp distribution

Autism is a developmental disorder with a neurobiological aetiology. Studies of the autistic brain identified atypical developmental trajectories that may lead to an impaired capacity to modulate electroencephalogram activity during sleep. We assessed the topography and characteristics of non‐rapid eye movement sleep electroencephalogram slow waves in 26 boys aged between 6 and 13 years old: 13 with an autism spectrum disorder and 13 typically developing. None of the participants was medicated, intellectually disabled, reported poor sleep, or suffered from medical co‐morbidities. Results are derived from a second consecutive night of polysomnography in a sleep laboratory. Slow waves (0.3–4.0 Hz; >75 µV) were automatically detected on artefact‐free sections of non‐rapid eye movement sleep along the anteroposterior axis in frontal, central, parietal and occipital derivations. Slow wave density (number per minute), amplitude (µV), slope (µV s^?1) and duration (s) were computed for the first four non‐rapid eye movement periods. Slow wave characteristics comparisons between groups, derivations and non‐rapid eye movement periods were assessed with three‐way mixed ANOVAs. Slow wave density, amplitude, slope and duration were higher in anterior compared with most posterior derivations in both groups. Children with autism spectrum disorder showed lower differences in slow waves between recording sites along the anteroposterior axis than typically developing children. These group differences in the topography of slow wave characteristics were stable across the night. We propose that slow waves during non‐rapid eye movement sleep could be an electrophysiological marker of the deviant cortical maturation in autism linked to an atypical functioning of thalamo‐cortical networks.     

Researching Children’s Adjustment in Stepfamilies: How is it Studied? What Do we Learn?

The probability that children whose parents have separated will become members of a stepfamily has increased considerably in the last decades. This situation has encouraged researchers to document the impact of this family transition on children’s adjustment. The present article examines empirical publications on this subject between 2000 and 2015. Screening and eligibility assessment based on inclusion and exclusion criteria yielded a final sample of 130 studies. The theoretical models used by the authors are described and discussed, with particular attention to how theories are relied upon in this field of research. Second, an examination of the methodology applied allowed us to take a critical look at the way children’s outcomes were examined. The studies’ main results were then analyzed so as to draw up a contemporary portrait of how stepfamily children adjust. Finally, an examination of the studies’ limitations and theoretical foundations points to avenues for future research.