Cerebral grey matter may not explain sleep slow-wave characteristics after severe brain injury.

Sleep slow waves are the hallmark of deeper non-rapid eye movement sleep. It is generally assumed that grey matter properties predict slow-wave density, morphology, and spectral power in healthy adults. Here, we tested the association between grey matter volume (GMV) and slow-wave characteristics in 27 moderate to severe traumatic brain injury patients (TBI; 32.0 ± 12.2 years old, eight women) compared to 32 healthy controls (29.2 ± 11.5 years old, nine women). Participants underwent overnight polysomnography and cerebral MRI with a 3-tesla scanner. A whole-brain voxel-wise analysis was performed to compare GMV between groups. Slow-wave density, morphology, and spectral power (0.4-6  Hz) were computed, and GMV was extracted from the thalamus, cingulate, insula, precuneus, and orbitofrontal cortex to test the relationship between slow waves and grey matter in regions implicated in the generation and/or propagation of slow waves. Compared to controls, TBI patients had significantly lower frontal and temporal GMV and exhibited a subtle decrease in slow-wave frequency. Moreover, higher GMV in the orbitofrontal cortex, insula, cingulate cortex, and precuneus was associated with higher slow-wave frequency and slope, only in healthy controls. Higher orbitofrontal GMV was also associated with higher slow-wave density in healthy participants. While we observed the expected associations between GMV and slow-wave characteristics in healthy controls, no such associations were observed in the TBI group despite lower GMV. This finding challenges the presumed role of GMV in slow-wave generation and morphology.Significance Statement Because sleep slow waves play a key role in cognition, synaptic plasticity, and restorative sleep, understanding how they relate to cerebral matter integrity is especially important in the context of brain atrophy following moderate to severe traumatic brain injury (TBI). We found that higher grey matter volume (GMV) in regions involved in slow-wave generation and propagation was associated with faster and steeper slow waves in healthy individuals. However, these associations were not observed in TBI participants, raising questions about the degree of contribution of GMV to slow-wave properties in patients with lower grey matter relative to controls. These findings challenge our current understanding of the link between grey matter integrity and slow waves, highlighting the complexity of this relationship.

Temporal cluster-based organization of sleep spindles underlies motor memory consolidation.

Sleep benefits motor memory consolidation, which is mediated by sleep spindle activity and associated memory reactivations during non-rapid eye movement (NREM) sleep. However, the particular role of NREM2 and NREM3 sleep spindles and the mechanisms triggering this memory consolidation process remain unclear. Here, simultaneous electroencephalographic and functional magnetic resonance imaging (EEG-fMRI) recordings were collected during night-time sleep following the learning of a motor sequence task. Adopting a time-based clustering approach, we provide evidence that spindles iteratively occur within clustered and temporally organized patterns during both NREM2 and NREM3 sleep. However, the clustering of spindles in trains is related to motor memory consolidation during NREM2 sleep only. Altogether, our findings suggest that spindles' clustering and rhythmic occurrence during NREM2 sleep may serve as an intrinsic rhythmic sleep mechanism for the timed reactivation and subsequent consolidation of motor memories, through synchronized oscillatory activity within a subcortical-cortical network involved during learning.

Targeted memory reactivation during post-learning sleep does not enhance motor memory consolidation in older adults.

Targeted memory reactivation (TMR) during sleep enhances memory consolidation in young adults by modulating electrophysiological markers of neuroplasticity. Interestingly, older adults exhibit deficits in motor memory consolidation, an impairment that has been linked to age-related degradations in the same sleep features sensitive to TMR. We hypothesised that TMR would enhance consolidation in older adults via the modulation of these markers. A total of 17 older participants were trained on a motor task involving two auditory-cued sequences. During a post-learning nap, two auditory cues were played: one associated to a learned (i.e., reactivated) sequence and one control. Performance during two delayed re-tests did not differ between reactivated and non-reactivated sequences. Moreover, both associated and control sounds modulated brain responses, yet there were no consistent differences between the auditory cue types. Our results collectively demonstrate that older adults do not benefit from specific reactivation of a motor memory trace by an associated auditory cue during post-learning sleep. Based on previous research, it is possible that auditory stimulation during post-learning sleep could have boosted motor memory consolidation in a non-specific manner.

Behavioural therapy for shift work disorder improves shift workers' sleep, sleepiness and mental health: A pilot randomised control trial.

The present study evaluates the efficacy of behavioural therapy adapted for shift work disorder with a randomised control design in a healthcare population. Forty-three night shift workers (m. age: 34 years; 77% women) experiencing shift work disorder were randomised to either the behavioural therapy for shift work disorder (BT-SWD) or a waiting-list control group offered after the waiting period. Participants completed questionnaires on insomnia, sleepiness and mental health pre- and post-treatment, pre- and post-waiting, and at follow-up, and a sleep diary. As night shift workers alternate between sleeping during the day after their night shifts and transitioning to nighttime sleep on days off, insomnia severity and sleep variables were analysed for daytime and nighttime sleep. The BT-SWD involved sleep restriction therapy, stimulus control and fixed sleep periods in the dark. Statistical analyses were performed under intent-to-treat and per-protocol approaches. Repeated-measures two-way ANCOVA analysis, controlling for age, sex and pre-treatment daytime total sleep time, was performed with Bonferroni corrections, and between-group effect sizes computed. Fourteen participants dropped out after randomisation. Under the intent-to-treat analysis, BT-SWD participants had a significant greater decrease in daytime insomnia severity and an increase in daytime total sleep time at post-treatment than the control group, with large between-group effect sizes (-1.25 and 0.89). These corresponding results were also significant with large effect sizes under the per-protocol analysis. Sleepiness, anxiety and depression levels improved at post-treatment and maintained at follow-up when the BT-SWD treated controls were added to the BT-SWD group. The behavioural therapy for shift work disorder can be used to improve the sleep and mental health of healthcare night workers.

Unrefreshing naps and sleep architecture during the multiple sleep latency test in idiopathic hypersomnia.

Patients with idiopathic hypersomnia frequently report having unrefreshing naps. However, whether they have abnormal sleep architecture during naps that may explain their unrefreshing aspect is unknown. We compared sleep architecture during short daytime naps in patients with idiopathic hypersomnia reporting unrefreshing and refreshing naps. One-hundred and thirty-four patients tested with one-night polysomnography, followed by an adapted version of the Multiple Sleep Latency Test with four naps, were included. They were asked about the refreshing aspect of their habitual naps during a clinical interview. They were classified as having objective (Multiple Sleep Latency Test ≤ 8 min) or subjective idiopathic hypersomnia (Multiple Sleep Latency Test > 8 min), and as presenting refreshing or unrefreshing naps. We tested Group differences (refreshing versus unrefreshing naps) on nap sleep architecture in the whole sample and for subjective and objective idiopathic hypersomnia subgroups separately using ANCOVAs. No Group effects were observed in the Multiple Sleep Latency Test architecture in the whole sample and in objective and subjective idiopathic hypersomnia subgroups. This study provides preliminary evidence that reporting unrefreshing naps is not associated with clinically significant findings in Multiple Sleep Latency Test sleep architecture in patients with idiopathic hypersomnia. Given that naps taken by patients with idiopathic hypersomnia are typically long, future studies should investigate longer daytime sleep episodes.

Technical challenges in REM sleep microstructure classification: A study of patients with REM sleep behaviour disorder.

While commonly treated as a uniform state in practice, rapid eye movement sleep contains two distinct microstructures-phasic (presence of rapid eye movement) and tonic (no rapid eye movement). This study aims to identify technical challenges during rapid eye movement sleep microstructure visual classification in patients with rapid eye movement sleep behaviour disorder, and to propose solutions to enhance reliability between scorers. Fifty-seven sleep recordings were randomly allocated into three subsequent batches (n = 10, 13 and 34) for scoring. To reduce single-centre bias, we recruited three raters/scorers, with each trained from a different institution. Two raters independently scored each 30-s rapid eye movement sleep into 10â€…× fSEM3-s phasic/tonic microstructures based on the AASM guidelines. The third rater acted as an "arbitrator" to resolve opposite opinions persisting during the revision between batches. Besides interrater differences in artefact rejection rate, interrater variance frequently occurred due to transitioning between microstructures and moderate-to-severe muscular/electrode artefact interference. To enhance interrater agreement, a rapid eye movement scoring schematic graph was developed, incorporating proxy electrode use, filters and cut-offs for microstructure transitioning. To assess potential effectiveness of the schematic graph proposed, raters were instructed to systematically apply it in scoring for the third batch. Of the 34 recordings, 27 reached a Cohen's kappa score above 0.8 (i.e. almost perfect agreement between raters), significantly improved from the prior batches (p = 0.0003, Kruskal-Wallis test). Our study illustrated potential solutions and guidance for challenges that may be encountered during rapid eye movement sleep microstructure classification.

Altered fornix integrity is associated with sleep apnea-related hypoxemia in mild cognitive impairment.

INTRODUCTION: The limbic system is critical for memory function and degenerates early in the Alzheimer's disease continuum. Whether obstructive sleep apnea (OSA) is associated with alterations in the limbic white matter tracts remains understudied. METHODS: Polysomnography, neurocognitive assessment, and brain magnetic resonance imaging (MRI) were performed in 126 individuals aged 55-86 years, including 70 cognitively unimpaired participants and 56 participants with mild cognitive impairment (MCI). OSA measures of interest were the apnea-hypopnea index and composite variables of sleep fragmentation and hypoxemia. Microstructural properties of the cingulum, fornix, and uncinate fasciculus were estimated using free water-corrected diffusion tensor imaging. RESULTS: Higher levels of OSA-related hypoxemia were associated with higher left fornix diffusivities only in participants with MCI. Microstructure of the other white matter tracts was not associated with OSA measures. Higher left fornix diffusivities correlated with poorer episodic verbal memory. DISCUSSION: OSA may contribute to fornix damage and memory dysfunction in MCI. HIGHLIGHTS: Sleep apnea-related hypoxemia was associated with altered fornix integrity in MCI. Altered fornix integrity correlated with poorer memory function. Sleep apnea may contribute to fornix damage and memory dysfunction in MCI.

Third-line treatment patterns in HER2-positive metastatic breast cancer: a retrospective analysis of real-world data in Canada.

There is an increasing demand for real-world data pertaining to the usage of cancer treatments, especially in settings where no standard treatment is specifically recommended. This study presents the first real-world analysis of third-line treatment patterns in HER2-positive metastatic breast cancer (mBC) patients in Canada. The purpose was to assess evolution of clinical practice and identify unmet needs in post-second-line therapy. Retrospective data from medical records of 66 patients who received third-line treatment before 31st October 2018, and data from 56 patients who received third-line treatment after this date, extracted from the Personalize My Treatment (PMT) cancer patient registry, were analyzed. In the first cohort, the study revealed heterogeneity in the third-line setting, with trastuzumab, lapatinib, and T-DM1 being the main treatment options. Even though data were collected before the wide availability of tucatinib, neratinib and trastuzumab deruxtecan in Canada, the PMT cohort revealed the emergence of new therapeutic combinations and a shift from lapatinib usage to T-DM1 choice was observed. These findings underscore the evolving nature of third-line treatment strategies in Canada, a facet that is intrinsically tied to the availability of new drugs. The absence of a consensus on post-second-line treatment highlights the pressing need for more efficient therapeutic alternatives beyond the currently available options. This study not only offers valuable insights into the present landscape of third-line treatment in Canada but validates the significance and effectiveness of the PMT registry as a tool for generating pan-Canadian real-world evidence in oncology and its capacity to provide information on evolution of therapeutic practices.

The Effects of Total Sleep Deprivation on Attention Capture Processes in Young and Older Adults: An ERP Study.

BACKGROUND: The present study investigated whether sleep deprivation affects attention capture in young and older adults using event-related potentials (ERPs). METHODS: Eleven young adults (20-30 y) and nine older adults (60-70 y) were tested following both normal sleep (NS) and total sleep deprivation (TSD). ERPs were recorded during an auditory discrimination task consisting of standard and deviant stimuli. RESULTS: Deviant stimuli elicited the MMN, P3a, and RON ERPs. TSD attenuated the differences in reaction times between standards and deviants in young adults but not older adults. The P3a was attenuated in older adults compared to young adults. Older adults had a larger RON amplitude compared to young adults following NS, but not TSD. CONCLUSIONS: The reduced P3a and the absence of behavioral performance alteration in the older group suggests that older adults may utilize different neural processing strategies compared to younger adults to compensate for age-related declines in neural resources for attention capture. Sleep loss influenced age-related differences on the RON, suggesting that older adults may have reduced access to compensatory strategies following sleep loss.

A Prodromal Brain-Clinical Pattern of Cognition in Synucleinopathies.

OBJECTIVE: Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor-first phenotype. Here, we aimed at identifying a brain-clinical signature that predicts dementia in iRBD. METHODS: A brain-clinical signature was identified in 48 patients with polysomnography-confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD. RESULTS: One latent variable explained 31% of the brain-clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p = 0.036, odds ratio [OR] = 2.249; 95% confidence interval [CI] = 1.053-4.803), specifically to DLB (OR = 4.754; 95% CI = 1.283-17.618, p = 0.020) and not PD (p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD. INTERPRETATION: We identified a brain-clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021;89:341-357.

Variability of sleep stage scoring in late midlife and early old age.

Sleep stage scoring can lead to important inter-expert variability. Although likely, whether this issue is amplified in older populations, which show alterations of sleep electrophysiology, has not been thoroughly assessed. Algorithms for automatic sleep stage scoring may appear ideal to eliminate inter-expert variability. Yet, variability between human experts and algorithm sleep stage scoring in healthy older individuals has not been investigated. Here, we aimed to compare stage scoring of older individuals and hypothesized that variability, whether between experts or considering the algorithm, would be higher than usually reported in the literature. Twenty cognitively normal and healthy late midlife individuals' (61 ± 5 years; 10 women) night-time sleep recordings were scored by two experts from different research centres and one algorithm. We computed agreements for the entire night (percentage and Cohen's κ) and each sleep stage. Whole-night pairwise agreements were relatively low and ranged from 67% to 78% (κ, 0.54-0.67). Sensitivity across pairs of scorers proved lowest for stages N1 (8.2%-63.4%) and N3 (44.8%-99.3%). Significant differences between experts and/or algorithm were found for total sleep time, sleep efficiency, time spent in N1/N2/N3 and wake after sleep onset (p ≤ 0.005), but not for sleep onset latency, rapid eye movement (REM) and slow-wave sleep (SWS) duration (N2 + N3). Our results confirm high inter-expert variability in healthy aging. Consensus appears good for REM and SWS, considered as a whole. It seems more difficult for N3, potentially because human raters adapt their interpretation according to overall changes in sleep characteristics. Although the algorithm does not substantially reduce variability, it would favour time-efficient standardization.

Exercising the Sleepy-ing Brain: Exercise, Sleep, and Sleep Loss on Memory.

We examine the novel hypothesis that physical exercise and sleep have synergistic effects on memory. Exercise can trigger mechanisms that can create an optimal brain state during sleep to facilitate memory processing. The possibility that exercise could counteract the deleterious effects of sleep deprivation on memory by protecting neuroplasticity also is discussed.

Prospective relations between sleep in preschool years and academic achievement at school entry.

It is often assumed that adequate sleep is a key ingredient of children's school success. Research to date, however, suggests modest associations between child sleep and academic achievement. Adopting a developmental perspective, this report investigates the associations between age-related changes in sleep across the preschool period and academic achievement at school entry. Sleep was assessed by actigraphy at ages 2, 3 and 4 among 128 children from mostly White middle-class families, and their performance in reading and mathematics was tested in Grade 1. The results revealed that children whose sleep duration decreased more rapidly across the preschool period showed better performance in both reading and mathematics. These results suggest that age-related developments may be a key characteristic of sleep in the preschool years.

Pandémie COVID-19, sommeil et séquelles psychologiques: au nom du Réseau canadien du sommeil et des rythmes circadiens* et de la Société canadienne du sommeil*.

Les données recueillies lors de crises et tragédies passées prouvent que les problèmes de sommeil survenant durant ou peu de temps après un événement traumatique sont reliés à une probabilité accrue de développer des symptômes psychiatriques durables. Or la pandémie COVID-19 et ses conséquences à moyen et long-terme combinent plusieurs facteurs de risque pour le sommeil, tant pour les intervenants de la santé que la population générale. Notre relevé mensuel des publications scientifiques qui combinent COVID-19 et sommeil/insomnie entre janvier et juillet 2020 révèle un taux de croissance comparable pour les articles qui portent plus précisément sur la santé mentale mais aucune ne porte sur les résultats d'une intervention. Nous proposons qu'il faille agir rapidement sur les difficultés de sommeil en cette période de pandémie afin de protéger l'équilibre psychologique individuel à moyen et long terme, d'autant plus que les outils nécessaires à la prévention de l'insomnie, sa détection et son traitement sont à la portée de tous les professionnels de la santé mentale.

G-quadruplex located in the 5'UTR of the BAG-1 mRNA affects both its cap-dependent and cap-independent translation through global secondary structure maintenance.

The anti-apoptotic BAG-1 protein isoforms are known to be overexpressed in colorectal tumors and are considered to be potential therapeutic targets. The isoforms are derived from alternative translation initiations occuring at four in-frame start codons of a single mRNA transcript. Its 5'UTR also contains an internal ribosome entry site (IRES) regulating the cap-independent translation of the transcript. An RNA G-quadruplex (rG4) is located at the 5'end of the BAG-1 5'UTR, upstream of the known cis-regulatory elements. Herein, we observed that the expression of BAG-1 isoforms is post-transcriptionally regulated in colorectal cancer cells and tumors, and that stabilisation of the rG4 by small molecules ligands reduces the expression of endogenous BAG-1 isoforms. We demonstrated a critical role for the rG4 in the control of both cap-dependent and independent translation of the BAG-1 mRNA in colorectal cancer cells. Additionally, we found an upstream ORF that also represses BAG-1 mRNA translation. The structural probing of the complete 5'UTR showed that the rG4 acts as a steric block which controls the initiation of translation at each start codon of the transcript and also maintains the global 5'UTR secondary structure required for IRES-dependent translation.

P1 promoter-driven HNF4α isoforms are specifically repressed by ß-catenin signaling in colorectal cancer cells.

HNF4α is a key nuclear receptor for regulating gene expression in the gut. Although both P1 and P2 isoform classes of HNF4α are expressed in colonic epithelium, specific inhibition of P1 isoforms is commonly found in colorectal cancer. Previous studies have suggested that P1 and P2 isoforms might regulate different cellular functions. Despite these advances, it remains unclear whether these isoform classes are functionally divergent in the context of human biology. Here, the consequences of specific inhibition of P1 or P2 isoform expression was measured in a human colorectal cancer cell transcriptome. Results indicate that P1 isoforms were specifically associated with the control of cell metabolism, whereas P2 isoforms globally supported aberrant oncogenic signalization, promoting cancer cell survival and progression. P1 promoter-driven isoform expression was found to be repressed by ß-catenin, one of the earliest oncogenic pathways to be activated during colon tumorigenesis. These findings identify a novel cascade by which the expression of P1 isoforms is rapidly shut down in the early stages of colon tumorigenesis, allowing a change in HNF4α-dependent transcriptome, thereby promoting colorectal cancer progression.This article has an associated First Person interview with the first author of the paper.

Cerebral white matter diffusion properties and free-water with obstructive sleep apnea severity in older adults.

Characterizing the effects of obstructive sleep apnea (OSA) on the aging brain could be key in our understanding of neurodegeneration in this population. Our objective was to assess white matter properties in newly diagnosed and untreated adults with mild to severe OSA. Sixty-five adults aged 55 to 85 were recruited and divided into three groups: control (apnea-hypopnea index ≤5/hr; n = 18; 65.2 ± 7.2 years old), mild (>5 to ≤15 hr; n = 27; 64.2 ± 5.3 years old) and moderate to severe OSA (>15/hr; n = 20; 65.2 ± 5.5 years old). Diffusion tensor imaging metrics (fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity, and mean diffusivity) were compared between groups with Tract-Based Spatial Statistics within the white matter skeleton created by the technique. Groups were also compared for white matter hyperintensities volume and the free-water (FW) fraction. Compared with controls, mild OSA participants showed widespread areas of lower diffusivity (p < .05 corrected) and lower FW fraction (p < .05). Participants with moderate to severe OSA showed lower AD in the corpus callosum compared with controls (p < .05 corrected). No between-group differences were observed for FA or white matter hyperintensities. Lower white matter diffusivity metrics is especially marked in mild OSA, suggesting that even the milder form may lead to detrimental outcomes. In moderate to severe OSA, competing pathological responses might have led to partial normalization of diffusion metrics.

Brain white matter damage and its association with neuronal synchrony during sleep.

The restorative function of sleep partly relies on its ability to deeply synchronize cerebral networks to create large slow oscillations observable with EEG. However, whether a brain can properly synchronize and produce a restorative sleep when it undergoes massive and widespread white matter damage is unknown. Here, we answer this question by testing 23 patients with various levels of white matter damage secondary to moderate to severe traumatic brain injuries (ages 18-56; 17 males, six females, 11-39 months post-injury) and compared them to 27 healthy subjects of similar age and sex. We used MRI and diffusion tensor imaging metrics (e.g. fractional anisotropy as well as mean, axial and radial diffusivities) to characterize voxel-wise white matter damage. We measured the following slow wave characteristics for all slow waves detected in N2 and N3 sleep stages: peak-to-peak amplitude, negative-to-positive slope, negative and positive phase durations, oscillation frequency, and slow wave density. Correlation analyses were performed in traumatic brain injury and control participants separately, with age as a covariate. Contrary to our hypotheses, we found that greater white matter damage mainly over the frontal and temporal brain regions was strongly correlated with a pattern of higher neuronal synchrony characterized by slow waves of larger amplitudes and steeper negative-to-positive slopes during non-rapid eye movement sleep. The same pattern of associations with white matter damage was also observed with markers of high homeostatic sleep pressure. More specifically, higher white matter damage was associated with higher slow-wave activity power, as well as with more severe complaints of cognitive fatigue. These associations between white matter damage and sleep were found only in our traumatic brain injured participants, with no such correlation in controls. Our results suggest that, contrary to previous observations in healthy controls, white matter damage does not prevent the expected high cerebral synchrony during sleep. Moreover, our observations challenge the current line of hypotheses that white matter microstructure deterioration reduces cerebral synchrony during sleep. Our results showed that the relationship between white matter and the brain's ability to synchronize during sleep is neither linear nor simple.

Attempted induction of signalled lucid dreaming by transcranial alternating current stimulation.

Neurophysiological correlates of self-awareness during sleep ('lucid dreaming') remain unclear despite their importance for clarifying the neural underpinnings of consciousness. Transcranial direct (tDC) and alternating (tAC) current stimulation during sleep have been shown to increase dream self-awareness, but these studies' methodological weaknesses prompted us to undertake additional study. tAC stimulation was associated with signal-verified and self-rated lucid dreams-but so was the sham procedure. Situational factors may be crucial to inducing self-awareness during sleep.

Dual-specificity phosphatase 6 deletion protects the colonic epithelium against inflammation and promotes both proliferation and tumorigenesis.

The Ras/mitogen-activated protein kinase (MAPK) pathway controls fundamental cellular processes such as proliferation, differentiation, and apoptosis. The dual-specificity phosphatase 6 (DUSP6) regulates cytoplasmic MAPK signaling by dephosphorylating and inactivating extracellular signal-regulated kinase (ERK1/2) MAPK. To determine the role of DUSP6 in the maintenance of intestinal homeostasis, we characterized the intestinal epithelial phenotype of Dusp6 knockout (KO) mice under normal, oncogenic, and proinflammatory conditions. Our results show that loss of Dusp6 increased crypt depth and epithelial cell proliferation without altering colonic architecture. Crypt regeneration capacity was also enhanced, as revealed by ex vivo Dusp6 KO organoid cultures. Additionally, loss of Dusp6 induced goblet cell expansion without affecting enteroendocrine and absorptive cell differentiation. Our data also demonstrate that Dusp6 KO mice were protected from acute dextran sulfate sodium-induced colitis, as opposed to wild-type mice. In addition, Dusp6 gene deletion markedly enhanced tumor load in Apc Min/+ mice. Decreased DUSP6 expression by RNA interference in HT29 colorectal cancer cells enhanced ERK1/2 activation levels and promoted both anchorage-independent growth in soft agar as well as invasion through Matrigel. Finally, DUSP6 mRNA expression in human colorectal tumors was decreased in advanced stage tumors compared with paired normal tissues. These results demonstrate that DUSP6 phosphatase, by controlling ERK1/2 activation, regulates colonic inflammatory responses, and protects the intestinal epithelium against oncogenic stress.