Aberrant MYCN expression drives oncogenic hijacking of EZH2 as a transcriptional activator in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of hematological cancers arising from the malignant transformation of mature T cells. In a cohort of 28 PTCL cases, we identified recurrent overexpression of MYCN, a member of the MYC family of oncogenic transcription factors. Approximately half of all PTCL cases was characterized by a MYC expression signature. Inducible expression of MYCN in lymphoid cells in a mouse model caused T-cell lymphoma that recapitulated human PTCL with an MYC expression signature. Integration of mouse and human expression data identified EZH2 as a key downstream target of MYCN. Remarkably, EZH2 was found to be an essential cofactor for the transcriptional activation of the MYCN-driven gene expression program, which was independent of methyltransferase activity but dependent on phosphorylation by CDK1. MYCN-driven T-cell lymphoma was sensitive to EZH2 degradation or CDK1 inhibition, which displayed synergy with US Food and Drug Administration-approved histone deacetylase (HDAC) inhibitors.

Executive and attentional functioning interventions in preterm children: a systematic review.

OBJECTIVE: This systematic review, performed in accordance with the PRISMA guidelines, seeks to summarize the interventions that have been developed in order to improve executive functioning and attention in children born prematurely. METHODS: The PICOS framework helped guide the structure and relevant terms selected for the study. Electronic systematic searches of the databases PubMed (NLM), Ovid Medline, Ovid All EBM Reviews, Ovid Embase, and Ovid PsycINFO were completed in March 2022. This review focuses on interventions that target attention and executive functioning in prematurely born children between birth and 12 years old, with outcome measures assessed between 3 and 12 years old, even if the age range in the study can exceed our own parameters. Data extraction included sample characteristics, country of recruitment, type of intervention, description of the intervention group and control group, outcome measures, and overall results. An assessment of the quality of methodology of studies was performed through an adaptation of the Downs and Black checklist for both randomized and nonrandomized studies in healthcare interventions. An assessment of the risk of bias was also presented using the Cochrane risk of bias tool for randomized trials 2.0. RESULTS: A total of 517 premature children received an intervention at some point between birth and early adolescence. Eleven different interventions were assessed in 17 studies, with rating of the quality of methodology and outcomes ranging from lower quality studies (44% quality rating) to robust studies (96% quality rating) in terms of reporting standards, external and internal validity, and power. Five of those studies focused on interventions administered in the neonatal intensive care unit or shortly postdischarge (e.g., the Mother-Infant Transaction Program and the Newborn Individualized Developmental Care and Assessment Program, documented in two articles each [11%] or the Infant Behavioral Assessment and Intervention Program assessed in one study [about 5%]), while 12 articles reported on interventions administered between the ages of 1.5-12 years old [mostly computerized cognitive training programs such as Cogmed (23%) and BrainGame Brian (17%)]. Of the 17 articles examined, 12 (70%) showed positive short-term outcomes postintervention and 3 (17%) demonstrated positive long-term results with small to large effect sizes (0.23-2.3). Among included studies, 50% showed an overall high risk of bias, 21.4% showed some concerns, and 28.6% were low risk of bias. CONCLUSIONS: Due to the heterogeneity of the programs reviewed, the presented findings should be interpreted as descriptive results. A careful and individualized selection from the various available interventions should be made based on the target population (i.e., age at intervention administration and outcome testing) before implementing these program protocols in clinical settings.

TAL1 cooperates with PI3K/AKT pathway activation in T-cell acute lymphoblastic leukemia.

TAL1 is ectopically expressed in about 30% of T-cell acute lymphoblastic leukemia (T-ALL) due to chromosomal rearrangements leading to the STIL-TAL1 fusion genes or due to non-coding mutations leading to a de novo enhancer driving TAL1 expression. Analysis of sequence data from T-ALL cases demonstrates a significant association between TAL1 expression and activating mutations of the PI3K-AKT pathway. We investigated the oncogenic function of TAL1 and the possible cooperation with PI3K-AKT pathway activation using isogenic pro-T-cell cultures ex vivo and in vivo leukemia models. We found that TAL1 on its own suppressed T-cell growth, in part by affecting apoptosis genes, while the combination with AKT pathway activation reduced apoptosis and was strongly driving cell proliferation ex vivo and leukemia development in vivo. As a consequence, we found that TAL1+AKTE17K transformed cells are more sensitive to PI3K-AKT pathway inhibition compared to AKTE17K transformed cells, related to the negative effect of TAL1 in the absence of activated PI3K-AKT signaling. We also found that both TAL1 and PI3K-AKT signaling increased the DNA-repair signature in T cells resulting in synergy between PARP and PI3K-AKT pathway inhibition. In conclusion, we have developed a novel mouse model for TAL1+AKTE17K driven T-ALL development and have identified a vulnerability of these leukemia cells to PI3K-AKT and PARP inhibitors.

Language brain responses and neurodevelopmental outcome in preschoolers with congenital heart disease: A fNIRS study.

Neurodevelopmental disabilities affect up to 50% of survivors of congenital heart disease (CHD). Language difficulties are frequently identified during preschool period and can lead to academic, social, behavioral, and emotional difficulties. Structural brain alterations are associated with poorer neurodevelopmental outcomes in patients with CHD during infancy, childhood, and adolescence. However, evidence is lacking about the functional brain activity in children with CHD and its relationship with neurodevelopment. This study therefore aimed to characterize brain responses during a passive story-listening task in 3-year-old children with CHD, and to investigate the relationship between functional brain patterns of language processing and neurodevelopmental outcomes. To do so, we assessed hemodynamic concentration changes, using functional near-infrared spectroscopy (fNIRS), and neurodevelopmental outcomes, using the Wechsler Preschool and Primary Scale of Intelligence - 4th Edition (WPPSI-IV), in children with CHD (n = 19) and healthy controls (n = 23). Compared to their healthy peers, children with CHD had significantly lower scores on the Verbal comprehension index (VCI), the Vocabulary acquisition index (VAI), the General ability index (GAI), and the Information and the Picture Naming subtests of the WPPSI-IV. During the passive story-listening task, healthy controls showed significant hemodynamic brain responses in the temporal and the temporal posterior regions, with stronger activation in the temporal posterior than in the temporal regions. In contrast, children with CHD showed reduced activation in the temporal posterior regions compared to controls, with no difference of activation between regions. Reduced brain responses in the temporal posterior regions were also correlated with lower neurodevelopmental outcomes in both groups. This is the first study that reveals reduced brain functional responses in preschoolers with CHD during a receptive language task. It also suggests that the temporal posterior activation could be a potential brain marker of cognitive development. These findings provide support for the feasibility of identifying brain correlates of neurodevelopmental vulnerabilities in children with CHD.

Pan-Canadian survey on the impact of the COVID-19 pandemic on cervical cancer screening and management: cross-sectional survey of healthcare professionals.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused disruptions to cancer care by delaying diagnoses and treatment, presenting challenges and uncertainties for both patients and physicians. We conducted a nationwide online survey to investigate the effects of the pandemic and capture modifications, prompted by pandemic-related control measures, on cervical cancer screening-related activities from mid-March to mid-August 2020, across Canada. Methods: The survey consisted of 61 questions related to the continuum of care in cervical cancer screening and treatment: appointment scheduling, tests, colposcopy, follow-up, treatment of pre-cancerous lesions/cancer, and telemedicine. We piloted the survey with 21 Canadian experts in cervical cancer prevention and care. We partnered with the Society of Canadian Colposcopists, Society of Gynecologic Oncology of Canada, Canadian Association of Pathologists, and Society of Obstetricians and Gynecologists of Canada, which distributed the survey to their members via email. We reached out to family physicians and nurse practitioners via MDBriefCase. The survey was also posted on McGill Channels (Department of Family Medicine News and Events) and social media platforms. The data were analyzed descriptively. Results: Unique responses were collected from 510 participants (November 16, 2020, to February 28, 2021), representing 418 fully and 92 partially completed surveys. Responses were from Ontario (41.0%), British Columbia (21.0%), and Alberta (12.8%), and mostly comprised family physicians/general practitioners (43.7%), and gynecologist/obstetrician professionals (21.6%). Cancelled screening appointments were mainly reported by family physicians/general practitioners (28.3%), followed by gynecologist/obstetrician professionals (19.8%), and primarily occurred in private clinics (30.5%). Decreases in the number of screening Pap tests and colposcopy procedures were consistently observed across Canadian provinces. About 90% reported that their practice/institution adopted telemedicine to communicate with patients. Conclusions: The area most severely impacted by the pandemic was appointment scheduling, with an important level of cancellations reported. Survey results may inform resumptions of various fronts in cervical cancer screening and management. Funding: The present work was supported by the Canadian Institutes of Health Research (operating grant COVID-19 May 2020 Rapid Research Funding Opportunity VR5-172666 Rapid Research competition and foundation grant 143347 to Eduardo L Franco). Eliya Farah and Rami Ali each received an MSc stipend from the Department of Oncology, McGill University.

Cervical cancer is a common cancer among women caused by infections with certain types of human papillomavirus (HPV). Nearly four in five people are infected with HPV during their lifetime, making it the most common sexually transmitted infection worldwide. Vaccination against the virus can prevent infections and routine screening for precancerous lesions can enable early diagnosis and treatment, improving outcomes. However, the COVID-19 pandemic has disrupted routine cervical cancer screening programs in several countries. This has caused delays in screening, which could result in more women being diagnosed with advanced-stage cancers. El-Zein et al. showed that despite the interrupted screening programmes, about half of practices in Canada were able to catch up on delayed screening by February 2021. Between November 2020 and February 2021, El-Zein et al. surveyed 510 Canadian healthcare professionals involved in cervical cancer screening and treatment. About 64%-75% of the respondents reported canceled or postponed screening appointments. Most appointment delays were less than four months. Fewer than one in ten delays were longer than six months. Most survey respondents said their practices pivoted to using telemedicine for some patient visits, such as cervical cancer screening follow-ups. About 40% of respondents suggested that the pandemic provided support to alternative screening options, such as HPV self-sampling at home. The survey results may help healthcare professionals and policymakers to develop plans that mitigate disruptions to cervical cancer screening during future emergencies.

Relationship between 4-month functional brain network topology and 24-month neurodevelopmental outcome in children with congenital heart disease.

Survivors of complex forms of congenital heart disease (CHD)∗ are at high risk of neurodevelopmental disabilities. Neuroimaging studies have pointed to brain anomalies and immature networks in infants with CHD, yet less is known about their functional network topology and associations with neurodevelopment. To characterize the functional network topology in 4-month-old infants with repaired CHD, we compared graph theory metrics measured using resting-state functional near-infrared spectroscopy (rs-fNIRS) between infants with CHD (n = 22) and healthy controls (n = 30). We also investigated the moderating effect of graph theory metrics on the relationship between group (CHD vs. Controls) and developmental outcomes at 24 months. At 4 months, both groups presented similar functional brain network topology. At 24 months, children with CHD had lower scores on the language scale and the expressive communication subscale of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), as well as lower scores on the Grammatical Form scale of the MacArthur-Bates Communicative Development Inventory (MBCDI). The relationship between group and expressive language was moderated by the normalized characteristic path length (λ) and the degree (k). Although infants with CHD have functional brain topology similar to that of healthy controls, our findings suggest that they do not benefit from an optimal functional brain organization in comparison with healthy infants.

Brain language networks and cognitive outcomes in children with frontotemporal lobe epilepsy.

Introduction: Pediatric frontal and temporal lobe epilepsies (FLE, TLE) have been associated with language impairments and structural and functional brain alterations. However, there is no clear consensus regarding the specific patterns of cerebral reorganization of language networks in these patients. The current study aims at characterizing the cerebral language networks in children with FLE or TLE, and the association between brain network characteristics and cognitive abilities. Methods: Twenty (20) children with FLE or TLE aged between 6 and 18 years and 29 age- and sex-matched healthy controls underwent a neuropsychological evaluation and a simultaneous functional near-infrared spectroscopy and electroencephalography (fNIRS-EEG) recording at rest and during a receptive language task. EEG was used to identify potential subclinical seizures in patients. We removed these time intervals from the fNIRS signal to investigate language brain networks and not epileptogenic networks. Functional connectivity matrices on fNIRS oxy-hemoglobin concentration changes were computed using cross-correlations between all channels. Results and discussion: Group comparisons of residual matrices (=individual task-based matrix minus individual resting-state matrix) revealed significantly reduced connectivity within the left and between hemispheres, increased connectivity within the right hemisphere and higher right hemispheric local efficiency for the epilepsy group compared to the control group. The epilepsy group had significantly lower cognitive performance in all domains compared to their healthy peers. Epilepsy patients' local network efficiency in the left hemisphere was negatively associated with the estimated IQ (p = 0.014), suggesting that brain reorganization in response to FLE and TLE does not allow for an optimal cognitive development.

Functional brain connectivity after corrective cardiac surgery for critical congenital heart disease: a preliminary near-infrared spectroscopy (NIRS) report.

Patients with congenital heart disease (CHD) requiring cardiac surgery in infancy are at high risk for neurodevelopmental impairments. Neonatal imaging studies have reported disruptions of brain functional organization before surgery. Yet, the extent to which functional network alterations are present after cardiac repair remains unexplored. This preliminary study aimed at investigating cortical functional connectivity in 4-month-old infants with repaired CHD, using resting-state functional near-infrared spectroscopy (fNIRS). After fNIRS signal frequency decomposition, we compared values of magnitude-squared coherence as a measure of connectivity strength, between 21 infants with corrected CHD and 31 healthy controls. We identified a subset of connections with differences between groups at an uncorrected statistical level of p < .05 while controlling for sex and maternal socioeconomic status, with most of these connections showing reduced connectivity in infants with CHD. Although none of these differences reach statistical significance after FDR correction, likely due to the small sample size, moderate to large effect sizes were found for group-differences. If replicated, these results would therefore suggest preliminary evidence that alterations of brain functional connectivity are present in the months after cardiac surgery. Additional studies involving larger sample size are needed to replicate our data, and comparisons between pre- and postoperative findings would allow to further delineate alterations of functional brain connectivity in this population.

Efficacy and safety of a self-applied carrageenan-based gel to prevent human papillomavirus infection in sexually active young women (CATCH study): an exploratory phase IIB randomised, placebo-controlled trial.

Background: Carrageenan demonstrated potent anti-HPV (human papillomavirus) activity in vitro and in animal models. The Carrageenan-gel Against Transmission of Cervical Human papillomavirus trial's interim analysis (n = 277) demonstrated a 36% protective effect of carrageenan against incident HPV infections. Herein, we report the trial's final results. Methods: In this exploratory phase IIB randomised, placebo-controlled trial, we recruited healthy women aged ≥18 years primarily from health service clinics at two Canadian Universities in Montreal. Participants were randomised (1:1) by the study coordinator (using computer-assisted block randomisation with randomly variable block sizes up to a block size of eight) to a carrageenan-based or placebo gel to be self-applied every other day for the first month and before/after intercourse. Participants, study nurses, and laboratory technicians (HPV testing and genotyping) were blinded to group assignment. At each visit (months 0, 0.5, 1, 3, 6, 9, 12), participants provided questionnaire data and a self-collected vaginal sample (tested for 36 HPV types, Linear Array). The primary outcome was type-specific HPV incidence (occurring at any follow-up visit). Intention-to-treat analyses for incidence were conducted using Cox proportional hazards regression models, including participants with ≥2 visits. Safety analyses included all participants randomised. This trial is registered with the ISRCTN registry, ISRCTN96104919. Findings: Between Jan 16, 2013 and Sept 30, 2020, 461 participants (enrolled) were randomly assigned to the carrageenan (n = 227) or placebo (n = 234) groups. Incidence and safety analyses included 429 and 461 participants, respectively. We found 51.9% (108/208) of participants in carrageenan and 66.5% (147/221) in placebo arm acquired ≥1 HPV type (hazard ratio 0.63 [95% CI: 0.49-0.81], p = 0.0003). Adverse events were reported by 34.8% (79/227) and 39.7% (93/234) of participants in carrageenan and placebo arm (p = 0.27), respectively. Interpretation: Consistent with the interim analysis, use of a carrageenan-based gel compared to placebo resulted in a 37% reduction in risk of incident genital HPV infections in women with no increase in adverse events. A carrageenan-based gel may complement HPV vaccination. Funding: Canadian Institutes of Health Research, CarraShield Labs Inc.

Utility of the Ages and Stages Questionnaires 3rd Edition for Developmental Screening in Children with Surgically Repaired Congenital Heart Disease.

Aim: This study sought to evaluate the accuracy of the Ages and Stages Questionnaires 3rd Edition (ASQ-3) in identifying developmental delay (DD) in children with congenital heart disease (CHD) born at term who underwent surgical repair.Methods: Participants had to complete ASQ-3 and Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III) at 12 and 24 months. A child was considered at risk of DD for a ASQ-3 domain when he scored below the cutoff (≤-1SD or ≤-2SD). A child had a DD in a BSID-III domain when the score was ≤-1SD. The validity for each ASQ-3 domain and for overall ASQ-3 was measured.Results: At 12 months (n = 64), overall ASQ-3 (≤-2SD) sensitivity was 88%, specificity 74%. At 24 months (n = 82), overall ASQ-3 (≤-2SD) sensitivity was 74%, specificity 88%.Conclusion: The results support the utility of the ASQ-3 for screening the overall risk of DD in children with CHD.

PSEN1-selective gamma-secretase inhibition in combination with kinase or XPO-1 inhibitors effectively targets T cell acute lymphoblastic leukemia.

BACKGROUND: T cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype that comprises 10-15% of childhood and 20-25% of adult ALL cases. Over 70% of T-ALL patients harbor activating mutations in the NOTCH1 signaling pathway and are predicted to be sensitive to gamma-secretase inhibitors. We have recently demonstrated that selective inhibition of PSEN1-containing gamma-secretase complexes can overcome the dose-limiting toxicity associated with broad gamma-secretase inhibitors. In this study, we developed combination treatment strategies with the PSEN1-selective gamma-secretase inhibitor MRK-560 and other targeted agents (kinase inhibitors ruxolitinib and imatinib; XPO-1 inhibitor KPT-8602/eltanexor) for the treatment of T-ALL. METHODS: We treated T-ALL cell lines in vitro and T-ALL patient-derived xenograft (PDX) models in vivo with MRK-560 alone or in combination with other targeted inhibitors (ruxolitinib, imatinib or KPT-8602/eltanexor). We determined effects on proliferation of the cell lines and leukemia development and survival in the PDX models. RESULTS: All NOTCH1-signaling-dependent T-ALL cell lines were sensitive to MRK-560 and its combination with ruxolitinib or imatinib in JAK1- or ABL1-dependent cell lines synergistically inhibited leukemia proliferation. We also observed strong synergy between MRK-560 and KPT-8602 (eltanexor) in all NOTCH1-dependent T-ALL cell lines. Such synergy was also observed in vivo in a variety of T-ALL PDX models with NOTCH1 or FBXW7 mutations. Combination treatment significantly reduced leukemic infiltration in vivo and resulted in a survival benefit when compared to single treatment groups. We did not observe weight loss or goblet cell hyperplasia in single drug or combination treated mice when compared to control. CONCLUSIONS: These data demonstrate that the antileukemic effect of PSEN1-selective gamma-secretase inhibition can be synergistically enhanced by the addition of other targeted inhibitors. The combination of MRK-560 with KPT-8602 is a highly effective treatment combination, which circumvents the need for the identification of additional mutations and provides a clear survival benefit in vivo. These promising preclinical data warrant further development of combination treatment strategies for T-ALL based on PSEN1-selective gamma-secretase inhibition.

Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires ß-catenin activity to drive T-cell acute lymphoblastic leukemia.

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the ß-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/ß-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/ß-catenin interaction.

Impacts of an Interdisciplinary Developmental Follow-Up Program on Neurodevelopment in Congenital Heart Disease: The CINC Study.

Objectives: This study investigates the impact of an early systematic interdisciplinary developmental follow-up and individualized intervention program on the neurodevelopment of children with complex congenital heart disease (CHD) who required cardiac surgery. Study Design: We prospectively enrolled 80 children with CHD: 41 were already followed at our neurocardiac developmental follow-up clinic from the age of 4 months, while 39 were born before the establishment of the program and therefore received standard health care. We conducted cognitive, motor, and behavioral assessments at 3 years of age. We used one-way multivariate analyses of variance to compare the neurodevelopmental outcome of both groups. Results: Between-group analyses revealed a distinct neurodevelopmental profile with clinically significant effect size (P < 0.001, partial η2 = 0.366). Children followed at our clinic demonstrated better receptive language performances (P = 0.048) and tended to show higher scores on visuo-constructive tasks (P = 0.080). Children who received standard health care exhibited greater performances in working memory tasks (P = 0.032). We found no group differences on global intellectual functioning, gross and fine motor skills, and behaviors. Referral rates for specific remedial services were higher in patients followed at our neurocardiac clinic compared to the historical cohort (P < 0.005). Conclusions: Overall, the impact of the developmental follow-up and individualized intervention program on neurodevelopmental outcomes remains subtle. Nevertheless, results, although limited by several factors, point toward an advantage for the children who took part in the program regarding receptive language skills over children who received standard health care. We hypothesize that group differences may be greater with growing age. Further research involving larger cohorts is needed to clearly assess the effectiveness of neurocardiac developmental follow-up programs at school age.

Deciphering the potential involvement of PXMP2 and PEX11B in hydrogen peroxide permeation across the peroxisomal membrane reveals a role for PEX11B in protein sorting.

Peroxisomes have the intrinsic ability to produce and scavenge hydrogen peroxide (H2O2), a diffusible second messenger that controls diverse cellular processes by modulating protein activity through cysteine oxidation. Current evidence indicates that H2O2, a molecule whose physicochemical properties are similar to those of water, traverses cellular membranes through specific aquaporin channels, called peroxiporins. Until now, no peroxiporin-like proteins have been identified in the peroxisomal membrane, and it is widely assumed that small molecules such as H2O2 can freely permeate this membrane through PXMP2, a non-selective pore-forming protein with an upper molecular size limit of 300-600 Da. By employing the CRISPR-Cas9 technology in combination with a Flp-In T-REx 293 cell line that can be used to selectively generate H2O2 inside peroxisomes in a controlled manner, we provide evidence that PXMP2 is not essential for H2O2 permeation across the peroxisomal membrane, neither in control cells nor in cells lacking PEX11B, a peroxisomal membrane-shaping protein whose yeast homologue facilitates the permeation of molecules up to 400 Da. During the course of this study, we unexpectedly noted that inactivation of PEX11B leads to partial localization of both peroxisomal membrane and matrix proteins to mitochondria and a decrease in peroxisome density. These findings are discussed in terms of the formation of a functional peroxisomal matrix protein import machinery in the outer mitochondrial membrane.