BRD3 (bromodomain containing 3)

BRD3 is a ubiquitously expressed member of the bromodomain and extraterminal motif (BET) family of proteins that use their tandem N-terminal bromodomains to associate with acetylated histones and transcription factors. Translocations involving BRD3 and NUT generate oncogenic fusion proteins that drive NUT midline carcinoma (NMC), an aggressive squamous cell malignancy. In addition, small molecule inhibitors that target the bromodomain-acetyl lysine interaction of all BET proteins are in clinical development for both hematologic malignancies and diverse solid tumors

Object Permanence and the Relationship to Sitting Development in Infants With Motor Delays

Purpose: This study examines object permanence development in infants with motor delays (MD) compared with infants with typical development (TD) and in relation to sitting skill. Methods: Fifty-six infants with MD (mean age = 10 months) and 36 with TD (mean age = 5.7 months) were assessed at baseline and then at 1.5, 3, and 6 months postbaseline. A scale was developed to measure object permanence (Object Permanence Scale [OPS]), and the Gross Motor Function Measure sitting subsection (GMFM-SS), and the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III) were administered. Results: Interrater reliability of the OPS was excellent and correlation between the OPS and Bayley-III cognitive scores was moderately positive. Compared with TD, infants with MD were delayed in development of object permanence but demonstrated increased understanding over time and as sitting skills improved. Conclusion: In children with MD, object permanence, as quantified by the OPS, emerges in conjunction with sitting skill

Observing Brane Inflation

Linking the slow-roll scenario and the Dirac-Born-Infeld scenario of ultra-relativistic roll (where, thanks to the warp factor, the inflaton moves slowly even with an ultra-relativistic Lorentz factor), we find that the KKLMMT D3/anti-D3 brane inflation is robust, that is, enough e-folds of inflation is quite generic in the parameter space of the model. We show that the intermediate regime of relativistic roll can be quite interesting observationally. Introducing appropriate inflationary parameters, we explore the parameter space and give the constraints and predictions for the cosmological observables in this scenario. Among other properties, this scenario allows the saturation of the present observational bound of either the tensor/scalar ratio r (in the intermediate regime) or the non-Gaussianity f_NL (in the ultra-relativistic regime), but not both.Comment: 31 pages, 12 figures; typo correcte

Targeted Physical Therapy Combined with Spasticity Management Changes Motor Development Trajectory for a 2- Year-Old with Cerebral Palsy

Therapies for children with cerebral palsy (CP) often fail to address essential components of early rehabilitation: intensity, child initiation, and an embodied approach. Sitting Together And Reaching To Play (START-Play) addresses these issues while incorporating intensive family involvement to maximize therapeutic dosage. While START-Play was developed and tested on children aged 7–16 months with motor delays, the theoretical construct can be applied to intervention in children of broader ages and skills levels. This study quantifies the impact of a broader STARTPlay intervention combined with Botulinum toxin-A (BoNT-A) and phenol on the developmental trajectory of a 24 month-old child with bilateral spastic CP. In this AB +1 study, A consisted of multiple baseline assessments with the Gross Motor Function Measure-66 and the Assessment of Problem Solving in Play. The research participant demonstrated a stable baseline during A and changes in response to the combination of BoNT-A/phenol and 12 START-Play sessions during B, surpassing the minimal clinically important difference on the Gross Motor Function Measure-66. The followup data point (+1) was completed after a second round of BoNT-A/phenol injections. While the findings suggest the participant improved his gross motor skills with BoNT-A/phenol and STARTPlay, further research is needed to generalize these findings

Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas

Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies.</p

Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas

Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies.</p

Ranitidine Use and Incident Cancer in a Multinational Cohort

Importance: Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020. Given the worldwide exposure to this drug, the potential risk of cancer development associated with the intake of known carcinogens is an important epidemiological concern. Objective: To examine the comparative risk of cancer associated with the use of ranitidine vs other H2RAs. Design, Setting, and Participants: This new-user active comparator international network cohort study was conducted using 3 health claims and 9 electronic health record databases from the US, the United Kingdom, Germany, Spain, France, South Korea, and Taiwan. Large-scale propensity score (PS) matching was used to minimize confounding of the observed covariates with negative control outcomes. Empirical calibration was performed to account for unobserved confounding. All databases were mapped to a common data model. Database-specific estimates were combined using random-effects meta-analysis. Participants included individuals aged at least 20 years with no history of cancer who used H2RAs for more than 30 days from January 1986 to December 2020, with a 1-year washout period. Data were analyzed from April to September 2021. Exposure: The main exposure was use of ranitidine vs other H2RAs (famotidine, lafutidine, nizatidine, and roxatidine). Main Outcomes and Measures: The primary outcome was incidence of any cancer, except nonmelanoma skin cancer. Secondary outcomes included all cancer except thyroid cancer, 16 cancer subtypes, and all-cause mortality. Results: Among 1 183 999 individuals in 11 databases, 909 168 individuals (mean age, 56.1 years; 507 316 [55.8%] women) were identified as new users of ranitidine, and 274 831 individuals (mean age, 58.0 years; 145 935 [53.1%] women) were identified as new users of other H2RAs. Crude incidence rates of cancer were 14.30 events per 1000 person-years (PYs) in ranitidine users and 15.03 events per 1000 PYs among other H2RA users. After PS matching, cancer risk was similar in ranitidine compared with other H2RA users (incidence, 15.92 events per 1000 PYs vs 15.65 events per 1000 PYs; calibrated meta-analytic hazard ratio, 1.04; 95% CI, 0.97-1.12). No significant associations were found between ranitidine use and any secondary outcomes after calibration. Conclusions and Relevance: In this cohort study, ranitidine use was not associated with an increased risk of cancer compared with the use of other H2RAs. Further research is needed on the long-term association of ranitidine with cancer development.</p

WISEA J041451.67–585456.7 and WISEA J181006.18–101000.5: The First Extreme T-type Subdwarfs?

We present the discoveries of WISEA J041451.67−585456.7 and WISEA J181006.18−101000.5, two low-temperature (1200–1400 K), high proper motion T-type subdwarfs. Both objects were discovered via their high proper motion (>0".5 yr⁻¹); WISEA J181006.18−101000.5 as part of the NEOWISE proper motion survey and WISEA J041451.67−585456.7 as part of the citizen science project Backyard Worlds; Planet 9. We have confirmed both as brown dwarfs with follow-up near-infrared spectroscopy. Their spectra and near-infrared colors are unique among known brown dwarfs, with some colors consistent with L-type brown dwarfs and other colors resembling those of the latest-type T dwarfs. While no forward model consistently reproduces the features seen in their near-infrared spectra, the closest matches suggest very low metallicities ([Fe/H] ⩽ −1), making these objects likely the first examples of extreme subdwarfs of the T spectral class (esdT). WISEA J041451.67−585456.7 and WISEA J181006.18−101000.5 are found to be part of a small population of objects that occupy the "substellar transition zone," and have the lowest masses and effective temperatures of all objects in this group

Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network

BACKGROUND: Mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause autosomal dominant forms of Alzheimer disease (ADAD). More than 280 pathogenic mutations have been reported in APP, PSEN1, and PSEN2. However, understanding of the basic biological mechanisms that drive the disease are limited. The Dominantly Inherited Alzheimer Network (DIAN) is an international observational study of APP, PSEN1, and PSEN2 mutation carriers with the goal of determining the sequence of changes in presymptomatic mutation carriers who are destined to develop Alzheimer disease. RESULTS: We generated a library of 98 dermal fibroblast lines from 42 ADAD families enrolled in DIAN. We have reprogrammed a subset of the DIAN fibroblast lines into patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized for pluripotency markers. CONCLUSIONS: This library represents a comprehensive resource that can be used for disease modeling and the development of novel therapeutics

Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease

OBJECTIVE: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management