FOG-2 mediated recruitment of the NuRD complex regulates cardiomyocyte proliferation during heart development.

FOG-2 is a multi-zinc finger protein that binds the transcriptional activator GATA4 and modulates GATA4-mediated regulation of target genes during heart development. Our previous work has demonstrated that the Nucleosome Remodeling and Deacetylase (NuRD) complex physically interacts with FOG-2 and is necessary for FOG-2 mediated repression of GATA4 activity in vitro. However, the relevance of this interaction for FOG-2 function in vivo has remained unclear. In this report, we demonstrate the importance of FOG-2/NuRD interaction through the generation and characterization of mice homozygous for a mutation in FOG-2 that disrupts NuRD binding (FOG-2(R3K5A)). These mice exhibit a perinatal lethality and have multiple cardiac malformations, including ventricular and atrial septal defects and a thin ventricular myocardium. To investigate the etiology of the thin myocardium, we measured the rate of cardiomyocyte proliferation in wild-type and FOG-2(R3K5A) developing hearts. We found cardiomyocyte proliferation was reduced by 31±8% in FOG-2(R3K5A) mice. Gene expression analysis indicated that the cell cycle inhibitor Cdkn1a (p21(cip1)) is up-regulated 2.0±0.2-fold in FOG-2(R3K5A) hearts. In addition, we demonstrate that FOG-2 can directly repress the activity of the Cdkn1a gene promoter, suggesting a model by which FOG-2/NuRD promotes ventricular wall thickening by repression of this cell cycle inhibitor. Consistent with this notion, the genetic ablation of Cdkn1a in FOG-2(R3K5A) mice leads to an improvement in left ventricular function and a partial rescue of left ventricular wall thickness. Taken together, our results define a novel mechanism in which FOG-2/NuRD interaction is required for cardiomyocyte proliferation by directly down-regulating the cell cycle inhibitor Cdkn1a during heart development.

Quantitative differences in volumetric calculations for radiation dosimetry in segmental Y90 treatment planning using hybrid angiography-CT compared with anatomic segmentation.

OBJECTIVE: To compare treatment volumes reconstructed from hybrid Angio-CT catheter-directed infusion imaging and Couinaud anatomic model as well as the implied differences in Y-90 radiation dosimetry. METHODS: Patients who underwent transarterial radioembolization (TARE) using Y-90 glass microspheres with pretreatment CT or MRI imaging as well as intraprocedural angiography-CT (Angio-CT) were analysed. Treatment volumes were delineated using both tumoural angiosomes (derived from Angio-CT) and Couinaud anatomic landmarks. Segmental and lobar treatment volumes were calculated via semi-automated contouring software. Volume and dose differences were compared by the two-tailed Student t test or Wilcoxon signed-rank test. Factors affecting volume and dose differences were assessed via simple and/or multiple variable linear regression analysis. RESULTS: From September 2018 to March 2021, 44 patients underwent 45 lobar treatments and 38 patients received 56 segmental treatments. All target liver lobes and all tumours were completely included within the field-of-view by Angio-CT. Tumour sizes ranged between 1.1 and 19.5 cm in diameter. Segmental volumes and treatment doses were significantly different between the Couinaud and Angio-CT volumetry methods (316 vs 404 mL, P < .0001 and 253 vs 212 Gy, P < .01, respectively). Watershed tumours were significantly correlated with underestimated volumes by the Couinaud anatomic model (P < .001). There was a significant linear relationship between tumour diameter and percent volume difference (R2 = 0.44, P < .0001). The Couinaud model overestimated volumes for large tumours that exhibited central hypovascularity/necrosis and for superselected peripheral tumours. CONCLUSIONS: Angio-CT may confer advantages over the Couinaud anatomic model and enable more accurate, personalized dosimetry for TARE. ADVANCES IN KNOWLEDGE: Angio-CT may confer advantages over traditional cross-sectional and cone-beam CT imaging for selective internal radiation therapy planning.

An Interactive App with Multi-parametric MRI - Whole-Mount Histology Correlation for Enhanced Prostate MRI Training of Radiology Residents.

RATIONALE AND OBJECTIVES: To validate the educational value of a newly created learning application in enhancing prostate MRI training of radiologists for detecting prostate cancer using an observer study. MATERIALS AND METHODS: An interactive learning app, LearnRadiology, was developed using a web-based framework to display multi-parametric prostate MRI images with whole-mount histology for 20 cases curated for unique pathology and teaching points. Twenty new prostate MRI cases, different from the ones used in the web app, were uploaded on 3D Slicer. Three radiologists (R1: radiologist; R2, R3: residents) blinded to pathology results were asked to mark areas suspected of cancer and provide a confidence score (1-5, with 5 being high confidence level). Then after a minimum memory washout period of 1 month, the same radiologists used the learning app and then repeated the same observer study. The diagnostic performance for detecting cancers before and after accessing the learning app was measured by correlating MRI with whole-mount pathology by an independent reviewer. RESULTS: The 20 subjects included in the observer study had 39 cancer lesions (13 Gleason 3 + 3, 17 Gleason 3 + 4, 7 Gleason 4 + 3, and 2 Gleason 4 + 5 lesions). The sensitivity (R1: 54% â†’ 64%, P = 0.08; R2: 44% â†’ 59%, P = 0.03; R3: 62% â†’ 72%, P = 0.04) and positive predictive value (R1: 68% â†’ 76%, P = 0.23; R2: 52% â†’ 79%, P = 0.01; R3: 48% â†’ 65%, P = 0.04) for all 3 radiologists improved after using the teaching app. The confidence score for true positive cancer lesion also improved significantly (R1: 4.0 ± 1.0 â†’ 4.3 ± 0.8; R2: 3.1 ± 0.8 â†’ 4.0 ± 1.1; R3: 2.8 ± 1.2 â†’ 4.1 ± 1.1; P < 0.05). CONCLUSION: The web-based and interactive LearnRadiology app learning resource can support medical student and postgraduate education by improving diagnostic performance of trainees for detecting prostate cancer.

Relationship of Cardiorespiratory Fitness and Adiposity With Left Ventricular Strain in Middle-Age Adults (from the Dallas Heart Study).

Low cardiorespiratory fitness (CRF) and obesity are significant risk factors for heart failure (HF). However, given the inverse association between CRF and obesity, the independent contributions of low CRF and adiposity toward HF risk are not well established. We evaluated the association of CRF and measures of adiposity with left ventricular (LV) peak systolic strain-a subclinical measure of LV dysfunction-among the Dallas Heart Study phase II participants without cardiovascular disease who had CRF estimated using a submaximal treadmill test and LV systolic circumferential strain assessment by tissue-tagged cardiac magnetic resonance imaging. Peak midwall systolic circumferential strain (Ecc) was determined by harmonic phase imaging. Associations of CRF and adiposity measures with Ecc were determined using adjusted linear regression analysis. A total of 1,617 participants were included in the analysis. After adjustment for baseline risk factors, higher waist circumference (WC) and lower CRF were associated with higher Ecc (WC: ß = 0.07; p = 0.01; CRF: ß = -0.17; p = < 0.0001), whereas % body fat and body mass index were not associated with Ecc. The relationship between WC and Ecc was attenuated completely after additional adjustment for CRF. In contrast, the association between CRF and Ecc did not attenuate after additional adjustment for WC and other measures of LV structure and function (ß = -0.18; p = < 0.0001). Taken together, our study findings suggest that lower CRF, but not measures of adiposity, is associated with greater impairment in LV strain independent of LV mass and ejection fraction.