Citations

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease that affects aging populations. Current MRI techniques are often limited in their sensitivity to underlying neuropathological changes.PurposeTo characterize differences in voxel‐based morphometry (VBM), apparent diffusion coefficient (ADC), and intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI) metrics in aging populations. Additionally, to investigate the connection between cognitive assessments and neuroimaging metrics.Study TypeProspective/cross‐sectional.PopulationIn all, 49 subjects, including 13 with AD dementia, 12 with mild cognitive impairment (MCI), and 24 healthy controls (HC).Field Strength/Sequence3T/magnetization‐prepared rapid acquisition gradient echo (MP‐RAGE) and IVIM‐DWIAssessmentAll participants completed a cognitive screening battery prior to MRI. IVIM‐DWI maps (pure diffusion coefficient [D], pseudodiffusion coefficient [D*], and perfusion fraction [f]) were generated from a biexponential fit of diffusion MRI data. VBM was performed on the standard T1‐weighted MP‐RAGE structural images. Group‐wise templates were used to compare across groups.Statistical TestsAnalysis of covariance (ANCOVA) with gender and age as covariates (familywise error [FWE] corrected, post‐hoc comparisons using Bonferroni correction) for group comparisons. Partial‐η2 and Hedges' g were used for effect‐size analysis. Spearman's correlations (false discovery rate [FDR]‐corrected) for the relationship between cognitive scores and imaging.ResultsClusters of significant group‐wise differences were found mainly in the temporal lobe, hippocampus, and amygdala using all VBM and IVIM methods (P < 0.05 FWE). While VBM showed significant changes between MCI and AD groups and between HC and AD groups, no significant clusters were observed between HC and MCI using VBM. ADC and IVIM‐D demonstrated significant changes, at P < 0.05 FWE, between HC and MCI, notably in the amygdala and hippocampus. Several voxel‐based correlations were observed between neuroimaging metrics and cognitive tests within the cognitively impaired groups (P < 0.05 FDR).Data ConclusionThese findings suggest that IVIM‐DWI metrics may be earlier biomarkers for AD‐related changes than VBM. The use of these techniques may provide novel insight into subvoxel neurodegenerative processes.Level of Evidence2Technical Efficacy Stage2 J. MAGN. RESON. IMAGING 2020;52:1811–1826.

Produced by senescent cells, the senescence-associated secretory phenotype (SASP) is a potential driver of age-related dysfunction. We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20–90 years (retrospective cross-sectional) was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60–90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis (prospective longitudinal) or ovarian cancer (prospective case-control) were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes. We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), TNF receptor superfamily member 6 (FAS), osteopontin (OPN), TNF receptor 1 (TNFR1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

The use of intraoperative epicardial ultrasound in order to aid physicians and surgeons in open cardiac surgery has been established for quite some time. Recently, the development of ultra-high frequency ultrasound (UFHUS) technology has resulted in high-resolution imaging capabilities previously unavailable for clinical use. This report is the first to describe the use of intraoperative UFHUS epicoronary scanning to assess coronary anatomy and visualize cardioplegia flow within native coronary vessels.

Background: Long-QT syndrome (LQTS) is characterized by a prolonged heart rate–corrected QT interval (QTc). Genome-wide association studies identified common genetic variants that collectively explain ≈8% to 10% of QTc variation in the general population. Methods: Overall, 423 patients with LQT1, LQT2, or LQT3 were genotyped for 61 QTc-associated genetic variants used in a prototype QTc–polygenic risk score (QTc-PRS). A weighted QTc-PRS (range, 0–154.8 ms) was calculated for each patient, and the FHS (Framingham Heart Study) population-based reference cohort (n=853). Results: The average QTc-PRS in LQTS was 88.0±7.2 and explained only ≈2.0% of the QTc variability. The QTc-PRS in LQTS probands (n=137; 89.3±6.8) was significantly greater than both FHS controls (87.2±7.4, difference-in-means±SE: 2.1±0.7, P <0.002) and LQTS genotype-positive family members (87.5±7.4, difference-in-mean, 1.8±.7, P <0.009). There was no difference in QTc-PRS between symptomatic (n=156, 88.6±7.3) and asymptomatic patients (n=267; 87.7±7.2, difference-in-mean, 0.9±0.7, P=0.15). LQTS patients with a QTc≥480 ms (n=120) had a significantly higher QTc-PRS (89.3±6.7) than patients with a QTc<480 ms (n=303, 87.6±7.4, difference-in-mean, 1.7±0.8, P <0.05). There was no difference in QTc-PRS or QTc between genotypes. Conclusions: The QTc-PRS explained <2% of the QTc variability in our LQT1, LQT2, and LQT3 cohort, contributing 5× less to their QTc value than in the general population. This prototype QTc-PRS does not distinguish/predict the clinical outcomes of individuals with LQTS.

AbstractThe modulation of GLI2, an oncogenic transcription factor commonly upregulated in cancer, is in many cases not due to genetic defects, suggesting dysregulation through alternative mechanisms. The identity of these molecular events remains for the most part unknown. Here, we identified TFII-I as a novel repressor of GLI2 expression. Mapping experiments suggest that the INR region of the GLI2 promoter is necessary for GLI2 repression. ChIP studies showed that TFII-I binds to this INR. TFII-I knockdown decreased the binding of NELF-A, a component of the promoter–proximal pausing complex at this site, and enriched phosphorylated RNAPII serine 2 in the GLI2 gene body. Immunoprecipitation studies demonstrate TFII-I interaction with SPT5, another pausing complex component. TFII-I overexpression antagonized GLI2 induction by TGFβ, a known activator of GLI2 in cancer cells. TGFβ reduced endogenous TFII-I binding to the INR and increased RNAPII SerP2 in the gene body. We demonstrate that this regulatory mechanism is not exclusive of GLI2. TGFβ-induced genes CCR7, TGFβ1 and EGR3 showed similar decreased TFII-I and NELF-A INR binding and increased RNAPII SerP2 in the gene body post-TGFβ treatment. Together these results identify TFII-I as a novel repressor of a subset of TGFβ-responsive genes through the regulation of RNAPII pausing.

This essay compares the approaches that scientific societies in the ACCESS meta-organization use to implement and assess travel award programs for URM trainees and presents a set of recommendations, including both short- and long-term outcomes assessment in populations of interest and specialized programmatic activities coupled to travel award programs.

10538 Background: Rhabdomyosarcoma (RMS) of the female genital tract is rare, accounting for 3.5% of cases of rhabdomyosarcomas. Germline DICER1 mutations are associated with predisposition to pleuropulmonary blastoma and other tumors including sarcomas. Recently DICER1-associated RMS of the uterus/ovary has ben reported.. The aim of this study is to evaluate demographic characteristics, molecular pathogenesis, treatment and long term outcome of female genital tract rhabdomyosarcoma. Methods: Files of children with RMS of the female genital tract diagnosed at the Istanbul University, Oncology Institute during 1990-2019 were reviewed. Molecular genetic sequencing was performed by polymerase chain reaction amplification of genomic DNA extracted from the formalin-fixed, paraffin embedded tumors, followed by Sanger sequencing. Genetic testing for DICER1 variants of the proband and family members was performed if DICER1 mutation was detected in the tumor of the proband. Results: Of 210 RMS cases, 11 arose from the female genital tract. The median age at diagnosis was 52 months (10 months-15 years). Primary sites were vaginal (n = 5), uterus (n = 4), and ovary(n = 2). Presenting symptoms included vaginal mass (n = 6), vaginal bleeding (n = 5), and abdominal pain (n = 3). Four had group 1, five group 3, two group 2 disease and all received chemotherapy (vincristine, actinomycinD + cyclophosphamide).Three received radiotherapy; three underwent hysterectomy. DICER1 mutation was detected in tumor tissue in three patients:[ c.5113G > A (p.E1705K); c.5428G > T (p.D1810Y); c.1870C > T (p.Arg624Ter)] Genetic testing revealed germline DICER1 pathogenic variation in two patients and their family members, one of whom had cystic nephroma in infancy and history of Wilms tumor in an uncle. They were referred for surveillance for the DICER1 related diseases. A patient with metachronous bilateral ovarian RMS died. Two are married, one has children. The 5 year survival for RMS of the female genital tract was 85.7 % at a median follow-up of 34 (4-298) months. Conclusions: Rhabdomyosarcoma of the female genital tract is associated with a favorable prognosis, however some individuals undergo aggressive local therapies. Individuals with RMS of the female genital tract should be tested for DICER1 pathogenic variation. The detection of a DICER1 mutation in an individual or family members is important to facilitate surveillance for related tumors, so that they may be detected at the earliest possible stage, potentially increasing survival and decreasing risks of late effects.