Can Conventional MRI Features Predict H3K27M Mutation Status of Diffuse Midline Gliomas?

Purpose Pre-surgical prediction of H3K27M mutation in diffuse midline gliomas (DMG) on MRI is desirable. The purpose of the study is to elaborate conventional MRI (cMRI) of H3K27M-mutant DMGs and identify features that could discriminate them from WT (wild type)-DMGs.Methods cMRI features of 123 patients with DMG were evaluated conforming to the institutional research protocols. Multimodality MRI was performed on 1.5 or 3.0 Tesla MR Scanners with imaging protocol including T1w, T2w, FLAIR, diffusion-weighted, susceptibility-weighted and post- contrast T1w sequences. Pertinent cMRI features were annotated along the lines of Visually AcceSAble Rembrandt Images (VASARI) features and Intra Tumoral Susceptibility Signal score (ITSS) were evaluated. R software was used for statistical analysis.Results Sixty-one DMGs were H3K27M-mutant (mutant DMGs). The patients in the H3K27M-mutant DMG group were younger compared to the WT-DMG group (WT DMGs) (mean age 24.13+13.13 years vs. 35.79+18.74 years) (P= 0.016). The two groups differed on 5 cMRI features– i) enhancement quality (P=0.032), ii) thickness of enhancing margin (P=0.05), iii) proportion of edema (P=0.002), iv) definition of non-contrast enhancing tumor (NCET) margin (P=0.001) and v) cortical invasion (P=0.037). The mutant DMGs showed greater enhancement and greater thickness of enhancing margin while the WT DMGs exhibited significantly larger edema proportion with poorly defined NCET margins and cortical invasion. ITSS was not significantly different among the groups. Conclusion cMRI features like enhancement quality, thickness of the enhancing margin, proportion of edema, definition of NCET margin and cortical invasion can discriminate between the H3K27M-mutant and WT DMGs.

Multi-omics analysis of tumor angiogenesis characteristics and potential epigenetic regulation mechanisms in renal clear cell carcinoma

Background Tumor angiogenesis, an essential process for cancer proliferation and metastasis, has a critical role in prognostic of kidney renal clear cell carcinoma (KIRC), as well as a target in guiding treatment with antiangiogenic agents. However, tumor angiogenesis subtypes and potential epigenetic regulation mechanisms in KIRC patient remains poorly characterized. System evaluation of angiogenesis subtypes in KIRC patient might help to reveal the mechanisms of KIRC and develop more target treatments for patients. Method Ten independent tumor angiogenesis signatures were obtained from molecular signatures database (MSigDB) and gene set variation analysis was performed to calculate the angiogenesis score in silico using the Cancer Genome Atlas (TCGA) KIRC dataset. Tumor angiogenesis subtypes in 539 TCGA-KIRC patients were identified using consensus clustering analysis. The potential regulation mechanisms was studied using gene mutation, copy number variation, and differential methylation analysis (DMA). The master transcription factors (MTF) that cause the difference in tumor angiogenesis signals were completed by transcription factor enrichment analysis. Results The angiogenesis score of a prognosis related angiogenesis signature including 189 genes was significantly correlated with immune score, stroma score, hypoxia score, and vascular endothelial growth factor (VEGF) signal score in 539 TCGA KIRC patients. MMRN2, CLEC14A, ACVRL1, EFNB2, and TEK in candidate gene set showed highest correlation coefficient with angiogenesis score in TCGA-KIRC patients. In addition, all of them were associated with overall survival in both TCGA-KIRC and E-MTAB-1980 KIRC data. Clustering analysis based on 183 genes in angiogenesis signature identified two prognosis related angiogenesis subtypes in TCGA KIRC patients. Two clusters also showed different angiogenesis score, immune score, stroma score, hypoxia score, VEGF signal score, and microenvironment score. DMA identified 59,654 differential methylation sites between two clusters and part of these sites were correlated with tumor angiogenesis genes including CDH13, COL4A3, and RHOB. In addition, RFX2, SOX13, and THRA were identified as top three MTF in regulating angiogenesis signature in KIRC patients. Conclusion Our study indicate that evaluation the angiogenesis subtypes of KIRC based on angiogenesis signature with 183 genes and potential epigenetic mechanisms may help to develop more target treatments for KIRC patients.

Improved Detection Criteria for Detecting Drug-Drug Interaction Signals Using the Proportional Reporting Ratio

There is a current demand for “safety signal” screening, not only for single drugs but also for drug-drug interactions. The detection of drug-drug interaction signals using the proportional reporting ratio (PRR) has been reported, such as through using the combination risk ratio (CRR). However, the CRR does not consider the overlap between the lower limit of the 95% confidence interval of the PRR of concomitant-use drugs and the upper limit of the 95% confidence interval of the PRR of single drugs. In this study, we proposed the concomitant signal score (CSS), with the improved detection criteria, to overcome the issues associated with the CRR. “Hypothetical” true data were generated through a combination of signals detected using three detection algorithms. The signal detection accuracy of the analytical model under investigation was verified using machine learning indicators. The CSS presented improved signal detection when the number of reports was ≥3, with respect to the following metrics: accuracy (CRR: 0.752 → CSS: 0.817), Youden’s index (CRR: 0.555 → CSS: 0.661), and F-measure (CRR: 0.780 → CSS: 0.820). The proposed model significantly improved the accuracy of signal detection for drug-drug interactions using the PRR.

Hundreds of new periodic signals detected in the first year of TESS with the weirddetector

ABSTRACT We apply the weirddetector, a non-parametric signal detection algorithm based on phase dispersion minimization, in a search for low duty-cycle periodic signals in the Transiting Exoplanet Survey Satellite (TESS) photometry. Our approach, in contrast to commonly used model-based approaches specifically for flagging transits, eclipsing binaries, or other similarly periodic events, makes minimal assumptions about the shape of a periodic signal, with the goal of finding ‘weird’ signals of unexpected or arbitrary shape. In total, 248 301 TESS sources from the first-year Southern sky survey are run through the weirddetector, of which we manually inspect the top 21 500 for periodicity. To minimize false-positives, we here only report on the upper decile in terms of signal score, a sample for which we obtain 97% recall of TESS eclipsing binaries and 62% of the TOIs. In our sample, we find 377 previously unreported periodic signals, for which we make a first-pass assignment that 26 are ultra-short periods (<0.3 d), 313 are likely eclipsing binaries, 28 appear planet-like, and 10 are miscellaneous signals.

Abstract TMP92: Characteristic Brain MRI Features of Manifesting Heterozygotes With Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Introduction: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a cerebral small-vessel disease (CSVD). Mutations in the high-temperature requirement serine peptidase A1 gene ( HTRA1 ) cause CARASIL via a decrease in protease activity of HTRA1. Although most of the heterozygotes with the HTRA1 mutation are healthy, manifesting heterozygotes have been reported. We have elucidated that the mutant HTRA1s that develops CSVD in a heterozygote state have a distinct molecular mechanism, resulting in the dominant negative effect. These individuals showed mild phenocopy of CARASIL. However, it is not clear whether brain MRI findings in manifesting heterozygotes are different from those of CARASIL. In this study, we aimed to clarify the characteristic brain MRI features in manifesting heterozygotes by comparing them to those in CARASIL. Methods: We have evaluated 19 MRIs in eight manifesting heterozygotes and 21 MRIs in seven CARASIL patients and scored the MRIs by using a semi-quantitative scale for CARASIL, which scored white matter lesions (WMLs) (signal score) and atrophy (atrophy score) (Nozaki et al. Neurology 2015). Statistical analysis was conducted using software R 3.2.2. We obtained written informed consent from all individuals. Results: Signal score in manifesting heterozygotes was significantly lower than that in CARASIL (Mean ± SD; 14.6 ± 1.9 vs. 23.1 ± 5.0, p < 0.0001), however, there was no difference in atrophy score between the two groups (Mean ± SD; 5.5 ± 2.2 vs. 7.5 ± 5.5, p = 0.20). Atrophy score showed positive correlation with the disease duration in both groups (r 2 = 0.48, p = 0.0014 vs r 2 = 0.41, p = 0.0041), however signal score showed no correlation with the disease duration. Conclusion: WMLs is milder in manifesting heterozygote as compared with CARASIL. In contrast, the brain atrophy is not influenced by the HTRA1 mutation status but positively correlated with the disease duration. The rate of carriers for pathogenic HTRA1 mutations are higher than expected. These characteristic findings of brain MRIs might be useful to pick up the candidate for the genetic screening for HTRA1 .

Vascular Remodeling Underlies Re-Bleeding in Hemophilic Arthropathy

Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. To better understand these mechanisms, we investigated the time course of synovial, vascular, stromal and cartilage changes in response to a single induced hemarthrosis in FVIII-deficient mice, compared the observed changes in vascular architecture to the changes in mouse models of rheumatoid arthritis (RA) and osteoarthritis (OA), and explored the extent to which these findings correlated with the development of hemophilic arthropathy in patients. Following a single induced hemarthrosis in the FVIII-deficient mouse, we found soft tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture in the injured joint. While soft tissue changes were rapidly reversible, and cartilage changes were mild and mostly reversible, ongoing structural changes of abnormal vascularity persisted for months. These vascular changes involved pronounced remodeling with expression of α-Smooth Muscle Actin (SMA), Endoglin (CD105) and vascular endothelial growth factor (VEGF), as well as altered joint perfusion as determined by in vivo imaging. Surprisingly, these vascular changes were also seen in uninjured joints, suggesting systemic mediation of the observed effects. Changes in vascular architecture and pronounced expression of α-SMA were unique to hemophilia, and were not found in joint tissue obtained from RA or OA mice or from tissue from patients with OA or RA. Since FVIII-deficient mice do not suffer from spontaneous joint bleeding, human studies needed to be designed to reveal if such vascular changes were associated with joint bleeding and joint deterioration. Therefore, to determine if vascular perfusion changes were also present in hemophilia patients and to what extent they were related with joint bleeding and the degree of arthropathy, a cohort of 26 adult patients with hemophilia was studied prospectively. Radiographic Pettersson Scores and clinical Hemophilia Joint Health Scores (HJHS) were assessed and joint bleed status and vascularity changes were investigated by dynamic in vivo imaging using power Doppler (PD) during high resolution musculoskeletal ultrasound examinations of 156 joints (both elbows, knees and ankles of each patient) at baseline and, subsequently of 10 joints during painful episodes. Subclinical joint bleeding was present in 41% of joints at baseline. Positive PD signals were more frequently present in joints with subclinical bleeding than in joints without (83% vs. 55%; p< 0.01), while the mean PD signal score was significantly higher in bleeding joints (3.1 vs. 1.5; p < 0.01). Importantly, joint bleed status was independently associated with PD signal score (odds ratio [OR] = 1.45 [95% CI: 1.13, 1.86, p = 0.0035]) and with Pettersson score (OR = 1.21 [95%CI: 1.03, 1.43, p = 0.0185]) after adjusting for HJHS. Acute bleeding episodes, irrespective of occurring in previously non-bleeding or in previously subclinically bleeding joints only happened in joints where vascularity changes were present at baseline. Moreover, during these episodes, mean PD signal increased significantly from 3.5 at baseline to 6.0 (maximum 9 per joint; p≤0.05). Therefore, in vivo imaging demonstrated that those vascular changes, first observed in the FVIII-deficient mouse, were significantly associated with bleeding and joint deterioration in hemophilia patients. In aggregate, our observations in hemophilic mice and patients provide strong evidence that abnormal blood vessel formation and dynamic vascular remodeling facilitate and perpetuate joint bleeding in response to local and/or systemic stimuli. While changes in vascularity appear to be an important link to repeated bleeding and progression of arthropathy, the interrelations of bleeding and vascular changes are complicated and will require further study. These findings not only provide new insights into the pathobiology of progression of hemophilic arthroapthy, but also open new avenues to study molecular targets for angiogenesis inhibition to prevent aberrant vessel formation, potentially increasing the effectiveness of clotting factor replacement therapy. Disclosures Von Drygalski: CSL Behring: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Research Funding; Pfizer: Honoraria; Baxalta: Honoraria, Research Funding. Mosnier:Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Ecosystem Health of Lake Tamrangabeel, Bongaigaon District, Assam, India with Special Reference to Aquatic Insect Assemblage

This study investigated the ecosystem health of a floodplain lake, Tamrangabeel of Bongaigaon district, Assam, India using aquatic insects as bioindicator. The aquatic community of Tamrangabeel was represented by 37 species belonging to 19 families and 5 orders. Shannon –Wiener diversity index (Shannon Hꞌ) values were recorded less than 1 in all the sites of the lake which indicated perturbed condition of the lake. Order Hemiptera was found to be the largest order with highest number of species. Eudominant species recorded in this lake were Micronecta siva (order Hemiptera) and Cloeon sp. (order Ephemeroptera). Biological Monitoring Working Party (BMWP) Score, Average Score per taxon (ASPT), and Stream Invertebrate Grade Number-Average Level (SIGNAL) Score reported from the study reflected good ecological potential as well as slightly impacted nature of the water body. The values of different environmental variables of water of all the sites of the lake were found conducive for aquatic life. This study provided an early warning of perturbation of the lake which is to be addressed before it is too late.