Citations

Abstract OBJECTIVES Paragangliomas have unique features in the mediastinum, in part due to their location. Because of their paucity, they have not been thoroughly investigated. We studied the clinical, pathological, immunohistochemical and molecular features of mediastinal paragangliomas. METHODS Immunohistochemistry, next-generation sequencing mutation panel and the Oncoscan assay were performed. RESULTS Twenty-four patients with mediastinal paraganglioma (7 men, 29.2%) had a median age of 45.5 years (19.8–72.2). Twenty-one (87.5%) paragangliomas were completely resected. Six (of 24, 25.0%) tumours were considered metastatic. Mitotic activity occurred in 11 (of 24, 45.8%) paragangliomas. Programmed death-ligand 1 (PD-L1) (n = 23) was expressed in 6 (26%) patients in 10% (n = 2) and 1% (n = 4) of tumour cells, respectively. SDHB expression was lost in 19 (of 22, 86.4%) cases. ATRX expression was lost in 11 (of 23, 47.8%) cases. Next-generation sequencing revealed a single pathogenic mutation in 10 (of 19) specimens including SDHB (n = 4), SDHD (n = 6), SDHC (n = 1), ATRX (n = 1), and ≥2 mutations in 2 cases [SDHC and TERT (n = 1); SDHB, ATRX and TP53 (n = 1)]. Germline mutation analysis revealed the same succinate dehydrogenase mutation (or lack thereof) as identified in the paraganglioma in 11 (of 12) cases. During a median follow-up (n = 21) of 4.8 years (0.8–14.9), 3 patients developed metastases; 4 patients died, at least 1 of disease. CONCLUSIONS Mediastinal paragangliomas can be associated with morbidity and mortality. Many mediastinal paragangliomas have been reported to be associated with syndromes such as multiple endocrine neoplasia, von Hippel-Lindau or succinate dehydrogenase syndrome with mutation profiles dominated by alterations in genes associated with these syndromes.

Introduction: African American women are 5 times less likely than white women to meet at least 5 or more ideal cardiovascular health metrics as defined by the American Heart Association Life’s Simple 7 (LS7) components (smoking, diet, physical activity, BMI, blood pressure, total cholesterol, and glucose). There are few studies probing the influence of sociocultural factors, such as body image dissatisfaction (BID), on these disparities. A better understanding of the impact of BID on cardiovascular health could assist in the design of more effective behavior change interventions for African American women. Hypothesis: We hypothesized that BID would have a negative association with cardiovascular health in overweight and obese African American women. Methods: We enrolled 32 women (mean age 49 years [SD 12.9]), from 5 predominantly African American churches participating in a larger community-based participatory study (FAITH! App Pilot Study) of a mobile health lifestyle intervention among African American women and men. We conducted a cross-sectional analysis of baseline data to evaluate the association between BID and both cardiovascular health and select psychosocial factors (e.g. motivation for healthy eating, diet self-regulation). A LS7 composite score was calculated as a measure of overall cardiovascular health (range 0-14). The Pulvers scale, consisting of images of women across the BMI spectrum, was used to measure perceived current and goal body size (rating of figures, 1-9; underweight to very obese). A BID score was calculated as the difference between perceived current and desired body image (range -8-8; BID < 0 [desire to be heavier], BID > 0 [desire to be thinner], BID = 0 [no dissatisfaction]). The BID score range for our cohort was 0-4. Thus, we categorized BID as no/low BID (BID score 0-1) or high BID (BID score 2-4). Results: Twenty-two percent (7/32) of women were overweight (BMI 25-29.9) and 78% (25/32) were obese (BMI (≥ 30). Forty-four percent (14/32) had no/low BID and 56% (18/32) had high BID. Those with high BID were more likely to be obese as compared to no/low BID (94% (17/18) versus 57% (8/14), p=0.03). Although not statistically significant, the mean LS7 composite score was 1 point higher among those with no/low BID, versus high BID (8.83 versus 7.76, p=0.25). Compared to women with high BID, those with no/low BID were more likely to have greater: intrinsic motivation (P=0.01) and integrated regulation for healthy eating (P=0.007), and self-regulation to reduce fat and caloric intake (P=0.01). Conclusion: Ultimately, although small, our study suggests that African-American women with obesity are more likely to have high BID. High BID was associated with lower motivation and self-regulation, which predict cardiovascular health. BID and other psychosocial factors for behavior change are potential targets for culturally-tailored lifestyle interventions in this group.

Objective Obesity is a risk factor for colorectal cancer (CRC), accounting for more than 14% of CRC incidence. Microbial dysbiosis and chronic inflammation are common characteristics in both obesity and CRC. Human and murine studies, together, demonstrate the significant impact of the microbiome in governing energy metabolism and CRC development; yet, little is understood about the contribution of the microbiome to development of obesity-associated CRC as compared to individuals who are not obese. Design In this study, we conducted a meta-analysis using five publicly available stool and tissue-based 16S rRNA and whole genome sequencing (WGS) data sets of CRC microbiome studies. High-resolution analysis was employed for 16S rRNA data, which allowed us to achieve species-level information to compare with WGS. Results Characterisation of the confounders between studies, 16S rRNA variable region and sequencing method did not reveal any significant effect on alpha diversity in CRC prediction. Both 16S rRNA and WGS were equally variable in their ability to predict CRC. Results from diversity analysis confirmed lower diversity in obese individuals without CRC; however, no universal differences were found in diversity between obese and non-obese individuals with CRC. When examining taxonomic differences, the probability of being classified as CRC did not change significantly in obese individuals for all taxa tested. However, random forest classification was able to distinguish CRC and non-CRC stool when body mass index was added to the model. Conclusion Overall, microbial dysbiosis was not a significant factor in explaining the higher risk of colon cancer among individuals with obesity.

AbstractPrimary aneurysmal bone cyst (ABC) is a benign multiloculated cystic lesion of bone that is defined cytogenetically by USP6 gene rearrangements. Rearrangements involving USP6 are promoter swaps, usually generated by fusion of the noncoding upstream exons of different partner genes with exon 1 or 2 of USP6, thus leading to transcriptional upregulation of full‐length USP6 coding sequence. Testing for USP6 rearrangements is used diagnostically to distinguish it from secondary ABC and other giant cell‐rich primary bone tumors. In this report, we present a case of a 16‐year‐old male with a primary ABC of the left distal femur. USP6 break apart fluorescence in situ hybridization was positive for a rearrangement and conventional chromosome analysis identified a reciprocal X;17 translocation. In order to identify the putative USP6 fusion partner, we performed RNA sequencing and uncovered a novel USP9X‐USP6 promoter swap fusion. This result was confirmed by reverse transcription‐polymerase chain reaction (RT‐PCR) and by mate pair sequencing thus showing the utility of these alternative methodologies in identifying novel fusion candidates. Ubiquitin‐specific protease 9X (USP9X), like USP6, encodes a highly conserved substrate‐specific deubiquitylating enzyme. USP9X is highly expressed in a number of tissue types and acts as both an oncogene and tumor suppressor in several human cancers. We conclude that oncogenic activation of USP6 via USP9X promoter exchange represents a novel driver of primary ABC formation.

Abstract Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P &lt; 5.69 × 10−6, we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 × 10−6). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis. Significance: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.