Browsing by Author "Ryan, Michael"

Now showing 1 - 3 of 3
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    The Integrated Genomic Landscape of Thymic Epithelial Tumors
    (Elsevier, 2018-02) Radovich, Milan; Pickering, Curtis R.; Felau, Ina; Ha, Gavin; Zhang, Hailei; Jo, Heejoon; Hoadley, Katherine A.; Anur, Pavana; Zhang, Jiexin; McLellan, Mike; Bowlby, Reanne; Matthew, Thomas; Danilova, Ludmila; Hegde, Apurva M.; Kim, Jaegil; Leiserson, Mark D. M.; Sethi, Geetika; Lu, Charles; Ryan, Michael; Su, Xiaoping; Cherniack, Andrew D.; Robertson, Gordon; Akbani, Rehan; Spellman, Paul; Weinstein, John N.; Hayes, D. Neil; Raphael, Ben; Lichtenberg, Tara; Leraas, Kristen; Zenklusen, Jean Claude; Pathology and Laboratory Medicine, School of Medicine
    Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy.
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    Splicing factor ESRP1 controls ER-positive breast cancer by altering metabolic pathways
    (EMBO Press, 2019-02) Gökmen‐Polar, Yesim; Neelamraju, Yaseswini; Goswami, Chirayu P.; Gu, Yuan; Gu, Xiaoping; Nallamothu, Gouthami; Vieth, Edyta; Janga, Sarath C.; Ryan, Michael; Badve, Sunil S.; Pathology and Laboratory Medicine, School of Medicine
    The epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) control the epithelial-to-mesenchymal transition (EMT) splicing program in cancer. However, their role in breast cancer recurrence is unclear. In this study, we report that high levels of ESRP1, but not ESRP2, are associated with poor prognosis in estrogen receptor positive (ER+) breast tumors. Knockdown of ESRP1 in endocrine-resistant breast cancer models decreases growth significantly and alters the EMT splicing signature, which we confirm using TCGA SpliceSeq data of ER+ BRCA tumors. However, these changes are not accompanied by the development of a mesenchymal phenotype or a change in key EMT-transcription factors. In tamoxifen-resistant cells, knockdown of ESRP1 affects lipid metabolism and oxidoreductase processes, resulting in the decreased expression of fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), and phosphoglycerate dehydrogenase (PHGDH) at both the mRNA and protein levels. Furthermore, ESRP1 knockdown increases the basal respiration and spare respiration capacity. This study reports a novel role for ESRP1 that could form the basis for the prevention of tamoxifen resistance in ER+ breast cancer.
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    Trends in Complications Among Patients Undergoing Aortic Valve Replacement in the United States
    (American Heart Association, 2024) Harvey, James E., III; Kapadia, Samir R.; Cohen, David J.; Kalra, Ankur; Irish, William; Gunnarsson, Candace; Ryan, Michael; Chikermane, Soumya G.; Thompson, Christin; Puri, Rishi; Medicine, School of Medicine
    Background: The treatment of severe aortic stenosis has evolved considerably since the introduction of transcatheter aortic valve replacement (TAVR), yet trends in complications for patients undergoing TAVR or surgical aortic valve replacement (SAVR) at a national level have yet to be evaluated. Methods and results: We performed a retrospective cohort study using Medicare data to evaluate temporal trends in complications among beneficiaries, aged ≥65 years, treated with elective isolated transfemoral TAVR or SAVR between 2012 and 2019. The study end point was the occurrence of a major complication (composite outcome) during index and up to 30 days after. Multivariable logistic regression was used to assess odds of complications for TAVR and SAVR, individually over time, and for TAVR versus SAVR, over time. The cohort included 211 212 patients (mean±SD age, 78.6±7.3 years; 45.0% women). Complication rates during index following elective isolated aortic valve replacement decreased from 49% in 2012 to 22% in 2019. These reductions were more pronounced for TAVR (41% to >19%, Δ=22%) than SAVR (51% to >47%, Δ=4%). After risk adjustment, the risk of any complication with TAVR was 47% (P<0.0001) lower compared with SAVR in 2012, and 78% (P<0.0001) lower in 2019. TAVR was independently associated with reduced odds of complications each year compared with 2012, with the magnitude of benefit increasing over time (2013 versus 2012: odds ratio [OR], 0.89 [95% CI, 0.81-0.97]; 2019 versus 2012: OR, 0.35 [95% CI, 0.33-0.38]). These findings are consistent for complications up to 30 days from index. Conclusions: Between 2012 and 2019, the risk of complications after aortic valve replacement among Medicare beneficiaries decreased significantly, with larger absolute and relative changes among patients treated with TAVR than SAVR.