Browsing by Author "Goel, Ajay"

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    Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines
    (Elsevier, 2023) Cavestro, Giulia Martina; Mannucci, Alessandro; Balaguer, Francesc; Hampel, Heather; Kupfer, Sonia S.; Repici, Alessandro; Sartore-Bianchi, Andrea; Seppälä, Toni T.; Valentini, Vincenzo; Boland, Clement Richard; Brand, Randall E.; Buffart, Tineke E.; Burke, Carol A.; Caccialanza, Riccardo; Cannizzaro, Renato; Cascinu, Stefano; Cercek, Andrea; Crosbie, Emma J.; Danese, Silvio; Dekker, Evelien; Daca-Alvarez, Maria; Deni, Francesco; Dominguez-Valentin, Mev; Eng, Cathy; Goel, Ajay; Guillem, Josè G.; Houwen, Britt B. S. L.; Kahi, Charles; Kalady, Matthew F.; Kastrinos, Fay; Kühn, Florian; Laghi, Luigi; Latchford, Andrew; Liska, David; Lynch, Patrick; Malesci, Alberto; Mauri, Gianluca; Meldolesi, Elisa; Møller, Pål; Monahan, Kevin J.; Möslein, Gabriela; Murphy, Caitlin C.; Nass, Karlijn; Ng, Kimmie; Oliani, Cristina; Papaleo, Enrico; Patel, Swati G.; Puzzono, Marta; Remo, Andrea; Ricciardiello, Luigi; Ripamonti, Carla Ida; Siena, Salvatore; Singh, Satish K.; Stadler, Zsofia K.; Stanich, Peter P.; Syngal, Sapna; Turi, Stefano; Urso, Emanuele Damiano; Valle, Laura; Vanni, Valeria Stella; Vilar, Eduardo; Vitellaro, Marco; You, Yi-Qian Nancy; Yurgelun, Matthew B.; Zuppardo, Raffaella Alessia; Stoffel, Elena M.; Associazione Italiana Familiarità Ereditarietà Tumori; Collaborative Group of the Americas on Inherited Gastrointestinal Cancer; European Hereditary Tumour Group; International Society for Gastrointestinal Hereditary Tumours; Medicine, School of Medicine
    Background & aims: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. Methods: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. Results: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. Conclusions: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.
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    H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer
    (Elsevier, 2016-11) Ohtsuka, Masahisa; Ling, Hui; Ivan, Cristina; Pichler, Martin; Matsushita, Daisuke; Goblirsch, Matthew; Stiegelbauer, Verena; Shigeyasu, Kunitoshi; Zhang, Xinna; Chen, Meng; Vidhu, Fnu; Bartholomeusz, Geoffrey A.; Toiyama, Yuji; Kusunoki, Masato; Doki, Yuichiro; Mori, Masaki; Song, Shumei; Gunther, Jillian R.; Krishnan, Sunil; Slaby, Ondrej; Goel, Ajay; Ajani, Jaffer A.; Radovich, Milan; Calin, George A.; Department of Surgery, IU School of Medicine
    The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unexplored. Here, we analyzed a large panel of lncRNA candidates with The Cancer Genome Atlas (TCGA) CRC dataset, and identified H19 as the most significant lncRNA associated with CRC patient survival. We further validated such association in two independent CRC cohorts. H19 silencing blocked G1-S transition, reduced cell proliferation, and inhibited cell migration. We profiled gene expression changes to gain mechanism insight of H19 function. Transcriptome data analysis revealed not only previously identified mechanisms such as Let-7 regulation by H19, but also RB1-E2F1 function and β-catenin activity as essential upstream regulators mediating H19 function. Our experimental data showed that H19 affects phosphorylation of RB1 protein by regulating gene expression of CDK4 and CCND1. We further demonstrated that reduced CDK8 expression underlies changes of β-catenin activity, and identified that H19 interacts with macroH2A, an essential regulator of CDK8 gene transcription. However, the relevance of H19-macroH2A interaction in CDK8 regulation remains to be experimentally determined. We further explored the clinical relevance of above mechanisms in clinical samples, and showed that combined analysis of H19 with its targets improved prognostic value of H19 in CRC.