Salloum, R; McConechy, MK; Mikael, LG; Fuller, C; Drissi, R; DeWire, M; Nikbakht, H; De Jay, N; Yang, X; Boue, D; Chow, LML; Finlay, JL; Gayden, T; Karamchandani, J; Hummel, TR; Olshefski, R; Osorio, DS; Stevenson, C; Kleinman, CL; Majewski, J; Fouladi, M; Jabado, N. Characterizing temporal genomic heterogeneity in pediatric high-grade gliomas. Acta Neuropathologica Communications. 2017; 5(1).
Pediatric high-grade gliomas (pHGGs) are aggressive neoplasms representing approximately 20% of brain tumors in children. Current therapies offer limited disease control, and patients have a poor prognosis. Empiric use of targeted therapy, especially at progression, is increasingly practiced despite a paucity of data regarding temporal and therapy-driven genomic evolution in pHGGs. Our findings indicate that specific key driver mutations in pHGGs conserve at recurrence and are prime targets for therapeutic development and clinical trials (e.g. H3 post-translational modifications, IDH1, BRAF V600E). Other actionable mutations acquired or lost, indicate that re-biopsy at recurrence will provide better guidance for effective targeted therapy of pHGGs.
Valanejad, L; Lewis, K; Wright, M; Jiang, Y; D'Souza, A; Karns, R; Sheridan, R; Gupta, A; Bove, K; Witte, D; Geller, J; Tiao, G; Nelson, DL; Timchenko, L; Timchenko, N. FXR-Gankyrin axis is involved in development of pediatric liver cancer. Carcinogenesis. 2017; 38(7):738-747.
The development of hepatoblastoma (HBL) associates with failure of hepatic stem cells (HSC) to differentiate into hepatocytes. Despite intensive investigations, mechanisms of the failure of HSC to differentiate are not known. We found the involvement that oncogene Gankyrin (Gank) has in the inhibition of differentiation of HSC via triggering degradation of tumor suppressor proteins (TSPs) Rb, p53, C/EBPα and HNF4α. We conclude that FXR-Gank-TSPs-Stem cells pathway is a key determinant of liver cancer in animal models and in pediatric liver cancer. Our data provide a strong basis for development of FXR-Gank-based therapy for treatment of patients with hepatoblastoma.
Cast, A; Valanejad, L; Wright, M; Nguyen, P; Gupta, A; Zhu, L; Shin, S; Timchenko, N. C/EBP-dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer. Hepatology. 2018; 67(5):1857-1871.
Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes, while the cause of hepatocellular carcinoma (HCC) is by the dedifferentiation of hepatocytes into cancer stem cells. However, the mechanisms of aggressive HBL and the mechanisms that cause dedifferentiation of hepatocytes into cancer stem cells are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of dedifferentiation of hepatocytes into cancer stem cells. The earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include conversion of the tumor suppressor C/EBP into an oncogenic isoform, which further creates preneoplastic foci where hepatocytes dedifferentiate into cancer cells, giving rise to liver cancer.
Huang, L; Liu, D; Wang, N; Ling, S; Tang, Y; Wu, J; Hao, L; Luo, H; Hu, X; Sheng, L; Zhu, L; Wang, D; Luo, Y; Shang, Z; Xiao, M; Mao, X; Zhou, K; Cao, L; Dong, L; Zheng, X; Sui, P; He, J; Mo, S; Yan, J; Ao, Q; Qiu, L; Zhou, H; Liu, Q; Zhang, H; Li, J; Jin, J; Fu, L; Zhao, W; Chen, J; Du, X; Qing, G; Liu, H; Liu, X; Huang, G; Ma, D; Zhou, J; Wang, QF. Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia. Cell Research. 2018; 28(2):172-186.
Aggressive NK-cell leukemia (ANKL) is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Collectively, the JAK-STAT pathway represents a major target for genomic alterations and IL10 stimulation in ANKL. This newly discovered JAK/STAT-MYC-biosynthesis axis may provide opportunities for the development of novel therapeutic strategies in treating this subtype of leukemia.
Setchell, KDR. The history and basic science development of soy isoflavones. Menopause: The Journal of the North American Menopause Society. 2017; 24(12):1338-1350.
This review summarizes the 2016 NAMS/Pfizer-Wulf H. Utian Endowed Lecture that focused on the history and basic science of soy isoflavones. Described is a personal perspective of the background and history that led to the current interest in soy and isoflavones with a specific focus on the role that soy isoflavones play in the health of postmenopausal women. This overview covers the metabolism and physiological behavior of isoflavones, their biological properties that are of potential relevance to aging, issues related to the safety of soy isoflavones, and the role of the important intestinally derived metabolite S-(-)equol.