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Articles by J Shan
Total Records ( 3 ) for J Shan
  A Quintas Cardama , H Kantarjian , D Jones , J Shan , G Borthakur , D Thomas , S Kornblau , S O'Brien and J. Cortes

Patients not in complete cytogenetic response (CCyR) continuously face the competing possibilities of eventually achieving a cytogenetic response versus progressing. We analyzed the probability of achieving a CCyR, major molecular response, and progression in 258 patients with chronic myeloid leukemia in early chronic phase at 3, 6, and 12 months from imatinib start. The initial imatinib dose was 800 mg/day in 208 (81%) and 400 mg/day in 50 (19%) patients. For patients not in CCyR, the probability of achieving CCyR (P = .002) or major molecular response (P = .004) significantly decreased, whereas the risk of progression increased (P = .16) at each time point. Patients with a BCR-ABL1/ABL1 ratio greater than 1% to 10% after 3 months of imatinib had a 92% probability of achieving CCyR with continued therapy, similar to the 98% for those with 1% or less, but their risk of progression (11%) was almost 3-fold that of patients with a BCR-ABL1/ABL1 transcript ratio of 1% or less (4%) and similar to that of patients with transcript levels more than 10% (13%). These results suggest that patients not in CCyR after 12 months on imatinib have a higher risk of progression. This risk is discernible as early as 3 months into imatinib therapy by molecular analysis and may provide the rationale to institute therapies that render higher rates of early response.

  J Shan , M. C Lopez , H. V Baker and M. S. Kilberg

Dietary protein malnutrition is manifested as amino acid deprivation of individual cells, which activates an amino acid response (AAR) that alters cellular functions, in part, by regulating transcriptional and posttranscriptional mechanisms. The AAR was activated in HepG2 human hepatoma cells, and the changes in mRNA content were analyzed by microarray expression profiling. The results documented that 1,507 genes were differentially regulated by P < 0.001 and by more than twofold in response to the AAR, 250 downregulated and 1,257 upregulated. The spectrum of altered genes reveals that amino acid deprivation has far-reaching implications for gene expression and cellular function. Among those cellular functions with the largest numbers of altered genes were cell growth and proliferation, cell cycle, gene expression, cell death, and development. Potential biological relationships between the differentially expressed genes were analyzed by computer software that generates gene networks. Proteins that were central to the most significant of these networks included c-myc, polycomb group proteins, transforming growth factor β1, nuclear factor (erythroid-derived 2)-like 2-related factor 2, FOS/JUN family members, and many members of the basic leucine zipper superfamily of transcription factors. Although most of these networks contained some genes that were known to be amino acid responsive, many new relationships were identified that underscored the broad impact that amino acid stress has on cellular function.

  D Grandy , J Shan , X Zhang , S Rao , S Akunuru , H Li , Y Zhang , I Alpatov , X. A Zhang , R. A Lang , D. L Shi and J. J. Zheng

Dishevelled (Dvl) is an essential protein in the Wnt signaling pathways; it uses its PDZ domain to transduce the Wnt signals from the membrane receptor Frizzled to downstream components. Here, we report identifying a drug-like small molecule compound through structure-based ligand screening and NMR spectroscopy and show the compound to interact at low micromolar affinity with the PDZ domain of Dvl. In a Xenopus testing system, the compound could permeate the cell membrane and block the Wnt signaling pathways. In addition, the compound inhibited Wnt signaling and reduced the levels of apoptosis in the hyaloid vessels of eye. Moreover, this compound also suppressed the growth of prostate cancer PC-3 cells. These biological effects suggest that by blocking the PDZ domain of Dvl, the compound identified in our studies effectively inhibits the Wnt signaling and thus provides a useful tool for studies dissecting the Wnt signaling pathways.

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