The HPV16 E7 oncoprotein and 17β-estradiol are important factors for the induction of premalignant lesions and cervical cancer. The study of these factors is crucial for a better understanding of cervical tumorigenesis. Here, we assessed the global gene expression profiles induced by the HPV16 E7 oncoprotein and/or 17β-estradiol in cervical tissue of FvB and K14E7 transgenic mice. We found that the most dramatic changes in gene expression occurred in K14E7 and FvB groups treated with 17β-estradiol. A large number of differentially expressed genes involved in the immune response were observed in 17β-estradiol treated groups. The E7 oncoprotein mainly affected the expression of genes involved in cellular metabolism. Our microarray data also identified differentially expressed genes that have not previously been reported in cervical cancer. The identification of genes regulated by E7 and 17β-estradiol, provides the basis for further studies on their role in cervical carcinogenesis.

The human T-lymphotropic virus type I (HTLV-I IntroductionInfection with the retrovirus human T-lymphotropic virus type I (HTLV-I) is associated with the development of HTLV-Iassociated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). HAM/TSP is an immune-mediated inflammatory disorder of the central nervous system that leads to progressive neurologic disability in affected individuals. 1 A key mechanism in the pathogenesis of HAM/TSP is considered to be the HTLV-I-induced immune activation that supports the establishment of central nervous system inflammation. 2 Immune activation is a hallmark of HAM/TSP, as evidenced by the increased expression of lymphocyte activation markers, the induction of pro-inflammatory cytokines, and spontaneous lymphoproliferation. [3][4][5] The HTLV-I-encoded transactivating protein Tax is thought to play a role in the immune activation associated with HAM/TSP by activating hostsignaling molecules such as the cyclic AMP-responsive elementbinding protein, the serum response factor, and the nuclear factor-B (NF-B), thereby up-regulating the expression of pro-inflammatory cytokines and/or their receptors. 6 The activation of the NF-B pathway is considered a key event in the HTLV-I-induced leukemogenesis leading to ATLL, 7 but the contribution of the NF-B pathway to the pathogenesis of HAM/TSP has not been fully defined.The NF-B proteins, which include the RelA (p65), c-Rel, RelB, NF-B1 (p105/p50), and NF-B2 (100/p52) subunits, comprise a family of Rel-homology domain-containing transcription factors that play a key role in regulating inflammation. 8 NF-B signaling occurs by activation of either the canonical or the noncanonical pathways, leading to nuclear translocation of the RelA/p50 or RelB/p52 heterodimers, respectively. 9 Key signaling events involve the release of NF-B subunits from the cytoplasmic sequestration by the inhibitor of NF-B (IB), the subsequent nuclear translocation, and the binding of NF-B heterodimers to NF-B response elements that ultimately lead to gene transcription. The HTLV-I protein Tax is capable of activating both the canonical and the noncanonical NF-B pathways by interacting with the IB kinase subunits, leading to the release of NF-B from cytoplasmic sequestration. 10,11 The NF-B-dependent induction of pro-inflammatory cytokines such as [13][14][15]14 and the induction of IL-2 receptor␣ (IL-2R␣) 15 in HTLV-I-infected cells suggests that NF-B activation may play a critical role in the development of diseases associated with HTLV-I infection.To further define the contribution of NF-B activation to the pathogenesis of HAM/TSP, we compared NF-B activation in peripheral blood mononuclear cells (PBMCs) from subjects with HAM/TSP against that of healthy donors, and examined the relationship of HTLV-I viral protein expression and NF-B activation. We developed several series of novel inhibitor of NF-B targeting the DNA-binding Rel transcription factors. [16][17][18] To define the contribution of NF-B activation to immune...

Context.—Acquired mutations in the fms-like tyrosine kinase 3 gene (FLT3) adversely impact relapse risk after chemotherapy in patients with acute myeloid leukemia (AML). The FLT3 mutation status may differ at diagnosis and relapse, suggesting a potential role in chemoresistance, yet few reports have addressed the cytogenetic and pathologic correlates of FLT3 mutations in relapsed AML. Objectives.—To determine FLT3 mutations at diagnosis and relapse in a cohort of adult patients with chemoresistant AML and to correlate mutation status with multiple variables. Design.—We retrospectively determined FLT3 internal tandem duplication (FLT3/ITD) and FLT3 tyrosine kinase domain mutations in 50 diagnosis/relapse pairs. We correlated FLT3 status with karyotype, World Health Organization 2008 subtype, white blood cell count, biopsy cellularity, blast percentage, and the presence of invaginated (“cuplike”) blast nuclei. Results.—In 11 of 50 patients (22%) the FLT3 mutation status differed at relapse and diagnosis, with a trend toward gain of FLT3/ITD (n  =  7) and loss of FLT3 tyrosine kinase domain (n  =  5) mutations. FLT3-mutated AMLs correlated with the World Health Organization 2008 subtype, AML, not otherwise specified, hyperproliferative features at diagnosis and relapse, and cytogenetic evolution. FLT3-wild type AMLs correlated with the subtype AML with myelodysplasia-related changes and frequently had adverse presentation karyotypes. Cuplike blast morphology was associated with FLT3/ITD+ status and with high mutation levels. Four of 7 patients with relapse-only FLT3/ITD mutations exhibited cuplike blasts at relapse after being noncuplike at diagnosis. Conclusions.—In addition to well-known correlates in pretreatment specimens, FLT3 mutation status has pathologic and cytogenetic significance at relapse. A shift to cuplike blast morphology at relapse may herald emergence of a previously undetected FLT3/ITD mutation.

We provide aggregate statistics on U.S. dealers' bilateral repurchase agreements and economically equivalent securities lending activities. The data were collected from the U.S.-affiliated securities dealers of nine bank holding companies under a voluntary pilot program run by the Office of Financial Research (OFR) and the Federal Reserve System with input from the Securities and Exchange Commission. We found that the majority of this activity involves the delivery or receipt of U.S. Treasuries, with equities a distant second. The most common maturity is one day. Finally, rates are widely dispersed across asset classes.