Citations

ABSTRACT The measles virus P gene products V and C antagonize the host interferon (IFN) response, blocking both IFN signaling and production. Using Moraten vaccine strain-derived measles virus and isogenic mutants deficient for either V or C protein production (V ko and C ko , respectively), we observed that the C ko virus was a potent inducer of IFN-β, while induction by V ko virus was an order of magnitude lower than that by the C ko virus. The parental recombinant Moraten virus did not significantly induce IFN-β. The enhanced IFN-inducing capacity of the C ko virus correlated with an enhanced activation of IFN regulatory factor 3 (IRF-3), NF-κB, and ATF-2 in C ko -infected compared to V ko or parental virus-infected cells. Furthermore, protein kinase PKR and mitochondrial adapter IPS-1 were required for maximal C ko -mediated IFN-β induction, which correlated with the PKR-mediated enhancement of mitogen-activated protein kinase and NF-κB activation. Our results reveal multiple consequences of C protein expression and document an important function for PKR as an enhancer of IFN-β induction during measles virus infection.

Renal interstitial fibrosis is a major determinant of renal failure in the majority of chronic renal diseases. Transforming growth factor-β (TGF-β) is the single most important cytokine promoting renal fibrogenesis. Recent in vitro studies identified novel non-smad TGF-β targets including p21-activated kinase-2 (PAK2), the abelson nonreceptor tyrosine kinase (c-Abl), and the mammalian target of rapamycin (mTOR) that are activated by TGF-β in mesenchymal cells, specifically in fibroblasts but less in epithelial cells. In the present studies, we show that non-smad effectors of TGF-β including PAK2, c-Abl, Akt, tuberin (TSC2), and mTOR are activated in experimental unilateral obstructive nephropathy in rats. Treatment with c-Abl or mTOR inhibitors, imatinib mesylate and rapamycin, respectively, each blocks noncanonical (non-smad) TGF-β pathways in the kidney in vivo and diminishes the number of interstitial fibroblasts and myofibroblasts as well as the interstitial accumulation of extracellular matrix proteins. These findings indicate that noncanonical TGF-β pathways are activated during the early and rapid renal fibrogenesis of obstructive nephropathy. Moreover, the current findings suggest that combined inhibition of key regulators of these non-smad TGF-β pathways even in dose-sparing protocols are effective treatments in renal fibrogenesis.

Abstract The head and neck region is a frequent site for potentially confusing incidental benign findings not related to the primary pathologic process and having no impact on patient prognosis. Several lesions are thymic in origin. We report 3 cases of lymphocyte-poor thymic remnants identified in central cervical (level VI) lymph node dissections for unrelated benign and malignant pathology. In each, the rests were nearly completely composed of bland epithelial cells with rare admixed lymphocytes. These cells were immunophenotypically similar to thymic epithelial cells, although they differed in the paucity of associated thymic lymphocytes and lack of Hassall corpuscles. Lymphocyte-depleted thymic remnants in the central cervical compartment are not well described in the literature. It is important to be aware of these and other benign inclusions to avoid making incorrect diagnoses of malignancy.

After decades of disuse because of its teratogenic effects, thalidomide has had a resurgence of use as a promising therapeutic agent for multiple myeloma. Its mechanism of action involves activation of the immune system, antiangiogenic effects, and inhibition of cytokines. Thalidomide does not interact with the cytochrome oxidase system. It is not significantly metabolized, but it does undergo nonenzymatic hydrolysis in plasma. The resulting products are inactive. Despite the potential adverse effects of peripheral neuropathy, constipation, deep vein thrombosis, somnolence, rash, and orthostatic hypotension, thalidomide is an effective first-line agent for multiple myeloma in combination with dexamethasone or melphalan and prednisone. It has also been studied in the palliative care of patients with cytokine-based syndromes such as anorexia-cachexia syndrome. This review describes its use in oncology, hematology, and palliative care.

Abstract The Sleeping Beauty (SB) transposon system has been used as a somatic mutagen to identify candidate cancer genes. In previous studies, efficient leukemia/lymphoma formation on an otherwise wild-type genetic background occurred in mice undergoing whole-body mobilization of transposons, but was accompanied by high levels of embryonic lethality. To explore the utility of SB for large-scale cancer gene discovery projects, we have generated mice that carry combinations of different transposon and transposase transgenes. We have identified a transposon/transposase combination that promotes highly penetrant leukemia/lymphoma formation on an otherwise wild-type genetic background, yet does not cause embryonic lethality. Infiltrating gliomas also occurred at lower penetrance in these mice. SB-induced or accelerated tumors do not harbor large numbers of chromosomal amplifications or deletions, indicating that transposon mobilization likely promotes tumor formation by insertional mutagenesis of cancer genes, and not by promoting wide-scale genomic instability. Cloning of transposon insertions from lymphomas/leukemias identified common insertion sites at known and candidate novel cancer genes. These data indicate that a high mutagenesis rate can be achieved using SB without high levels of embryonic lethality or genomic instability. Furthermore, the SB system could be used to identify new genes involved in lymphomagenesis/leukemogenesis. [Cancer Res 2009;69(21):8429–37]