Transforming growth factor ␤ (TGF␤) is a pleiotropic factor that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGF␤ pathway in tumor cells often leads to resistance to the antiproliferative effects of TGF␤ while supporting other cellular processes that promote tumor invasiveness and growth. In the present study, SD-208, a 2,4-disubstituted pteridine, ATP-competitive inhibitor of the TGF␤ receptor I kinase (TGF␤RI), was used to inhibit cellular activities and tumor progression of PANC-1, a human pancreatic tumor line. SD-208 blocked TGF␤-dependent Smad2 phosphorylation and expression of TGF␤-inducible proteins in cell culture. cDNA microarray analysis and functional gene clustering identified groups of TGF␤-regulated genes involved in metastasis, angiogenesis, cell proliferation, survival, and apoptosis. These gene responses were inhibited by SD-208. Using a Boyden chamber motility assay, we demonstrated that SD-208 inhibited TGF␤-stimulated invasion in vitro. An orthotopic xenograft mouse model revealed that SD-208 reduced primary tumor growth and decreased the incidence of metastasis in vivo. Our findings suggest mechanisms through which TGF␤ signaling may promote tumor progression in pancreatic adenocarcinoma. Moreover, they suggest that inhibition of TGF␤RI with a small-molecule inhibitor may be effective as a therapeutic approach to treat human pancreatic cancer.

Transforming growth factor-␤ (TGF␤) is a major mediator of normal wound healing and of pathological conditions involving fibrosis, such as idiopathic pulmonary fibrosis. TGF␤ also stimulates the differentiation of myofibroblasts, a hallmark of fibrotic diseases. In this study, we examined the underlying processes of TGF␤RI kinase activity in myofibroblast conversion of human lung fibroblasts using specific inhibitors of TGF␤RI (SD-208) and p38 mitogen-activated kinase (SD-282). We demonstrated that SD-208, but not SD-282, inhibited TGF␤-induced SMAD signaling, myofibroblast transformation, and collagen gel contraction. Furthermore, we extended our findings to a rat bleomycin-induced lung fibrosis model, demonstrating a significant decrease in the number of myofibroblasts at fibroblastic foci in animals treated with SD-208 but not those treated with SD-282. SD-208 also reduced collagen deposition in this in vivo model. Microarray analysis of human lung fibroblasts identified molecular fingerprints of these processes and showed that SD-208 had global effects on reversing TGF␤-induced genes involved in fibrosis, inflammation, cell proliferation, cytoskeletal organization, and apoptosis. These studies also revealed that although the p38 pathway may not be needed for appearance or disappearance of the myofibroblast, it can mediate a subset of inflammatory and fibrogenic events of the myofibroblast during the process of tissue repair and fibrosis. Our findings suggest that inhibitors such as SD-208 may be therapeutically useful in human interstitial lung diseases and pulmonary fibrosis.

We have generated transgenic mice expressing a kinase-deficient type II transforming growth factor-␤ (TGF␤) receptor selectively on fibroblasts (T␤RII⌬k-fib). These mice develop dermal and pulmonary fibrosis. In the present study we explore activation of TGF␤ signaling pathways in this strain and examine the profibrotic properties of explanted transgenic fibroblasts including myofibroblast differentiation and abnormal metalloproteinase production. Gene expression profiles of littermate wild type or transgenic fibroblasts were compared using high-density gene arrays and validated by Taqman reverse transcriptase-PCR, Northern and Western blotting. Using a specific inhibitor (SD-208) we demonstrate that the abnormal phenotype of these cells is dependent upon T␤RI kinase (ALK5) activity, and that transgenic fibroblasts show enhanced expression and activation of TGF␤ together with increased levels of wild type T␤RII. Moreover, we confirm that transgene expression is itself regulated by TGF␤ and that expression at low levels facilitates signaling, whereas high level expression is inhibitory. For a subset of TGF␤ responsive genes basal up-regulation is normalized or suppressed by exogenous recombinant TGF␤1 at time points coincident with increased transgene expression. These findings explain the profound refractoriness of T␤RII⌬k-fib fibroblasts to exogenous TGF␤1, despite their activated phenotype. Thus, transgenic fibroblasts recapitulate many hallmark biochemical properties of fibrotic cells, including high level CTGF (CCN2) expression and type I collagen overproduction, altered MMP production, and myofibroblast differentiation. These cells also show an enhanced ability to contract collagen gel matrices. Our study demonstrates that altered high affinity TGF␤ receptor function may lead to ligand-dependent activation of downstream signaling, and provides further evidence of a pivotal role for sustained TGF␤ overactivity in fibrosis.

In the H,S promoted oxidative dehydrogenation of ethane to ethylene, high once through conversions and selectivities ( -90%) have been achieved. This is due to the abstraction of hydrogen from ethane by active sulphur produced by the "in situ" reaction between H2S and 0, in the presence of a suitable catalyst. The extensive catalyst screening programme carried out to achieve the above results is described. The effect of processing conditions, e.g. temperature, space velocity and diluent type and amount, using one of the better catalysts found, i.e. cadmium on alundum is discussed.thylene is one of the largest volume petrochemicals E in the world today. I t is used mainly in the production of polyethylene, ethylene oxide, ethyl alcohol and styrene, and is manufactured predominantly by a variety of different thermal cracking processes USing feedstocks ranging from ethane to heavy fuel oils. However, because product complexity increases markedly as the molecular weight of the feed increases, ethane is theoretically the ideal feedstock for ethylene manufacture and high conversions and selectivities are obtained in the following pyrolytic dehydrogenation reaction : CzHe C2H4 + H2.In a fixed tubular furnace, a 60% per pass ethane conversion and an 80 mole % ethylene selectivity are typical of those obtained in the thermal process"'. The loss of selectivity is due mainly to the formation of methane, propylene, butylene and C5/400"F. naphtha a t the high reaction temperatures (>1500"F.) in the cracking furnace.In an attempt to achieve even higher ethane conversions and ethylene selectivities than those indicated above an experimental programme was initiated using the H B promoted oxidative dehydrogenation process described in an earlier paper for the dehydrogenation of butene to butadieneC2'. I t was thought that very high ethylene yields could be obtained if the equilibrium limitation of reaction (1) could be removed by the use of the new oxydehydrogenation technique. The reactions involved can be written :It was realized, however, that in order to obtain high olefin yields from a paraffinic feed it would be necessary to define a suitable catalyst to promote the oxidative reaction and/or minimize the uncontrolled combustion of hydrocarbon. All previous w~r k '~,~,~) had been carried out on the dehydrogenation of an olefinic feed and paraffin dehydrogenation is a much more difficult process to accomplish successfully. It is the purpose of this paper to indicate the extent of the H,S Dam la deshydrogknation par oxydation de I'hthane en Cthylhne favorishe par H,S, on a obtenu des degres ClevCs de transformation et de s8ectivit6 ( -90%); cela est dO B la capture de I'hydroghe de I'kthane par le soufre actif produit par la rtaction "in situ" entre H2S et 02, en prbence dun catalyseur appropriC. On dCcrit le vaste programme d'examen selectif des catalyseurs qu'on a suivi pour rbliser les resultats precitks. On discute l'effet des conditions de traitement, telles que temperature, v8ocit6 spatiale, genre et quantitk de diluant,...

The H2S promoted oxidative dehydrogenation of butane to butadiene can be efficiently carried out if a molten salt medium, e.g. LiCl/KCl, is used to dissipate the heat from the highly exothermic reaction. The reaction is catalyzed by the addition of soluble salts such at Tl2O3, BaCl2 or MnCl2. Optimization of reaction conditions by varying temperature, space velocity and quantity of promoter results in a 53% olefin yield (5% butenes, 48% butadiene) at 80% butane conversion. The system is also shown to be efficient for the dehydrogenation of ethane to ethylene, propane to propylene, butene to butadiene and ethylbenzene to styrene.