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Purpose: Hemostatic activation is common in pancreatic cancer and may be linked to angiogenesis and venous thromboembolism.We investigated expression of tissue factor (TF), the prime initiator of coagulation, in noninvasive and invasive pancreatic neoplasia.We correlatedTF expression with vascular endothelial growth factor (VEGF) expression, microvessel density, and venous thromboembolism in resected pancreatic cancer. Experimental Design: Tissue cores from a tri-institutional retrospective series of patients were used to build tissue microarrays. TF expression was graded semiquantitatively using immunohistochemistry in normal pancreas (n = 10), intraductal papillary mucinous neoplasms (n = 70), pancreatic intraepithelial neoplasia (n = 40), and resected or metastatic pancreatic adenocarcinomas (n = 130). Results: TF expression was observedin a majority of noninvasive and invasive pancreatic neoplasia, including 77% of pancreatic intraepithelial neoplasias, 91% of intraductal papillary mucinous neoplasms, and 89% of pancreatic cancers, but not innormalpancreas. Sixty-six of122 resectedpancreatic cancers (54%) were found to have high TF expression (defined as grade z2, the median score). Carcinomas with high TF expression were more likely to also expressVEGF (80% versus 27% with low TF expression, P < 0.0001) and had a higher median MVD (8 versus 5 per tissue core with low TF expression, P = 0.01). Pancreatic cancer patients with high TF expression had a venous thromboembolism rate of 26.3% compared with 4.5% in patients with low TF expression (P = 0.04). Conclusions: TF expression occurs early in pancreatic neoplastic transformation and is associated with VEGF expression, increased microvessel density, and possibly clinical venous thromboembolism in pancreatic cancer. Prospective studies evaluating the role of TF in pancreatic cancer outcomes are warranted.

Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies. The enzyme transport vehicle (ETV) is a lysosomal enzyme fused to an Fc domain that has been engineered to bind to the transferrin receptor, which facilitates receptor-mediated transcytosis across the BBB. We demonstrate that ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II, exhibited high intrinsic activity and degraded accumulated substrates in both IDS-deficient cell and in vivo models. ETV substantially improved brain delivery of IDS in a preclinical model of disease, enabling enhanced cellular distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a reduction in accumulated substrates in these CNS cell types and peripheral tissues and resulted in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage. These data highlight the therapeutic potential of the ETV platform for LSDs and provide preclinical proof of concept for TV-enabled therapeutics to treat CNS diseases more broadly.

June 22, 2007; doi:10.1152/ajplung.00321.2006.-Severe pulmonary arterial hypertension (PAH) occurs in idiopathic form and in association with diverse diseases. The pathological hallmarks are distal smooth muscle hypertrophy, obliteration of small pulmonary arteriole lumens, and disorganized cellular proliferation in plexiform lesions. In situ thrombosis is also observed. A detailed understanding of the disease progression has been hampered by the absence of an animal model bearing all the pathological features of human disease. To create a model with these characteristics, we gave young (200-g) rats monocrotaline 1 wk following left pneumonectomy; controls with vehicle treatment or sham operation were also studied. In experimental rats, pulmonary arteries had distal smooth muscle hypertrophy and proliferative perivascular lesions. The lesions had a plexiform appearance, occurred early in disease development, and were composed of cells expressing endothelial antigens. Three-dimensional microangiography revealed severe vascular pruning and disorganized vascular networks. We found that expression of tissue factor (TF), the membrane glycoprotein that initiates coagulation, facilitates angiogenesis, and mediates arterial injury in the systemic circulation, was increased in the pulmonary arterioles and plexiform-like lesions of the rats. TF was also heavily expressed in the vessels and plexiform lesions of humans with pulmonary arterial hypertension. We conclude that plexiform-like lesions can be reproduced in rats, and this model will facilitate experiments to address controversies about the role of these lesions in PAH. Increased TF expression may contribute to the prothrombotic diathesis and vascular cell proliferation typical of human disease. vascular biology; monocrotaline; neointimal formation; angiography PULMONARY ARTERIAL HYPERTENSION (PAH) is the marked elevation of precapillary resistance in the pulmonary circulation. It occurs in idiopathic form and in association with such diseases as congenital heart malformation, scleroderma, human immunodeficiency virus (HIV) infection, and cirrhosis (5, 7). There are few effective therapies for PAH, and even with the best available therapy, only 60% of patients live 5 yr, a striking statistic for patients whose mean age is less than 50 (14). While some progress has been made in treating patients, our understanding of the disease pathogenesis remains limited (19).In advanced PAH of many etiologies, endothelial proliferation and medial hypertrophy ultimately obliterate the arterial lumen. Most patients also have disorganized cellular proliferation in glomeruloid structures called plexiform lesions (18,23,33). Plexiform lesions are not seen in systemic arterial disease; however, these unique structures resemble vessels in a rare form of cancer, glioblastoma multiforme (33). Although the role of plexiform lesions in the progression of PAH is controversial, one study of human lung specimens supports the hypothesis that plexiform lesions precede the development of concent...

The conversion of SBA into NAB depends to some degree on the SBA titer, but other mechanisms may be involved. Once NAB have developed, the bioavailability of IFNbeta as measured by MxA is completely inhibited.

Cigarette smoke is a potent inhibitor of pulmonary T cell responses, resulting in decreased immune surveillance and an increased incidence of respiratory tract infections. The ␣,␤-unsaturated aldehydes in cigarette smoke (acrolein and crotonaldehyde) inhibited production of interleukin-2 (IL-2), IL-10, granulocyte-macrophage colony-stimulating factor, interferon-␥, and tumor necrosis factor-␣ by human T cells but did not inhibit production of IL-8. The saturated aldehydes (acetaldehyde, propionaldehyde, and butyraldehyde) in cigarette smoke were inactive. Acrolein inhibited induction of NF-B DNA binding activity after mitogenic stimulation of T cells but had no effect on induction of NFAT or AP-1. Acrolein inhibited NF-B1 (p50) binding to the IL-2 promoter in a chromatin immunoprecipitation assay by >99%. Using purified recombinant p50 in an electrophoretic mobility shift assay, we demonstrated that acrolein was 2000-fold more potent than crotonaldehyde in blocking DNA binding to an NF-B consensus sequence. Matrix-assisted laser desorption/ionization time-offlight and tandem mass spectrometry demonstrated that acrolein alkylated two amino acids (Cys-61 and Arg-307) in the DNA binding domain. Crotonaldehyde reacted with Cys-61, but not Arg-307, whereas the saturated aldehydes in cigarette smoke did not react with p50. These experiments demonstrate that aldehydes in cigarette smoke can regulate gene expression by direct modification of a transcription factor.Cigarette smoke produces profound suppression of pulmonary immunity, resulting in an increased incidence and severity of respiratory tract infections. A recent Institute of Medicine study concluded that smoking increased the incidence of influenza and bacterial pneumonia and accounted for 19,000 smoking-related deaths per year (1). Children infected with Mycobacterium tuberculosis are five times more likely to develop pulmonary tuberculosis if exposed to cigarette smoke (2), and smoking doubles the risk of developing Pneumocystis carinii pneumonia in human immunodeficiency virus-infected individuals (3). Several studies have demonstrated that smoking suppresses T and B cell responses in the lungs without affecting cells in the peripheral blood (4 -7), but little research has been done to elucidate the underlying mechanism behind this phenomenon.We have recently identified two classes of immunosuppressive compounds in cigarette smoke. The dihydroxyphenols (hydroquinone and catechol) in the particulate phase inhibit T cell proliferation by blocking cell cycle progression in late G 1 and S phase (8 -12). In addition, the ␣,␤-unsaturated aldehydes, acrolein (CH 2 ACHCHO) and crotonaldehyde (CH 3 CHACHCHO) in the gas phase of cigarette smoke inhibit the production of several proinflammatory cytokines including IL-2, 4 tumor necrosis factor-␣, and granulocyte-macrophage colony-stimulating factor, with an IC 50 of 3 and 6 M, respectively (13). The saturated aldehydes (acetaldehyde, propionaldehyde, and butyraldehyde) have IC 50 values of Ͼ1500 M. The typical cigarett...

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Lumbar spine pain accounts for 5 to 8% of athletic injuries. Although back pain is not the most common injury, it is one of the most challenging for the sports physician to diagnose and treat. Factors predisposing the young athlete to back injury include the growth spurt, abrupt increases in training intensity or frequency, improper technique, unsuitable sports equipment, and leg-length inequality. Poor strength of the back extensor and abdominal musculature, and inflexibility of the lumbar spine, hamstrings and hip flexor muscles may contribute to chronic low back pain. Excessive lifting and twisting may produce sprains and strains, the most common cause of low back pain in adolescents. Blows to the spine may create contusions or fractures. Fractures in adolescents from severe trauma include compression fracture, comminuted fracture, fracture of the growth plate at the vertebral end plate, lumbar transverse process fracture, and a fracture of the spinous process. Athletes who participate in sports involving repeated and forceful hyperextension of the spine may suffer from lumbar facet syndrome, spondylolysis, or spondylolisthesis. The large sacroiliac joint is also prone to irritation. The signs and symptoms of disc herniation in adolescents may be more subtle than in adults. Disorders simulating athletic injury include tumours and inflammatory connective tissue disease. Often, however, a specific diagnosis cannot be made in the young athlete with a low back injury due to the lack of pain localisation and the anatomic complexity of the lumbar spine. A thorough history and physical examination are usually more productive in determining a diagnosis and guiding treatment than imaging techniques. Diagnostic tests may be considered, though, for the adolescent athlete whose back pain is severe, was caused by acute trauma, or fails to improve with conservative therapy after several weeks. Radiographs, bone scanning, computed tomography, and magnetic resonance imaging may help identify, or exclude serious pathology. Fortunately, the majority of cases of low back pain in adolescents respond to conservative therapy. Immediate treatment of an acute injury, such as a sprain or strain, includes cryotherapy, electrogalvanic stimulation, anti-inflammatory medications and gentle exercises. Prolonged bed rest should be avoided since atrophy may occur rapidly. Strong analgesics are also usually contraindicated, except for sleep, since they mask pain and may allow overvigorous activity. Early strengthening exercises include the Williams flexion exercises and/or McKenzie extension exercises. Both exercise motions may often be prescribed. Athletes with an acute disc herniation, however, should only perform extension exercises initially. Athletes with spondylolysis, spondylolisthesis and facet joint irritation should initially be limited to flexion exercises.(ABSTRACT TRUNCATED AT 400 WORDS)