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1.
Anticancer Res ; 34(9): 5001-6, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25202083

ABSTRACT

Peritoneal angiosarcoma is an extremely rare sarcoma (0.01287% incidence per 100,000) with an aggressive clinical course and a poor prognosis. We herein report a case of a young man with diagnosis of angiosarcoma whose tumor adhering to the inferior wall of his bladder and omentum was initially thought to be rhabdomyosarcoma. His disease state progressively worsened, despite initiation of different types of chemotherapies. Blood was tested for cytokine and soluble receptor levels. Unexpectedly and never previously reported, very high levels of interleukin-6 (IL-6), osteopontin, and prolactin were found. Surprisingly, angiogenic cytokines levels were low. The patient died 5 months after initial presentation. In the present report, we discuss the difficulties in diagnosing this rare sarcoma and possible therapeutic targets, including the IL-6 pathway that may provide more effective ways in controlling this cancer in its metastatic stage.


Subject(s)
Hemangiosarcoma/diagnosis , Peritoneal Neoplasms/diagnosis , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers/metabolism , Biopsy , Hemangiosarcoma/drug therapy , Hemangiosarcoma/metabolism , Humans , Male , Peritoneal Neoplasms/drug therapy , Positron-Emission Tomography , Rhabdomyosarcoma/diagnosis , Rhabdomyosarcoma/drug therapy , Tomography, X-Ray Computed , Young Adult
2.
Mov Disord ; 25(6): 760-3, 2010 Apr 30.
Article in English | MEDLINE | ID: mdl-20437541

ABSTRACT

We evaluated 38 consecutive patients with corticobasal syndrome to determine if inheritance of the H1/H1 genotype influences age at onset and disease severity and if Apolipoprotein E e4 increases the risk of cognitive disturbances. Inheritance of the H1/H1 genotype was associated with severity of motor function, but did not affect age at onset or cognition. There was a trend toward shorter survival in the H1/H1 group, but this study was underpowered to test influence on survival, even though it served to estimate the sample size for future studies. ApoE inheritance did not influence cognition.


Subject(s)
Dystonia/genetics , Genetic Predisposition to Disease , Psychomotor Disorders/genetics , tau Proteins/genetics , Age of Onset , Apolipoprotein E4/genetics , Case-Control Studies , Dystonia/complications , Female , Gene Frequency , Genotype , Humans , Male , Mental Status Schedule , Middle Aged , Psychomotor Disorders/complications , Severity of Illness Index , Syndrome
3.
FASEB J ; 24(3): 799-809, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19897662

ABSTRACT

Hypoxia can cause stress and structural changes to the epithelial cytoskeleton. The intermediate filament (IF) network is known to reorganize in response to stress. We examined whether rats exposed to hypoxia had altered keratin IF expression in their alveolar epithelial type II (ATII) cells. There was a significant decrease in keratin protein levels in hypoxic ATII cells compared with those in ATII cells isolated from normoxic rats. To define the mechanisms regulating this process we studied changes to the keratin IF network in A549 cells (an alveolar epithelial cell line) exposed to 1.5% oxygen. We observed a time-dependent disassembly-degradation of keratin 8 and 18 proteins, which was associated with an increase in reactive oxygen species (ROS). Hypoxia-treated A549 cells deficient in mitochondrial DNA or A549 cells treated with a small interfering RNA against the Rieske iron-sulfur protein of mitochondrial complex III did not have increased levels of ROS nor was the keratin IF network disassembled and degraded. The superoxide dismutase (SOD)/catalase mimetic (EUK-134) prevented the hypoxia-mediated keratin IF degradation as did the overexpression of SOD1 but not of SOD2. Accordingly, we provide evidence that hypoxia promotes the disassembly and degradation of the keratin IF network via mitochondrial complex III-generated reactive oxygen species.-Na, N., Chandel, N. S., Litvan, J., Ridge, K. M. Mitochondrial reactive oxygen species are required for hypoxia-induced degradation of keratin intermediate filaments.


Subject(s)
Cell Hypoxia/physiology , Intermediate Filaments/metabolism , Keratins/metabolism , Mitochondria/metabolism , Reactive Oxygen Species/metabolism , Animals , Cell Line, Tumor , Electrophoresis, Polyacrylamide Gel , Epithelial Cells/metabolism , Fluorescent Antibody Technique , Immunoblotting , Male , Pulmonary Alveoli/cytology , RNA Interference , Rats , Rats, Sprague-Dawley
4.
Am J Respir Crit Care Med ; 179(2): 113-22, 2009 Jan 15.
Article in English | MEDLINE | ID: mdl-18948426

ABSTRACT

RATIONALE: Endothelin-1 (ET-1) is increased in patients with high-altitude pulmonary edema and acute respiratory distress syndrome, and these patients have decreased alveolar fluid reabsorption (AFR). OBJECTIVES: To determine whether ET-1 impairs AFR via activation of endothelial cells and nitric oxide (NO) generation. METHODS: Isolated perfused rat lung, transgenic rats deficient in ETB receptors, coincubation of lung human microvascular endothelial cells (HMVEC-L) with rat alveolar epithelial type II cells or A549 cells, ouabain-sensitive 86Rb+ uptake. MEASUREMENTS AND MAIN RESULTS: The ET-1-induced decrease in AFR was prevented by blocking the endothelin receptor ETB, but not ETA. Endothelial-epithelial cell interaction is required, as direct exposure of alveolar epithelial cells (AECs) to ET-1 did not affect Na,K-ATPase function or protein abundance at the plasma membrane, whereas coincubation of HMVEC-L and AECs with ET-1 decreased Na,K-ATPase activity and protein abundance at the plasma membrane. Exposing transgenic rats deficient in ETB receptors in the pulmonary vasculature (ET-B(-/-)) to ET-1 did not decrease AFR or Na,K-ATPase protein abundance at the plasma membrane of AECs. Exposing HMVEC-L to ET-1 led to increased NO, and the ET-1-induced down-regulation of Na,K-ATPase was prevented by the NO synthase inhibitor l-NAME, but not by a guanylate cyclase inhibitor. CONCLUSIONS: We provide the first evidence that ET-1, via an endothelial-epithelial interaction, leads to decreased AFR by a mechanism involving activation of endothelial ETB receptors and NO generation leading to alveolar epithelial Na,K-ATPase down-regulation in a cGMP-independent manner.


Subject(s)
Endothelin-1/pharmacology , Endothelium, Vascular/metabolism , Extravascular Lung Water/metabolism , Nitric Oxide/biosynthesis , Pulmonary Alveoli/metabolism , Receptor, Endothelin B/metabolism , Adenosine Triphosphatases/metabolism , Animals , Cyclic GMP/metabolism , Disease Models, Animal , Female , Humans , In Vitro Techniques , Lung Injury/metabolism , Male , Rats , Rats, Transgenic , Receptor, Endothelin A/metabolism , Respiratory Distress Syndrome/metabolism
5.
J Biol Chem ; 281(29): 19892-8, 2006 Jul 21.
Article in English | MEDLINE | ID: mdl-16636055

ABSTRACT

Hypoxia has been shown to cause lung edema and impair lung edema clearance. In the present study, we exposed isolated rat lungs to pO(2) = 40 mm Hg for 60 min or rats to 8% O(2) for up to 24 h and then measured changes in alveolar fluid reabsorption (AFR) and Na,K-ATPase function. Low levels of oxygen severely impaired AFR in both ex vivo and in vivo models. The decrease in AFR was associated with a decrease in Na,K-ATPase activity and protein abundance in the basolateral membranes from peripheral lung tissue of hypoxic rats. Beta-adrenergic agonists restored AFR in rats exposed to 8% O(2) (from 0.02 +/- 0.07 ml/h to 0.59 +/- 0.03 ml/h), which was associated with parallel increases in Na,K-ATPase protein abundance in the basolateral membrane. Hypoxia is associated with increased production of reactive oxygen species. Therefore, we examined whether overexpression of SOD2, manganese superoxide dismutase, would prevent the hypoxia-mediated decrease in AFR. Spontaneously breathing rats were infected with a replication-deficient human type 5 adenovirus containing cDNA for SOD2. An otherwise identical virus that contained no cDNA was used as a control (Adnull). Hypoxic Adnull rats had decreased rates of AFR (0.12 +/- 0.1 ml/h) as compared with hypoxic AdSOD2 and normoxic control rats (0.47 +/- 0.04 ml/h and 0.49 +/- 0.02 ml/h, respectively), with parallel changes in Na,K-ATPase.


Subject(s)
Adenoviridae/genetics , Bronchoalveolar Lavage Fluid/virology , Cell Hypoxia/physiology , Pulmonary Alveoli/physiology , Receptors, Adrenergic, beta/physiology , Sodium-Potassium-Exchanging ATPase/metabolism , Superoxide Dismutase/genetics , Animals , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Viral , Oxygen , Partial Pressure , Pulmonary Edema/prevention & control , Rats
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