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Glucocorticoids inhibit lung cancer cell growth through both the extracellular signal-related kinase pathway and cell cycle regulators

Greenberg, Alissa K; Hu, Jing; Basu, Sharmila; Hay, John; Reibman, Joan; Yie, Ting-An; Tchou-Wong, Kam Meng; Rom, William N; Lee, Theodore C
Glucocorticoids inhibit the proliferation of various cell types, but the mechanism of this inhibition remains unclear. We investigated the effect of dexamethasone on non-small cell lung cancer cell growth and cell cycle progression. We showed that dexamethasone suppresses the proliferation of A549 and Calu-1 cells, with accumulation of cells in G1/G0 stage of the cell cycle, as determined by fluorescence-activated cell sorter analysis. Western blot analysis confirmed that this is associated with hypophosphorylation of retinoblastoma protein. Using Western blot analysis and in vitro kinase assays, we found that dexamethasone results in decreased activity of CDK2 and 4, decreased levels of cyclin D, E2F, and Myc, and increased levels of the CDK inhibitor p21(Cip1). In addition, we found that dexamethasone decreases activity of extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK). The kinetics of all these changes indicate that inhibition of the ERK/MAPK pathway precedes the cell cycle effects, suggesting that regulation of this MAPK-signaling pathway may be an alternative mechanism for glucocorticoid-induced cell cycle arrest and growth inhibition
PMID: 12204894
ISSN: 1044-1549
CID: 39599

Recollection memory deficits in patients with major depressive disorder predicted by past depressions but not current mood state or treatment status

MacQueen, G M; Galway, T M; Hay, J; Young, L T; Joffe, R T
BACKGROUND: Neuropsychological studies have suggested that memory systems reliant on medial temporal lobe structures are impaired in patients with depression. There is less data regarding whether this impairment is specific to recollection memory systems, and whether clinical features predict impairment. This study sought to address these issues. METHOD: A computerized process-dissociation memory task was utilized to dissociate recollection and habit memory in 40 patients with past or current major depression and 40 age, sex and IQ matched non-psychiatric control subjects. The Cognitive Failures Questionnaire was used to assess patients' perceptions of day-to-day memory failures. RESULTS: Patients had impaired recollection memory (t = 4.7, P < 0.001), but no impairment in habit memory when compared to controls. Recollection memory performance was not predicted by indices of current mood state, but was predicted by self-assessments of impairment (beta = -0.33; P = 0.008) and past number of depressions (beta = -0.41; P = 0.001). There was no evidence that standard therapy with antidepressant medication either improved or worsened memory performance. CONCLUSIONS: The results confirm that patients with multiple past depressions have reduced function on recollection memory tasks, but not on habit memory performance. The memory deficits were independent of current mood state but related to past course of illness and significant enough that patients detected impairment in day-to-day memory function
PMID: 11866320
ISSN: 0033-2917
CID: 139188

Wild-type adenovirus decreases tumor xenograft growth, but despite viral persistence complete tumor responses are rarely achieved-deletion of the viral e1b-19-kd gene increases the viral oncolytic effect

Harrison D; Sauthoff H; Heitner S; Jagirdar J; Rom WN; Hay JG
Strategies to target viral replication to tumor cells hold great promise for the treatment of cancer, but even with replicating adenoviruses complete tumor responses are rarely achieved. To evaluate replicating adenoviral vectors, we have used A549 human lung cancer nude mouse xenografts as a model system. Intratumoral injection of wild-type adenovirus (Ad309) significantly reduced tumor growth from day 14 (p = 0.04) onward; however, tumor volumes reached a plateau at day 50. At 100 days, high levels of titratable virus were present within persistent viable tumors. In contrast to viral injection into established tumors, when tumor cells were infected in vitro with wild-type virus and then mixed with uninfected tumor cells, 1% of infected cells was sufficient to prevent tumor establishment. An E1b-19kD-deleted viral mutant (Ad337) was more efficient than Ad309 in this cell-mixing model. Just 1 cell in 1000 infected with Ad337 prevented tumor growth. However, although better than wild-type virus, Ad337 was unable to eradicate established flank tumors. These data suggest that although replicating adenoviruses exhibit significant oncolytic activity, barriers within the established tumor, such as connective tissue and tumor matrix, may limit the spread of virus. Strategies to enhance viral spread through established tumors are therefore likely to greatly improve the therapeutic efficacy of replicating adenoviruses
PMID: 11440625
ISSN: 1043-0342
CID: 21145

Replicating adenoviral vectors persist in tumor xenographs for up to 100 days but viral spread is insufficient to support tumor eradication [Meeting Abstract]

Sauthoff, H; Harrison, D; Heitner, S; Rom, WN; Hay, JG
ISI:000165643400045
ISSN: 0929-1903
CID: 54416

Hut lung. A domestically acquired particulate lung disease [In Process Citation] [Case Report]

Gold JA; Jagirdar J; Hay JG; Addrizzo-Harris DJ; Naidich DP; Rom WN
We report an illustrative case of advanced 'hut lung,' or domestically acquired particulate lung disease (DAPLD), in a recently emigrated nonsmoking Bangladeshi woman with a history of 171 hour-years of exposure to biomass smoke. She presented with symptoms of chronic cough, dyspnea, and early parenchymal lung disease. High-resolution computed tomography (CT) of the chest demonstrated numerous 2- to 3-mm nodules, sparing the pleural surface. To our knowledge, this is the first such report of CT findings in the literature. Bronchoscopy yielded typical anthracotic plaques and diffuse anthracosis with interstitial inflammation on histopathologic examination of biopsy specimens. DAPLD is potentially the largest environmentally attributable disorder in the world, with an estimated 3 billion people at risk. Caused by the inhalation of particles liberated from the combustion of biomass fuel, DAPLD results in significant morbidity from infancy to adulthood. Clinically, DAPLD manifests a broad range of disorders from chronic bronchitis and dyspnea to advanced interstitial lung disease and malignancy. While a detailed environmental history is essential for making the diagnosis in most individuals, for patients with advanced DAPLD, invasive modalities such as bronchoscopy with transbronchial biopsy and examination of bronchoalveolar lavage fluid help differentiate it from other diseases. Recognition of this syndrome and removal of the patient from the environment is the only treatment. The development of well-controlled interventional trials and the commitment of sufficient resources to educate local populaces and develop alternative fuel sources, stove designs, and ventilation are essential toward reducing the magnitude of DAPLD
PMID: 11039079
ISSN: 0025-7974
CID: 15397

Molecular and genetic aspects of lung cancer

Rom WN; Hay JG; Lee TC; Jiang Y; Tchou-Wong KM
PMID: 10764334
ISSN: 1073-449x
CID: 11754

Deletion of the adenoviral E1b-19kD gene enhances tumor cell killing of a replicating adenoviral vector

Sauthoff H; Heitner S; Rom WN; Hay JG
Replicating adenoviral vectors are a promising new modality for cancer treatment and clinical trials with such vectors are ongoing. Targeting these vectors to cancer cells has been the focus of research. However, even if perfect targeting were to be achieved, a vector still must effectively kill cancer cells and spread throughout the bulk of the tumor. The adenoviral E1b-19kD protein is a potent inhibitor of apoptosis and may therefore compromise the therapeutic efficacy of an adenoviral vector. In this study we have investigated if an E1b-19kD gene deletion could improve the ability of a replicating adenoviral vector to spread through and kill cancer cells. In several lung cancer cell lines an E1b-19kD-deleted virus (Ad337) induced substantially more apoptosis than did a wild-type virus (Ad309), and tumor cell survival was significantly reduced in three of four cell lines. In addition, the apoptotic effects of cisplatin or paclitaxel were augmented by Ad337, but inhibited by wild-type virus. The number of infectious virus particles in the supernatant of infected cells was increased with Ad337 compared with wild-type virus, indicating enhanced early viral release. Ad337, in contrast to Ad309, induced significantly larger plaques after infection of A549 cells. This well-described large plaque phenotype of an E1b-19kD mutant virus is likely the result of early viral release and enhanced cell-to-cell viral spread. Loss of E1b-19kD function caused only minor cell line-specific increase or decrease in viral yield. We conclude that deletion of the E1b-19kD gene may enhance the tumoricidal effects of a replicating adenoviral vector
PMID: 10697113
ISSN: 1043-0342
CID: 8543

Deletion of the E1b-19-kDa gene enhances the tumoricidal effect of a replicating adenoviral vector [Meeting Abstract]

Sauthoff K; Heitner S; Rom WN; Hay JG
BACKGROUND, Fine-needle aspiration biopsy (FNA) has been successful in diagnosing epithelial lesions of the breast. Its role in the evaluation of spindle cell and mesenchymal lesions of the breast, which include a variety of benign and malignant conditions, is less clear. This article discusses the cytologic features and differential diagnosis of these lesions, as well as the potential diagnostic pitfalls associated with them. METHODS, FNAs of the breast, in which a spindle cell or mesenchymal component was a key or dominant feature, were retrieved. Fibroadenomas without cellular stroma and typical lipomas were excluded. RESULTS. Forty-six aspirates (0<87%) in a series of 5306 breast FNAs contained a significant spindle cell or mesenchymal component. The aspirates were classified into 4 categories: 1) reactive conditions, including 2 diabetic mastopathies, 3 granulation tissue specimens, and 7 granulomatous lesions; 2) benign neoplastic conditions, including 1 mammary hamartoma, 1 dermatofibroma, 1 fibromatosis, 2 granular cell tumors, 2 angiolipomas, and 7 cellular fibroadenomas; 3) low grade malignant neoplastic lesions, including 10 low grade phyllodes tumors; and 4) high grade malignant neoplastic lesions, including 1 metaplastic carcinoma with chondroid stroma, 1 pleomorphic liposarcoma, 2 malignant fibrous histiocytomas, 2 osteosarcomas, and 4 metastatic melanomas. A specific diagnosis was rendered in 38 cases (82<6%). The mammary hamartoma was diagnosed as fibrocystic changes; the dermatofibroma as benign spindle cell lesion, not otherwise specified (NOS); and the primary osteosarcoma as an atypical spindle cell proliferation, NOS. The reactive ductal epithelial cells in one of the granulomatous mastitis specimens, as well as the hyperplastic ductal epithelial cells in one of the phyllodes tumors, were interpreted as atypical ductal proliferation. The marked cytologic atypia displayed by one granular cell tumor was interpreted as low grade adenocarcinoma and the primary liposarcoma as poorly differentiated carcinoma. CONCLUSIONS. Breast lesions with a significant spindle cell or mesenchymal component are rarely encountered in FNA and constitute a heterogeneous group that may pose a diagnostic dilemma FNA should be the initial diagnostic procedure for investigating these lesions, as a specific diagnosis was rendered in the majority of cases. Cancer (Cancer Cytopathol) 1999;87:359-71. (C) 1999 American Cancer Society
ORIGINAL:0004114
ISSN: 0929-1903
CID: 8605

Targeting the replication of adenoviral gene therapy vectors to lung cancer cells: the importance of the adenoviral E1b-55kD gene

Hay JG; Shapiro N; Sauthoff H; Heitner S; Phupakdi W; Rom WN
It has been proposed that an adenovirus with the E1b-55kD gene deleted has a selective advantage in replicating in cancer cells that have mutations in the p53 gene (Bischoff et al., 1996). We have explored this hypothesis in several lung cancer cell lines, and evaluated potential mechanisms that might regulate the replication of Ad338, an E1b-55kD-deleted virus, with the objective of developing a rational approach for targeting gene therapy to lung tumors. Our data show that Ad338 replicates poorly in three lung cancer cell lines with various p53 mutations (H441, H446, and Calu1), yet this virus replicates to a high level in a lung cancer cell line with wild-type p53 (A549) and in a normal lung fibroblast line (IMR90). Viral DNA replication, expression of viral proteins, and shutoff of host cell proteins were not important variables in limiting the replication of the E1b-55kD-deleted virus. However, the cell lines resistant to host cell protein shutoff were also the most resistant to the cytopathic effect induced by mutant and wild-type virus and the only cells to survive for 8 days following infection. The E1b-55kD protein clearly has an important role in viral replication beyond its interaction with p53. Thus, an E1b-55kD-deleted virus cannot be used to specifically target viral replication to p53-mutated lung cancer cells
PMID: 10094201
ISSN: 1043-0342
CID: 7342

An E1b-55kD deleted adenovirus vector does not target p53 mutated lung cancer cells by specific viral replication [Meeting Abstract]

Sauthoff, H; Shapiro, N; Heitner, S; Phupakdi, W; Rom, WN; Hay, JG
ISI:000082237101289
ISSN: 1073-449x
CID: 53872