Faculty Bibliography

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

The cysteine protease inhibitor N-acetyl-leucinyl-leucinyl-norleucinal (LLnL) inhibited the growth of the Calu-1 lung carcinoma cells and induced a prolonged cell cycle arrest in the S phase. c-Jun N-terminal kinases (JNKs) participate in cellular responses to mitogenic stimuli, environmental stresses, and apoptotic signals but its role in cell cycle checkpoint control has not been elucidated. In this report, we examined the role of JNK in LLnL-induced S phase checkpoint by overexpression of a dominant-negative mutant of JNK1 (JNK1-APF) in Calu-1 cells. Expression of high levels of JNK1-APF blocked the growth-inhibitory effects of LLnL and abrogated S phase arrest induced by LLnL. These results support the role of JNK in the activation of cell cycle checkpoint induced by LLnL

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

Overexpression or activation of insulin-like growth factor I receptor (IGF-IR) has been observed in many human cancers including breast, lung, colon and gastric carcinomas. We demonstrate that inhibition of the endogenous insulin-like growth factor I receptor by stable expression of a dominant-negative IGF-IR represses the transforming activity in vitro and tumorigenicity of human lung carcinoma cells A549 in vivo. The suppression of tumorigenicity in nude mice is correlated with the induction of glandular differentiation. In addition, functional inhibition of the endogenous receptor dramatically increases the sensitivity of A549 cells to a variety of apoptotic signals including UV irradiation and proteasome inhibitors. These effects are due to the formation of a stable heterocomplex of the dominant-negative receptor with the endogenous wild type receptor which reduces the kinase activity of the latter by twofold. Thus, inhibition of the IGF-IR signaling pathway not only suppresses tumorigenicity but also enhances sensitivity to apoptosis-inducing agents. Antagonizing IGF-IR signaling by promoting tumor differentiation and enhancing sensitivity to apoptotic death are potential cancer therapeutic approaches

Soluble interleukin-2 receptor-alpha (IL-2Ralpha) has been reported to be increased in the sera of patients with advanced tuberculosis, and levels decline after therapy in accordance with improvement of radiologic findings. We investigated expression of the IL-2Ralpha in bronchoalveolar lavage (BAL) cells in active pulmonary tuberculosis, and evaluated the mechanism Mycobacterium tuberculosis induces in the IL-2Ralpha using the THP-1 mononuclear phagocyte cell line. We found IL-2Ralpha expression to be increased in BAL cells from involved sites of active pulmonary tuberculosis. Expression of the alpha-chain of IL-2Ralpha on peripheral blood monocytes (PBM) was induced by M. tuberculosis by flow cytometry evaluation. Northern analysis demonstrated increased IL-2Ralpha gene expression after stimulation with M. tuberculosis which was further induced by interferon-gamma (IFN-gamma). The IL-2Ralpha promoter containing the nuclear factor kappa B (NF-kappaB) site was transcriptionally induced by M. tuberculosis and this NF-kappaB site could confer inducibility to a heterologous herpes thymidine kinase (TK) promoter by M. tuberculosis. Electrophoretic mobility shift assays (EMSAs) revealed specific binding of nuclear protein to the NF-kappaB site upon induction with M. tuberculosis. Using antibodies against the p50 and p65 subunits of NF-kappaB in EMSAs, the involvement of both p50 and p65 proteins was further demonstrated. Functional expression of the IL-2Ralpha on mononuclear phagocytes in M. tuberculosis infection may play an important immunomodulatory role in the host response

SETTING: Several social service agencies in New York City, and the Chest Clinic of Bellevue Hospital, a large public hospital. OBJECTIVE: To determine the utility of screening as a preventive and control measure among persons at risk for tuberculosis. DESIGN: Persons seeking social services at several private agencies in New York City were screened, and those with a positive skin test or symptoms suggestive of active tuberculosis were referred to the Chest Clinic for evaluation. RESULTS: Of 3828 persons evaluated, 20 had active tuberculosis, and 33% of the screened cohort were tuberculin skin test positive. Of 466 persons with tuberculosis infection who were evaluated, only 55 persons were given isoniazid (INH), and only 20 completed preventive therapy. Most patients who were not given INH had taken it previously, were older than 35 years, or had continuing alcohol use which made physicians reluctant to prescribe isoniazid. CONCLUSION: Screening for tuberculosis may detect a significant number of cases of active disease when the background prevalence of the disease is very high. However, screening for infection as a means to prevent future cases is unlikely to be effective unless rates of administration and completion of isoniazid preventive therapy are increased

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