Faculty Bibliography

Signal transducer and activator of transcription 3 (STAT3) is a DNA-binding transcription factor activated by multiple cytokines and interferons. High expression of STAT3 has also been implicated in cancer and lymphoma. Here, we show a case of B cell lymphoma in which a defective human immunodeficiency virus 1 (HIV-1) integrated upstream of the first STAT3 coding exon. The lymphoma cells with anaplastic large cell morphology formed multiple nodular lesions in the lung of an acquired immunodeficiency syndrome (AIDS) patient with Kaposi's sarcoma. The provirus had a 5' long terminal repeat (LTR) deletion, but the 3' LTR had stronger promoter activity than the STAT3 promoter in reporter assays. Immunohistochemistry showed increased expression of STAT3 in the nuclei of lymphoma cells. Transfection of STAT3 resulted in transient cell proliferation in primary B cells in vitro. Although this is a very rare case of HIV-1-integrated lymphoma, these data suggest that up-regulation of STAT3 caused by HIV-1 integration resulted in the development of B cell lymphoma in this special case

The success of replicating adenoviruses for cancer therapy is limited by inefficient virus delivery and poor distribution within the tumor mass. Stromal matrix within the tumor may hinder the free cell-to-cell spread of the virus. In this study, in vitro cell culture experiments showed that collagen I blocked the passage of an adenoviral vector through a membrane. On the basis of reports of the effective collagen I-degrading activity of matrix metalloproteinase-8 (MMP-8), we constructed an adenovirus to express the MMP-8 transgene (AdMMP8). A549 cells infected in vitro with AdMMP8 did not show altered growth but were able to modify a fibrillar collagen substrate to allow viral diffusion. Further, AdMMP8 did not affect replication of the wild-type virus (Adwt300). Established human A549 lung cancer and BxPC-3 pancreatic cancer xenograft tumors that were injected with Adwt300 together with the non-replicating AdMMP8 virus showed significantly reduced growth compared with control tumors. Histochemical analysis showed reduced amounts of collagen within necrotic areas of MMP-8-injected tumors compared with controls. These results demonstrate that intra-tumoral expression of MMP-8 is a possible strategy for improving viral spread and improving the oncolytic activity of replicating adenovirus

RATIONALE: Following collapse of the World Trade Center (WTC), individuals reported new-onset respiratory symptoms. Despite symptoms, spirometry often revealed normal airway function. However, bronchial wall thickening and air trapping were seen radiographically in some subjects. We hypothesized that symptomatic individuals following exposure to WTC dust may have functional abnormalities in distal airways not detectable with routine spirometry. METHODS: One hundred seventy-four subjects with respiratory symptoms and normal spirometry results were evaluated. Impedance oscillometry (IOS) was performed to determine resistance at 5 Hz, 5 to 20 Hz, and reactance area. Forty-three subjects were also tested for frequency dependence of compliance (FDC). Testing was repeated after bronchodilation. RESULTS: Predominant symptoms included cough (67%) and dyspnea (65%). Despite normal spirometry results, mean resistance at 5 Hz, 5 to 20 Hz, and reactance area were elevated (4.36 +/- 0.12 cm H(2)O/L/s, 0.86 +/- 0.05 cm H(2)O/L/s, and 6.12 +/- 0.50 cm H(2)O/L, respectively) [mean +/- SE]. Resistance and reactance normalized after bronchodilation. FDC was present in 37 of 43 individuals with improvement after bronchodilation. CONCLUSIONS: Symptomatic individuals with presumed WTC dust/fume exposure and normal spirometry results displayed airway dysfunction based on the following: (1) elevated airway resistance and frequency dependence of resistance determined by IOS; (2) heterogeneity of distal airway function demonstrated by elevated reactance area on oscillometry and FDC; and (3) reversibility of these functional abnormalities to or toward normal following administration of a bronchodilator. Since spirometry results were normal in all subjects, these abnormalities likely reflect dysfunction in airways more distal to those evaluated by spirometry. Examination of distal airway function when spirometry results are normal may be important in the evaluation of subjects exposed to occupational and environmental hazards

BACKGROUND: S-Adenosylmethionine (AdoMet) is a major methyl donor for transmethylation reactions and propylamine donor for the biosynthesis of polyamines in biological systems, and therefore may play a role in lung cancer development. We hypothesized that AdoMet levels were elevated in patients with lung cancer and may prove useful as a biomarker for early lung cancer. METHODS: High-performance liquid chromatography was used to analyze plasma AdoMet levels in triplicate samples from 68 patients. This included 13 patients with lung cancer, 33 smokers with benign lung disease, and 22 healthy nonsmokers. The three groups of subjects were compared with respect to the distribution of demographic and disease characteristics and AdoMet levels. Distributions were examined using summary statistics and box plots, and nonparametric analysis of variance procedures. RESULTS: Serum AdoMet levels were elevated in patients with lung cancer as compared to smokers with benign lung disorders and healthy nonsmokers. There were no significant correlations between AdoMet levels and tumor cell types, nodule size, or other demographic variables. CONCLUSIONS: Our data demonstrate that plasma levels of AdoMet are significantly elevated in patients with lung cancer. Plasma AdoMet levels may prove to be a useful tool for the diagnosis of early lung cancer, in combination with chest CT. Registered at: clinicaltrials.gov (NCT00301119)

BACKGROUND: Pulmonary tuberculosis (TB) can present with polymorphonuclear neutrophil (PMN)-predominant alveolitis. TB accelerates acquired immunodeficiency syndrome by increasing human immunodeficiency virus type 1 (HIV-1) replication and mutation in alveolar macrophages. A 16-kDa CCAAAT/enhancer-binding protein beta (C/EBP beta ) isoform is a strong transcriptional repressor of the HIV long terminal repeat (LTR) in resting alveolar macrophages, leading to latent viral infection; its expression is lost during TB, derepressing the HIV LTR. METHODS: Lung segments were sampled from HIV/Mycobacterium tuberculosis-coinfected patients by means of bronchoalveolar lavage. In vitro coculture experiments defined the mechanism of induction of HIV-1 infection in macrophages by PMNs. RESULTS: Lung segments from patients with PMN-predominant TB had a markedly elevated viral load. Direct contact between activated PMNs and macrophages stimulated HIV-1 replication and LTR transcription and down-regulated inhibitory C/EBP beta . Isolated PMN membranes substituted for PMN contact, derepressing the HIV-1 LTR. The lipid raft fraction of PMN membranes expressed CD40 ligand (CD40L), CD28, and leukocyte function-associated antigen 1 (LFA-1 [i.e., CD11a and CD18]), and PMN activation increased lipid raft expression of CD40L and CD28. Blocking antibodies to CD40L, CD28, and LFA-1 inhibited PMN membrane-mediated HIV-1 LTR derepression. Alternately, cross-linking of macrophage receptors for CD40L, CD28, and LFA-1 (CD40, CD80/86, and intercellular adhesion molecule 1) abolished inhibitory C/EBP beta expression. CONCLUSION: PMN-macrophage contact derepresses the HIV-1 LTR and enhances HIV-1 replication in alveolar macrophages during pulmonary TB. Derepression is mediated through costimulatory molecule signaling.

Leprosy or Hansen's disease is a chronic infectious disease caused by an acid-fast bacillus, Mycobacterium leprae (M. leprae). The bacilli proliferate in macrophages infiltrating the skin and gain entry to the dermal nerves via the laminar surface of Schwann cells where they replicate. After entry, the Schwann cells proliferate and then die. Conclusive identification of M. leprae DNA in a sample can be obtained by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for the heat shock 65 gene (hsp65). Molecular epidemiology will make it possible to study the global distributions of M. leprae, explore the relationship between genotypes-incidence rates, mode of transmission, and the type of disease (tuberculoid vs. lepromatous). We amplified DNA using PCR for the hsp65 gene from 24 skin lesions from patients diagnosed with various types of leprosy. Fifteen out of 24 were positive for the hsp65 gene. Digestion with HaeIII-PAGE for the RFLP confirmation of the presence of M. leprae DNA showed the typical pattern in 5 out of 24 and 2 novel patterns in 10 out of 24 patients. We confirmed the presence of M. leprae DNA by sequencing the genes for gyraseA or B and folP, which contained only M. leprae specific single nucleotide polymorphisms (SNPs). Thus, we describe novel hsp65 RFLPs for M. leprae found in a high frequency making them ideal for future epidemiology and transmission studies

In September 2004 the American Thoracic Society released a revised set of guidelines for the clinical diagnosis of nonmalignant asbestos-related disease (Am J Resp Crit Care Med. 2004;170:691-715). The conditions of concern are asbestosis, pleural disorders, and chronic airways obstruction. The criteria are evidence of structural lesion consistent with asbestos-related disease, evidence of causation by asbestos, and exclusion of alternative diagnoses. Findings that satisfy each are described. These guidelines are an extension of the 1986 ATS criteria and expand on them by establishing three explicit criteria, accommodating newer diagnostic modalities, recommending evaluation of impairment appropriate to the diagnosis, and outlining initial management measures following diagnosis. A history of significant asbestos exposure obligates the responsible physician to provide a management plan for the patient that takes into consideration current disease, impairment, and future risk. Persons identified as having asbestos-related disease or having significant exposure histories may benefit from management directed at preserving lung function, preventing complications, reducing the risk of lung cancer, and screening for potentially treatable asbestos-related disease including malignancies. Various issues arising since the publication of the guidelines are addressed, including evidence for pleural plaques being a marker of risk for lung disease apart from history of asbestos exposure; evidence against smoking being associated with a greater frequency of pleural plaques; an association between asbestos exposure and colon cancer; the diagnostic sensitivity of the chest film in smokers; and affirming the adequacy of findings on plain chest films as sufficient for the diagnosis of nonmalignant asbestos-related disease but not always sufficient to rule it out.