Faculty Bibliography

BACKGROUND: The p53 tumor suppressor gene is altered in up to 70% of colorectal cancers. MATERIALS AND METHODS: We infected the colorectal cancer cell lines SW620 and KM12L4, in which p53 is mutated, with the replication-defective adenovirus Ad5/CMV/p53 to evaluate the effects of adenovirus-mediated wild-type p53 gene transfer. Gene transduction was measured by cytochemical staining of cells infected with the Ad5/CMV/beta-gal virus and expression of the wildtype p53 protein in these cells was demonstrated by immunoblotting. RESULTS: Significant suppression of in vitro cell proliferation and induction of apoptosis (as measured by TUNEL assay labeling) were observed following Ad5/CMV/p53 infection. More importantly, similar effects were observed in vivo in an established nude mouse subcutaneous tumor model; significant suppression of tumor growth (60%-70%) and induction of apoptosis were observed following intratumoral injections of Ad5/CMV/p53. CONCLUSION: This form of therapy may provide a novel approach to colorectal cancer.

The pathogenesis of emphysema is considered to be an imbalance of protease and antiprotease activity in the lower respiratory tract leading to uninhibited degradation of lung interstitium by elastolytic enzymes. An increased amount of the serine protease neutrophil elastase (NE) is though to play a major role in this degradation. Because the expression of NE is limited to neutrophil precursors in the bone marrow, we hypothesized that nicotine, which is readily absorbed from lung and distributed to tissue, including bone marrow, would increase expression of the NE gene and protein. HL-60 cells, a myeloblast/promyelocyte cell line, were cultured in the presence or absence of 0.06 and 0.8 microM nicotine for 5 d. Both concentrations of nicotine caused a 2.4- to 3.3-fold increase, respectively, in NE gene expression over unstimulated cells, and NE protein increased 4.8- to 3.4-fold over unstimulated cells, respectively, similar to our positive control DMSO. Nicotine did not induce upregulation of the NE gene by initiating cell differentiation. Both low and high nicotine concentrations upregulate the NE gene in HL-60 cells leading to increased NE protein concentration per cell suggesting a pathophysiologic mechanism for emphysema

Fluoroquinolones are potent antibacterial agents being used clinically against multidrug-resistant tuberculosis. Treatment failure is thought to arise from acquisition of fluoroquinolone resistance by Mycobacterium tuberculosis. A collection of 13 resistant clinical isolates of M. tuberculosis was examined for ciprofloxacin sensitivity relative to controls exhibiting the same IS6110 DNA type. Specific alleles were associated with distinct levels of drug susceptibility for 11 isolates that contained nucleotide changes expected to alter the amino acid sequence of the A subunit of DNA gyrase. Five different gyrA (ciprofloxacin resistance) alleles were present among 7 isolates having the W DNA subtype. These isolates, which are representative of an outbreak strain, constitute a panel of organisms that can be used to evaluate contributions of gyrase and DNA topoisomerase IV to resistance

A collection of 24 rifampin-resistant clinical isolates of Mycobacterium tuberculosis with characterized RNA polymerase beta-subunit (rpoB) gene mutations was tested against the antimycobacterial agents rifampin, rifapentine, and KRM-1648 to correlate levels of resistance with specific rpoB genotypes. The results indicate that KRM-1648 is more active in vitro than rifampin and rifapentine, and its ability to overcome rifampin resistance in strains with four different genetic alterations may prove to be useful in understanding structure-function relationships

An examination of the pattern of lipid biosynthetic responses to isoniazid (INH) treatment of Mycobacterium tuberculosis and Mycobacterium smegmatis suggests that the mode of action of activated INH differs between these 2 organisms. Transformation of M. smegmatis with inhA on a plasmid construct conferred high-level resistance to INH, while the same construct failed to confer resistance upon M. tuberculosis. The inhA region from 2 clinical isolates whose resistance has been attributed to changes in the upstream promoter region has been cloned and was not sufficient to impart INH resistance to the level of the parent strain on sensitive M. tuberculosis. These putative mutant promoter elements appear to elevate expression levels of gene fusion reporter constructs, suggesting some noncausal connection between the observed mutations and the lipid metabolism of drug-resistant organisms. These results suggest that InhA is not the major target for activated INH in M. tuberculosis

A series of 2,3-dihydro-1H-pyrrolo[1,2-a]indoles were prepared as analogs of the active intermediates of the natural products, mitomycin C and FR900482, and their reactions with various nucleophiles were studied

Dr. Francis S. Collins, the head of the government's project to map all human genes, said Tuesday that he is retracting five research papers on leukemia in leading scientific journals because a junior colleague fabricated data. The flawed papers involved laboratory research on the role of a defective gene in producing acute leukemia. The research did not involve patients or treatment of the disease. Upon learning of the problem in mid-August, Collins said in an interview, he 'thought it was an isolated instance whereby a trainee in my laboratory manipulated the data.'

Dr. Francis S. Collins, the head of the government's project to map all human genes, said yesterday that he was retracting five research papers on leukemia in leading scientific journals because a junior colleague fabricated data. On learning of the problem in mid-August, Collins said in an interview, he 'thought it was an isolated instance whereby a trainee in my laboratory manipulated the data.' Collins and officials at the institutes declined to name the student for legal reasons. But the student was identified as Amitov Hajra through an examination of the papers that Collins said he is retracting. One paper lists only two authors, Hajra and Collins

According to preliminary findings from a small study, the skin tumors of Kaposi's sarcoma, the most common form of cancer among people with AIDS, often yielded to injections of human chorionic gonadotropin, or hCG, a hormone produced in pregnancy. The study of 36 men is being reported on Oct 24, 1996 in the New England Journal of Medicine