CD4 responses to conserved HIV-1 T helper epitopes show both negative and positive associations with virus load in chronically infected subjects

Characterization of immune responses to immunodominant CD4 epitopes in HIV-1 that are associated with control of HIV infection could be used to strengthen the efficacy of polyepitope HIV vaccines. We measured both the proliferative and the CD4 interferon (IFN)-gamma and interleukin (IL)-2 cytokine responses specific for 11 previously identified HIV-1 T helper epitopes in 10 HIV-infected non-progressors (LTNPs) (infected for a median of 15 years with a stable CD4 count of >500 cells x 10(6)/l), and seven slow progressors (SPs) (infected for a median of 15 years with a CD4 count that had declined to <500 cells x 10(6)/l). Both groups were antiretroviral treatment-naive at the time of evaluation. The median virus load of SP group was higher than that of the LTNP group (P = 0.0002). The CD4 response to a peptide pool representing all potential CD4 Gag epitopes and to Gag p24 protein was also studied. Compared to SPs, LTNPs had higher numbers of Gag-specific IFN-gamma+IL-2+ CD4s (P = 0.0059). The Gag-specific cytokine and proliferative responses correlated inversely with virus load (P = 0.03 and 0.0002, respectively), highlighting the potential importance of this response in immunity to HIV. A direct correlation was noted between proliferation and the Gag-specific IL-2 (P = 0.0053) rather than IFN-gamma response (P = 0.1336), demonstrating that the proliferation assay reflected the IL-2 rather than the IFN-gamma secreting capacity of CD4 cells. Several subjects with diverse class II DRB1 alleles responded, confirming the 11 selected peptides to be both antigenic and conserved. CD4 cytokine responses to one Gag and two conserved Pol peptides correlated negatively with virus load. The cytokine response to two additional Pol peptides correlated positively with virus load. The data indicate that there is not an absolute correlation between the CD4 immune response to conserved and broadly antigenic helper T cell epitopes in HIV non-progression.     

The response to DNA damage induced by 4-nitroquinoline-1-oxide or its 3-methyl derivative in xeroderma pigmentosum fibroblasts belonging to different complementation groups: evidence for different epistasis groups involved in the repair of large adducts in human DNA

The data in this paper show that when the inhibition of growthis measured, xeroderma pigmentosum (XP) complementation groupsA, G and D are very sensitive to 4-nitroquinoline-1-oxide (4NQO),whereas only XP groups G and D are very sensitive to 3-methyl-4NQO(3me4NQO). Cells belonging to XP-C group are not particularlysensitive to either agent. Thus there are different epistasisgroups for the excision repair of DNA adducts induced by theseagents as opposed to the repair of u.v. damage. DNA polymerase is involved in the repair of 4NQO-induced lesions because aphidicolinblocks their repair. XP cells from all the above groups aredefective to some extent in this repair. The degree of repairdefectiveness follows that seen after u.v., with even the XP-Ccell line used having reduced repair (despite the fact thatthe inhibition of growth by 4NQO in this cell line was not markedlydifferent from normal). Aphidicolin did not induce breaks inthe normal or XP cell lines exposed to 3me4NQO, thus the repairof lesions induced by 3me4NQO does not involve DNA polymerase in any of the cell lines. Finally, catalase reduces the alkalinelabile lesions induced by 4NQO, but not 3me4NQO, suggestingthe latter agent does not induce substantial amounts of DNAdamage by the generation of radicals.     

Success of Maternal and Child Health Pipeline Training Programs: Alumni Survey Results

Maternal and Child Health Journal - The Maternal and Child Health (MCH) Pipeline Training Program, promotes development of a diverse health workforce by training undergraduate students from...     

The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

Current Status of the VU MFEL Compton X-Ray Program

The Vanderbilt University medical FEL (free electron laser) Compton x-ray program is close to being operational. The FEL modifications necessary for this new capability are near completion. The transport and detection systems for electron and IR beams have been designed, delivered, and tested. We initially expect to produce 108 x-ray photons per second in the 15- to 20-keV region.     

EFFICACY OF SUCRALFATE IN PREVENTING GASTROINTESTINAL SIDE EFFECTS OF NSAIDs

To find out the efficacy of sucralfate in preventing gastrointestinal side effects of non-steroidal anti-inflammatory drugs (NSAIDs) a prospective, randomised single blind study was conducted from 1989 to 1992. Patients with osteoarthritis, rheumatoid arthritis and other long standing painful conditions, who were expected to receive NSAIDs for over three months, were recruited into the study. All medicines were discontinued for a period of 10–15 days prior to initial endoscopic assessment. NSAID therapy was started and the patients were randomised to receive either placebo (group A) or sucralfate (group B) in addition. Patient were reassessed clinically every week and an endoscopic examination was repeated after 6–8 weeks of follow-up. A total of 176 patients were studied in group A (n=91) and group B (n=85). At the end of 8 weeks gastrointestinal symptoms were present in 30.6% and 26.4% patients of group A and B respectively. Endoscopic assessment showed superficial lesions in 36.5% and 18.7% while endoscopic ulcer in 2.4% and 1.1% patients of groups A and B respectively. Thus in patients receiving chronic NSAID therapy, simultaneous administration of sucralfate reduces the incidence of superficial gastric lesions but has no significant effect on symptoms or ulcer formation.KEY WORDS: Gastropathy, Sucralfate, Nonsteroidal anti-inflammatory drugs     

Destruction of WiDr multicellular tumor spheroids with the novel thymidylate synthase inhibitor 1843U89 at physiological thymidine concentrations

The activity of a novel thymidylate synthase inhibitor, 1843U89, against WiDr human colon carcinoma multicellular tumor spheroids was investigated. Continuous exposure of the spheroids to 3 nM 1843U89 for 10 days resulted in spheroid disruption, whereas 100 nM methotrexate (MTX) was required for similar effects. Short-term treatment experiments demonstrated that a 3-day exposure to 100 nM 1843U89 caused spheroid disruption 9 days after drug removal. A 4-day exposure to 10 nM 1843U89 caused spheroid disruption 8 days after drug removal. In contrast, treatment with 10 or 100 nM 1843U89 for 6–48 h or treatment with 1 nM 1843U89 for up to 5 days caused only growth delay. Continuous exposure of spheroids to 30 nM 1843U89 in the presence of 0.05–0.3 M thymidine was as effective in causing spheroid disruption as treatment in the absence of thymidine, but treatment in the presence of 0.7–3.0 M thymidine caused partial reversal of spheroid disruption. The results of these experiments suggest that 1843U89 should have potent solid tumor activity in humans but should be less effective in mice due to differences in circulating thymidine levels (0.1 vs 1 M, respectively).     

Breast Biopsies with ABBI(R): Experience with 183 Attempted Biopsies

When first introduced, the advanced breast biopsy instrumentation (ABBI^®) system seemed to have many advantages as a diagnostic procedure. Problems have arisen, however, both in terms of patient unsuitability and mechanical failure. In addition, there has been uncertainty as to whether the complete lesion removal it afforded could be considered definitive treatment in malignant cases. Incision margins were looked at to investigate that possibility. Of the 183 patients we saw in our first year of experience with ABBI, 48 (26%) were rejected for being poor candidates for it. In the remaining 132 biopsies there were 31 (23%) technical difficulties. All told, 14 malignancies were discovered, all of which appeared to have pathology-free incision margins radiologically. However, 13 of these 14 (93%) proved on pathologic examination to have residual malignancy. ▪