Biomedical subjects

M Hagmann

Publications and source records attributed to M Hagmann.

59 records · Page 4Linked to original sources

PubMed1995

Positive and negative regulation at the herpes simplex virus ICP4 and ICP0 TAATGARAT motifs.

The control of the ICP0 and ICP4 immediate early genes of herpes simplex virus (HSV) can critically determine the course of viral lytic or latent infections. Their promoters contain so-called TAATGARAT motifs that are activated via a multiprotein complex which includes cellular proteins Oct-1 and HCF and the viral activator (VP16 (= Vmw65, alpha TIF). Relative to the ICP4 promoter TAATGAGAT sequence, the ICP0 promoter motif has a 5' extension that includes a full octamer sequence (ATGCTAATGATAT). It seemed possible that this overlapping octamer site might render the ICP0 promoter element more active by allowing tighter binding of the Oct-1/VP16 complex or more vulnerable to repression by other Oct proteins. Our experiments favor the former possibility. On the one hand, the extended ICP0 site shows stronger binding of the Oct-1/VP16 complex compared to the ICP4 site. Moreover, transcription of a reporter gene with multiple ICP0 sites is strongly activated by VP16 in transfected cells. On the other hand, the ICP0 site is largely refractory toward repression by a different Oct factor (N-Oct2 = Brn1) which competes with Oct-1/VP16 for the site. In marked contrast, multiple copies of the conventional TAATGAGAT motif of ICP4 are poorly activated by VP16, and transcription from this site can be completely repressed by N-Oct2. However, inclusion of the neighboring CGGAAR motifs from the ICP4 promoter, which bind factors GABP alpha and beta, results in a strong synergistic activation. This activity, like that of the complete ICP4 promoter, becomes refractory to repression by competing N-Oct2. Thus the standard TAATGARAT motif of ICP4 is by itself less active and more vulnerable to repression than the extended ICP0 motif, and its activation depends upon synergism with neighboring DNA sites and their cognate factors. This difference between the two types of TAATGARAT motifs may allow for a more complex transcriptional regulation by factor combinations.

Base Sequence↗

PubMed1995

Comparison of the angiotensin II antagonist UP269-6 with the angiotensin converting enzyme inhibitor enalapril in normotensive volunteers challenged with angiotensin I.

We assessed the inhibitory effect of UP269-6, a new orally active angiotensin II (ANG II) receptor antagonist, on the pressor action of exogenous ANG I in healthy male volunteers maintained on an unrestricted sodium intake and compared it with that of enalapril. Seven different single doses of UP269-6 ranging from 5 to 180 mg, 20 mg enalapril, or placebo were administered to 16 subjects in a double-blind fashion. The order of placebo and enalapril was randomized, and UP269-6 was given in an ascending dose order. The peak systolic blood pressure (SBP) response to a test dose of ANG I was determined serially before and after oral drug administration by monitoring finger BP by a photoplethysmographic method. No drug-related side effect was observed. There was a dose-dependent inhibition of the SBP response to the ANG I challenge. Doses as low as 40 to 80 mg had blocking effects quite similar to that of enalapril 20 mg. Ten hours after the 20- and 40-mg doses of UP269-6, the SBP response was still attenuated when drug levels no longer were measurable in plasma. UP269-6 also produced a dose-related increase in active renin and ANG II levels at 24 h after drug intake. In these volunteers on unrestricted salt intake, no statistically significant effect on 24-h urinary aldosterone excretion was observed. Based on these preliminary data, the pharmacokinetic drug half-life (t 1/2) was estimated at 4.7 h and the EC50 was estimated at 41 ng/ml. UP269-6 appears to be a well-tolerated, potent, orally active, antagonist of ANG II receptors in men. Doses of 40-80 mg might block the ANG I pressor response as does enalapril 20 mg.

Administration, Oral↗

PubMed1993

Specific transcriptional activation in vitro by the herpes simplex virus protein VP16.

The herpes simplex virus protein VP16 interacts with cellular factors, including the protein Oct-1, to activate viral immediate early (IE) gene transcription. We have reproduced this effect by addition of purified, full-length VP16 and the DNA-binding 'POU' domain of Oct-1 (Oct-1/POU) to a HeLa cell in vitro transcription system. Stimulation of transcription was dependent on the IE-specific element, TAATGARAT. In agreement with earlier observations from electrophoretic mobility shift assays, activation was not observed when Oct-2/POU, the DNA-binding domain from the Oct-2 protein, was substituted for Oct-1/POU. Single round transcription assays revealed that, together, VP16 and Oct-1/POU facilitate the assembly of pre-initiation complexes at target gene promoters.

Base Sequence↗

PubMed1990

Preclinical evaluation of submillimeter diameter microwave interstitial hyperthermia applicators.

Ultra miniature coaxial cable has been used, with microscopic techniques, to fabricate interstitial hyperthermia applicators having diameters of 0.20 mm, 0.33 mm, and 0.58 mm; commercial applicators have a diameter of 1.1 mm. Animal studies with the 0.33 mm diameter applicators have shown that they produce less local tissue trauma than the larger-diameter devices. All of these applicators operate at 915 MHz and have similar heating patterns because they use the conventional monopole design and the catheters have been approximately scaled to the dimensions of each size applicator. We have measured the heating (SAR) patterns of these applicators in tissue-simulating phantoms, both singly and in arrays, using a miniature electric field probe. As an intermediate step to patient trials, we have examined the ability of these applicators to provide effective heating of perfused tissue, using pig thigh and liver as models. Test results suggest that the durability and power handling capabilities of our submillimeter applicators are adequate for use in patients. These new applicators should be useful in the percutaneous treatment of deep-seated tumors and in intraoperative treatments. The applicators also permit intraluminal or intravascular access to tumors.

Animals↗

PubMed1984

Heating pattern of a single-loop applicator buried in muscle-equivalent phantom material measured at S-band.

We measured the initial rate of energy deposition at S-band (2.455 GHz) for a single-turn grounded insulated coil buried in muscle-equivalent phantom material. Most of the electromagnetic field is confined within the horizontal dimensions of the coil, and 30% or more of the incident energy is deposited at depths up to 1 cm below the coil. We believe that this device, sheathed in biocompatible PTFE teflon, could be implanted in a tumor region and left in situ during the course of a fractionated hyperthermia protocol.

Biocompatible Materials↗