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Biomedical subjects

T Hoover

Publications and source records attributed to T Hoover.

8 recordsLinked to original sources
PubMed1996

A nuclear matrix-specific factor that binds a specific segment of the negative regulatory element (NRE) of HIV-1 LTR and inhibits NF-kappa(B) activity.

The negative regulatory element (NRE) of human immunodeficiency virus type-1 (HIV-1) long terminal repeat (LTR) is a defined region that has been reported to downregulate LTR-directed HIV gene expression. However, information on the precise role of this region in regulating HIV gone transcription is lacking. We have investigated the possibility that these NRE sequences regulate HIV transcription by a mechanism mediated through a nuclear matrix-specific DNA-protein interaction. We find a nuclear matrix attachment region (MAR) present within the NRE of the HIV-1 LTR that recognizes a sequence-specific DNA-binding protein present in the nuclear matrix of HIV infected cells. Moreover, we also show that the purified DNA-binding nuclear matrix protein (NMP) specifically represses the DNA-binding activity of NF-kappaB. It is likely that the MAR and MAR-enriched specific DNA-binding NMP are brought into juxtaposition by the non-chromatin scaffolding of the nucleus, thus influencing NF-kappaB (and other nuclear proteins) DNA-binding activity through protein-protein and protein-DNA interactions. Our date suggest that one possible role of the NRE could be to act as a matrix attachment site in the nuclear matrix, thus, allowing interaction with a sequence-specific trans-acting factor. The negative effect on NF-kappaB activity due to this MAR-NMP-specific interaction provides a mechanism by which the NRE downregulates HIV gene expression.

Antigens, Nuclear↗
PubMed1996

Long-term tacrine (Cognex) treatment: effects on nursing home placement and mortality, Tacrine Study Group.

OBJECTIVE: To assess the possible association between tacrine (Cognex, manufactured by Parke-Davis, Morris Plains, NJ) dose and likelihood of nursing home placement (NHP) or death in patients with AD. DESIGN: A 30-week, randomized, double-blind, placebo-controlled, parallel-group multicenter clinical trial involving 663 patients, after which patients were treated openly and followed up a minimum of 2 years later. PATIENTS: At baseline, outpatients were at least 50 years of age, met criteria for probable AD, with baseline Mini-Mental State Examination scores between 10 and 26 (inclusive), were otherwise healthy, and had a caregiver who could provide assessments and ensure medication compliance. INTERVENTIONS: mandomized assignment to placebo or one of three ascending dosage regimens of tacrine over 30 weeks, followed by open label treatment for all patients who began the double-blind trial. OUTCOME MEASURES: NHP and death were examined using logistic regression. RESULTS: PATIENTS who remained on tacrine and were receiving doses > 80 mg/d or > 120 mg/d were less likely to have entered a nursing home than patients on lower doses (odds ratios > 2.7,2.8, respectively.) There was a trend for lower mortality for patients receiving > 120 mg/d (p = 0.063). CONCLUSIONS: Treatment with tacrine at doses > 80 mg/d was associated with a reduced likelihood of NHP. These data demonstrate that tacrine's 30-week effects on cognitive function and clinicians' global ratings may generalize to effects on a major milestone of AD. Future studies should attempt to replicate these findings prospectively.

Aged↗
PubMed1995

Tat mediates transcriptional activation of HIV-1 gene in vitro.

Gene expression of human immunodeficiency virus (HIV-1) is greatly enhanced by a viral transactivator, the Tat protein, which interacts with R region sequences of the HIV-1 long terminal repeat (LTR). There is no direct evidence to indicate transcriptional activation of HIV-1 by Tat. Using an in vitro transcription system, we demonstrate that an established mouse cell line, which constitutively expresses Tat protein, selectively stimulates the steady state levels of the transcripts directed from the long terminal repeat (LTR) sequences of HIV-1. The gel binding retardation assays further demonstrate a stable activated complex, formed due to direct binding of Tat to DNA elements of the HIV-1 LTR. These data implicate transcription as the site of Tat action in trans-activation and could play an essential role in human immunodeficiency virus replication, similar to the nuclear trans-activators of other viruses.

Animals↗
PubMed1994

c-erbB-2 promoter-specific DNA-binding protein isolated from human breast cancer tissues displays mitogenic activity.

Amplification and overexpression of the c-erbB-2 gene appears to play a role in the pathogenesis of human breast and other cancers. Frequent amplification (20-30%) of the c-erbB-2 gene was observed in human adenocarcinomas of kidney, pancreas, lung, ovarian, and breast cancer. The gene product is a 185-kDa glycoprotein that has intrinsic tyrosine kinase activity and is believed to be a receptor. Several candidate ligands have been described. In the present study we have identified and purified a novel DNA-binding protein from malignant human breast tissues. The protein binds to a core element (-22 to +9, +1 being the transcription start site) of the c-erbB-2 promoter region in a sequence-specific manner. The affinity-purified protein has the ability to induce DNA synthesis in quiescent NIH/3T3 cells, suggesting that the factor has mitogenic activity. The purified protein induces c-erbB-2 expression on the surface of microinjected NIH/3T3 cells. This DNA-binding protein is a sequence-specific cellular factor that is associated with high level expression of the c-erbB-2 gene and appears to play a role in cell transformation. Understanding the control and expression of this DNA-binding protein may shed light on the mechanism(s) of c-erbB-2 gene regulation and its potential role in the pathogenesis of human adenocarcinomas.

3T3 Cells↗
PubMed1990

Early human trials in the assessment of cognition activators.

The assessment of cognition enhancers in the clinic is a broad topic that can be addressed from both academic/theoretical and therapeutic/drug development perspectives. The most important first step is to decide which perspective one is employing and to clearly specify, a priori, the goal of any intended study. Since the therapeutic benefit of cognition enhancers is not apparent until after many weeks of exposure, it is virtually impossible to demonstrate efficacy in early, short-duration Phase 2 trials. It is possible, however, to gain some knowledge of the doses that effect CNS, rCBF, PET etc. in either normal volunteers or the population of interest. However, these results should not be interpreted as evidence for, or lack of, efficacy. Recently, there has been growing interest in the reversal of scopolamine- or benzodiazepine-induced memory deficits in humans. A major problem is the potential for overinterpretation of the results of such studies. From a drug development approach, it is necessary to utilize larger numbers of subjects and longer-term studies. Specification of the indication should be as precise as possible and the outcome measures should accurately reflect both the current state of the patient and the course of the disease. The absence of normative and longitudinal data on such measures is a hurdle that is only now being overcome. Such data provide a scientific basis for the determination of the types of design and sample sizes that give adequate power to thoroughly assess new cognition enhancers.

Animals↗
PubMed1989

In vitro activity of the nitrogen fixation regulatory protein NIFA.

We have detected activity of the nitrogen fixation regulatory protein NIFA of Klebsiella pneumoniae in vitro. To do so we directed synthesis of NIFA in a coupled transcription-translation system and detected its ability to activate expression of a translational fusion between the nifH and lacZ genes. We infer that NIFA stimulates initiation of transcription by sigma 54 holoenzyme from the nifHDK promoter. The activity of NIFA was lost rapidly under both aerobic and anaerobic conditions at 30 degrees C and was lost somewhat less rapidly at 0 degrees C. Loss of activity was not accompanied by degradation of NIFA polypeptide. Loss of activity was approximately exponential and was not affected by NIFA concentration over a 5-fold range. Therefore, NIFA inactivation does not appear to be due to self-association. We found that the factor in crude extracts previously demonstrated to bind to the nifHDK promoter-regulatory region [Beynon, J., Cannon, M., Buchanan-Wollaston, V., and Cannon, F. (1983) Cell 34, 665-671] is the integration host factor, which is known to bend DNA. Since the binding site for integration host factor lies between the upstream binding site for NIFA and the nifHDK promoter, integration host factor may bend the DNA between these two sites to facilitate productive interactions between NIFA and sigma 54 holoenzyme.

Bacterial Proteins↗