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Biomedical subjects

K Haglund

Publications and source records attributed to K Haglund.

At least 19 recordsLinked to original sources
PubMed2001

Homeobox gene Cdx1 regulates Ras, Rho and PI3 kinase pathways leading to transformation and tumorigenesis of intestinal epithelial cells.

The Cdx1 homeobox gene encodes for an intestine-specific transcription factor involved in the control of proliferation and differentiation of epithelial cells. Although it has been indicated that Cdx1 may act as a proto-oncogene in cultured fibroblasts, its direct role in the regulation of intestinal tumorigenesis has not been demonstrated. Here we show that expression of Cdx1 in an intestinal epithelial cell line (IEC-6) induces anchorage-independent growth in soft agar and promotes the formation of adenocarcinoma in vivo. The phenotype of Cdx1-induced tumors was exacerbated when IEC-6/Cdx1 cells were injected together with matrigel containing mitogens and extracellular matrix components. These changes were correlated with an increase in the GTP-bound form of Ras, modulation of Cdc42 and Rho-A activities, and accumulation of phosphatidyl inositol 3 (PI3) kinase products. Moreover, combined inhibition of Ras/Rho and PI3 kinase signaling by synthethic inhibitors blocked colony formation of IEC-6/Cdx1 cells in soft agar. Taken together, these results demonstrate a direct involvement of Cdx1, and its collaboration with Ras, Rho and PI3 kinase pathways, in transformation and tumorigenesis of intestinal epithelial cells.

Animals↗
PubMed2000

Expression of human immunodeficiency virus type 1 Gag protein precursor and envelope proteins from a vesicular stomatitis virus recombinant: high-level production of virus-like particles containing HIV envelope.

Recombinant vesicular stomatitis viruses have been developed as high-level expression vectors which serve as effective vaccine vectors in animals (Roberts et al., 1998, J. Virol. 72, 4704-4711; Roberts et al., 1999, J. Virol. 73, 3723-3732). Here we show that two genes can be expressed simultaneously from a single, live-attenuated VSV recombinant. The genes used encode the Pr55(gag) protein precursor of HIV-1 (1.7-kb gene) and an HIV-1 envelope (Env) protein (2.4 kb gene). Our results show that VSV can accommodate up to a 40% increase in genome size with only a threefold reduction in virus titer. Recombinants expressing the Pr55(gag) protein precursor with or without Env protein produced abundant HIV virus-like particles (VLPs) in addition to bullet-shaped VSV particles. HIV Env protein expressed from a VSV recombinant also expressing Gag was specifically incorporated into the HIV VLPs but not into the VSV particles. In contrast, VSV G protein was found in both VSV particles and in HIV VLPs. Such VSV/HIV recombinants producing HIV VLPs with Env protein could be an effective source of HIV-like particles inducing both cellular and antibody-mediated immunity to HIV-1.

AIDS Vaccines↗
PubMed1997

Identification, expression, and immunogenicity of Kaposi's sarcoma-associated herpesvirus-encoded small viral capsid antigen.

We describe a recombinant antigen for use in serologic tests for antibodies to Kaposi's sarcoma (KS)-associated herpesvirus (KSHV). The cDNA for a small viral capsid antigen (sVCA) was identified by immunoscreening of a library prepared from the BC-1 body cavity lymphoma cell line induced into KSHV lytic gene expression by sodium butyrate. The cDNA specified a 170-amino-acid peptide with homology to small viral capsid proteins encoded by the BFRF3 gene of Epstein-Barr virus and the ORF65 gene of herpesvirus saimiri. KSHV sVCA was expressed from a 0.85-kb mRNA present late in lytic KSHV replication in BC-1 cells. This transcript was sensitive to phosphonoacetic acid and phosphonoformic acid, inhibitors of herpesvirus DNA replication. KSHV sVCA expressed in mammalian cells or Escherichia coli or translated in vitro was recognized as an antigen by antisera from KS patients. Rabbit antisera raised to KSHV sVCA expressed in E. coli detected a 22-kDa protein in KSHV-infected human B cells. Overexpressed KSHV sVCA purified from E. coli and used as an antigen in immunoblot screening assay did not cross-react with EBV BFRF3. Antibodies to sVCA were present in 89% of 47 human immunodeficiency virus (HIV)-positive patients with KS, in 20% of 54 HIV-positive patients without KS, but in none of 122 other patients including children born to HIV-seropositive mothers and patients with hemophilia, autoimmune disease, or nasopharyngeal carcinoma. Low-titer antibody was detected in three sera from 28 healthy subjects. Antibodies to recombinant sVCA correlate with KS in high-risk populations. Recombinant sVCA can be used to examine the seroepidemiology of infection with KSHV in the general population.

AIDS-Related Opportunistic Infections↗
PubMed1996

Expression of additional genes in a vector derived from a minimal RNA virus.

Previous studies have shown that expression of the vesicular stomatitis virus (VSV) glycoprotein (G) from a Semliki Forest virus (SFV) RNA replicon results in the production of propagating infectious particles that we call minimal viruses. These minimal viruses consist of vesicles containing VSV G protein that bud from the plasma membrane and trap the infectious SFV G RNA, but they do not contain other viral structural proteins. The cell binding and membrane fusion activity of the VSV G protein allow minimal viruses to propagate in tissue culture cells. To determine if these minimal viruses could be used to express foreign genes, we added a second SFV promoter and a multiple cloning site downstream of the VSV G gene. We report here expression of three different proteins from this modified, minimal virus vector. Although expression of each foreign, unselected gene was lost rapidly from the vector upon passaging, it was possible after the initial transfection to derive stocks of infectious particles that could be used to infect multiple additional cultures and transfer protein expression efficiently. When cells were infected with these minimal viruses, host protein synthesis was shut off and the foreign protein and VSV G proteins were the major proteins expressed in the infected cells. Both were expressed at similar levels and accumulated to about 1-2% of total cell protein.

Animals↗
PubMed1992

Multitarget-ribozyme directed to cleave at up to nine highly conserved HIV-1 env RNA regions inhibits HIV-1 replication--potential effectiveness against most presently sequenced HIV-1 isolates.

Several mono-, di-, tetra-, penta- and nonaribozymes were developed. These multitarget-ribozymes were targeted to cleave HIV-1 env RNA at up to nine different conserved sites. Each multitarget-ribozyme consisted of a chain of up to nine hammerhead motifs, each flanked by a different targeting sequence. The multitarget-ribozymes were functional in vitro and gave rise to multiple, specific partial and/or complete RNA digestion products. Per RNA copy, multitarget-ribozymes were more efficient than monoribozymes or ribozymes targeting a subset of the same sites. In contrast to monoribozymes, a 400nt nonaribozyme, targeted to cleave at nine different sites within a 1.3kb HIV-1 env RNA substrate, was active and showed the same specificity of cleavage when it was part of a large 3.3kb transcript. We conclude that multitarget-ribozymes retain the specificity of monoribozymes, but they are more efficient per ribozyme RNA copy and they remain active when they are part of a large transcript. A tetra-, penta- or nonaribozyme under control of the SV40 late promoter, the beta-actin gene promoter or the HIV-1 LTR, respectively, were cotransfected with the infectious HIV-1 DNA clone pNL4-3 into permissive HeLa T4 cells. Each cotransfection resulted in a specific inhibition of HIV-1 replication as determined by syncytia formation and p24 antigen release. In addition, coexpression of the nonaribozyme with an HIV-1 env RNA transcript resulted in the specific dramatic reduction of the env transcript. We conclude that the multitarget-ribozymes are also functional intracellularly. A nucleotide sequence comparison of the target sites indicates that the multitarget-ribozymes could potentially be effective against all thirty HIV-1 isolates presently sequenced. Their use may help to slow the selection of viral escape mutants and thereby prolong their effectiveness. We anticipate that multitarget-ribozymes will also be more effective in the successful targeting of less variable cellular RNAs.

Base Sequence↗
PubMed1988

Are effects of antihypertensive treatment on lipoproteins merely "side-effects"? A comparison of prazosin and metoprolol.

Thirty-seven patients with a supine systolic blood pressure greater than 160 and/or a diastolic blood pressure greater than 95 mmHg were enrolled in the study and treated for 6 months with prazosin and 6 months with metoprolol (in random order). Neither the systolic nor the diastolic blood pressures differed after the two types of treatment (median difference 0/0 mmHg). The mean and median differences in serum cholesterol, however, were 0.4 and 0.3 mmol/l respectively, which were 9 and 5% of the pretreatment values. The corresponding differences in the atherogenic index (in which cholesterol in high density lipoproteins is integrated) were 10 and 8% of the pretreatment values. This difference in the metabolic response to the two drugs at the same blood pressure level is most probably of importance in the long-term prevention of ischaemic heart disease, for which high levels of serum cholesterol and atherogenic index are major risk factors.

Clinical Trials as Topic↗
PubMed1987

Decreased plasma concentrations and clinical effects of alprenolol during combined treatment with pentobarbitone in hypertension.

The antihypertensive effect of alprenolol has been studied before, during and after additional pentobarbitone treatment. The combined alprenolol-pentobarbitone treatment significantly decreased alprenolol levels by 59% and 4-hydroxyalprenolol by 24%. The effect was significant after three doses and declined over 4-5 days after pentobarbitone withdrawal. The decreased alprenolol plasma levels were associated with increased pulse rate (6%), and systolic (8%) and diastolic (9%) blood pressure. The inhibition of exercise tachycardia by alprenolol was reduced by 18% at the end of pentobarbitone treatment compared to initial monotherapy with alprenolol. The interaction is probably clinically important in those patients with hypertension and angina pectoris that are treated with barbiturates and alprenolol.

Adult↗
PubMed1987

Calcium absorption and excretion in patients treated with verapamil.

1. The effect of verapamil on the intestinal absorption of calcium was studied using a single isotope technique. Serum calcium and urinary excretion of calcium in the urine were followed in nine patients during treatment with verapamil for 2 months. 2. A dose of 80-120 mg (three times daily) resulted in a significant reduction of systolic and diastolic blood pressure. 3. There was no change in the intestinal calcium absorption (alpha) expressed as the fraction of given activity absorbed per hour (alpha = 0.82 +/- 0.19 vs alpha = 0.83 +/- 0.25; +/- s.d., NS) or of the excretion of calcium in urine (Ca/creatinine ratio 0.35 +/- 0.20 vs 0.31 +/- 0.33; NS). 4. Serum calcium was not significantly different before and during treatment (2.43 mmol l-1 +/- 0.10 vs 2.47 mmol l-1 +/- 0.14; NS). 5. This study demonstrates that verapamil, at doses recommended for clinical use, does not seem to affect the intestinal absorption of calcium, the serum calcium concentration or the excretion of calcium in urine.

Aged↗
PubMed1987

Pharmacokinetics and haemodynamic effects of felodipine as monotherapy in hypertensive patients.

The acute and steady-state pharmacokinetics and dynamics of felodipine as monotherapy have been studied in 12 hypertensive patients. Felodipine was acutely administered by a constant infusion, 1.5 mg over a 30-min period, or as a 10-mg tablet. Chronic administration was performed on a fixed dose of 10 mg b.i.d. for 28 days. The systemic availability of felodipine after the acute dose was 15%, and at steady state 12% (N.S.), with a 3-fold variation between patients. The mean plasma clearance was 0.6 L/h. The half-life measured in the 4- to 10-h interval after dose was about the same: 3.4, 3.2, and 3.3 h after the i.v. dose, the acute oral dose, and at steady state, respectively. The mean terminal half-life was 24.5 h after the oral dose at steady state. Both the intravenous and the oral doses of felodipine decreased the diastolic blood pressure for about 8 hours after dosing. The reduction in diastolic blood pressure was about 20 mmHg 1 to 2 hours after dose. Supine diastolic blood pressure was significantly reduced up to 48 h after dose at steady state. Maximum reduction of diastolic blood pressure (-22 mmHg) already occurred on the first day of treatment, while systolic blood pressure was further decreased during chronic treatment. There was a correlation between the individual maximum decrease in diastolic blood pressure after the acute oral dose with that after repeated administration (r2 = 0.70, p less than 0.01). Changes in heart rate were non-significant at steady state.

Administration, Oral↗
PubMed1985

Long-term beta 1-selective adrenergic blockade and adrenergic receptors in human subcutaneous adipocytes.

The influence of beta-adrenergic blockade with metoprolol, a beta 1-selective agent, on the adrenergic regulation of lipid mobilization was explored in subcutaneous adipocytes removed from 13 patients with essential hypertension. Treatment with metoprolol, which was associated with adequate beta-adrenergic blockade and an antihypertensive effect, resulted in a significant increase (p less than 0.05) in the binding of the beta-adrenergic antagonist (-)-(3H)-dihydroalprenolol and a 50% increase (p less than 0.01) in the maximum lipolytic response to the beta-adrenergic agonist isopropylnoradrenaline. In 7 patients with normotriglyceridaemia the total plasma triglyceride level increased significantly (p less than 0.025) during metoprolol treatment, a change that was due to an increase in the very low density lipoprotein triglycerides. The findings suggest that chronic treatment with the beta 1-selective adrenergic blocker metoprolol leads to a significant increase in beta-adrenoceptor density and an increase in the lipolytic response to beta-adrenergic agonists. This latter finding may, in some measure, account for the increased plasma triglyceride level observed.

Adipose Tissue↗
PubMed1984

Short-term effects of felodipine, a new dihydropyridine, in hypertension.

Felodipine, a dihydropyridine, is a new vasodilating calcium antagonist which lowers blood pressure (BP) by selective action on vascular smooth muscle, especially in the resistance vessels. The effects on BP, heart rate (HR) and tolerance of different single oral doses of felodipine were studied in two series of hypertensive patients. When felodipine was given as single drug to 14 previously untreated hypertensives in a single-blind manner, BP was rapidly reduced by about 15% while HR increased by 25%. Felodipine given in a double-blind manner to eight patients on chronic beta-adrenoceptor blockade reduced BP by some 15-20% compared to placebo, while HR did not change. There was a significant correlation between the pre-treatment mean arterial BP (MAP) and the maximal relative change in MAP, i.e. the higher the initial BP the greater the reduction after felodipine. A significant correlation was also found between the plasma concentration of felodipine and the relative change in MAP. Felodipine was generally well tolerated. When given alone felodipine caused the side effects expected from a pure vasodilator, i.e. headache, flushing and palpitations. When given together with a beta-adrenoceptor blocker, the side effects were much less apparent.

Adult↗
PubMed1982

Effect of metoprolol and alprenolol on the metabolic, hormonal, and haemodynamic response to insulin-induced hypoglycaemia in hypertensive, insulin-dependent diabetics.

Insulin hypoglycaemia was induced three times in 6 insulin-dependent, hypertensive diabetics: before instituting antihypertensive long-term treatment and after obtaining a satisfactory blood pressure with either alprenolol or metoprolol given in a randomized order. The blood glucose concentration (1.6-1.9 mmol/l) at which the hypoglycaemia necessitated intravenous administration of glucose was almost identical on all three occasions. During hypoglycaemia the systolic and diastolic blood pressures increased significantly by a mean maximal rise of 27/14 mmHg on alprenolol treatment, but remained unchanged on metoprolol. The responses of adrenaline, noradrenaline, cortisol, and growth hormone did not differ significantly on the three occasions. None of the beta-adrenergic drugs counteracted the early hormone defence mechanisms in hypoglycaemia and the signs of hypoglycaemia were not masked. The haemodynamic response was altered only by the non-selective (alprenolol) and not by the selective beta-adrenergic blocking agent (metoprolol).

Adult↗