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Biomedical subjects

J Horvath

Publications and source records attributed to J Horvath.

At least 37 records · Page 2Linked to original sources
PubMed1995

Somatostatin analog RC-160 inhibits growth of CFPAC-1 human pancreatic cancer cells in vitro and intracellular production of cyclic adenosine monophosphate.

The effect of somatostatin analog RC-160 on the growth of CFPAC-1 human pancreatic cancer cells in vitro was investigated. RC-160 effectively inhibited the proliferation of CFPAC-1 cells in culture, inducing a time- and dose-dependent decrease in the number of treated cells. A significant suppression of cell growth was observed after 48 and 72 hr of the exposure to (1 microM) RC-160, the cell number being decreased by 38% and 46%, respectively. RC-160 was more potent than SS-14 or SMS201-995 in inhibiting the growth of CFPAC-1 cells, and after 48-hr treatment the cell number decreased by 49% for RC-160 compared with 12% for SS-14 and 27% for SMS201-995. Binding experiments demonstrated that specific receptors for somatostatin were present on CFPAC-1 cells. SS-14 showed a high binding affinity for [125I]-Tyr11-SS-14 receptors on CFPAC-1 cells. Scatchard analysis indicated the presence of 2 classes of somatostatin binding sites on the cells, one with high binding affinity and low capacity and the other with low binding affinity and high capacity. RC-160 could bind to somatostatin receptors on these cells with an affinity similar to SS-14 but significantly higher than that of SMS201-995. Radioimmunoassay of intracellular cAMP showed that RC-160 could powerfully inhibit forskolin-stimulated cAMP production in CFPAC-1 cells. Addition of forskolin to the cultures increased cAMP concentrations in the cellular lysate of treated cells. RC-160 attenuated or nullified in a dose-dependent manner the cAMP production stimulated by forskolin. Our observations indicate that somatostatin analog RC-160 inhibits the proliferation of CFPAC-1 human pancreatic cancer cells in vitro and that this effect may involve the intracellular cAMP pathway.

Amino Acid Sequence↗
PubMed1995

Preparative high-performance liquid chromatographic separation of proteins with HyperD ion-exchange supports.

HyperD ion-exchange media combine the mechanical strength of a rigid polystyrene-mineral composite skeleton with the high protein-binding capacity of a three-dimensional soft gel located inside the skeleton. The skeleton solid matrix is completely filled with functionalized, highly hydrophilic, chemically stable ion-exchange hydrogels. These materials gave very efficient columns for protein separation with superior dynamic capacity, high resolving power and excellent protein recovery. Various protein mixtures were used to study the chromatographic performance of these new stationary phases. Comparisons between different particle size packing materials demonstrated the potential of this ion-exchange material for use on a large scale.

Chromatography, High Pressure Liquid↗
PubMed1995

Predicted structure of the adenovirus DNA binding protein.

The DNA sequence of a portion of the MAV1 SmaI-D fragment coding for the C-terminal 147 amino acids of the adenoviral DNA-binding protein (DBP) has been determined. A multiple sequence alignment was constructed of the MAV1 fragment and the DBPs of Ad.2, 4, 5, 7, 12, 40, and 41 to examine the degree of conservation of features that have been mapped on the Ad.2 DBP and to identify further conserved features. The less conserved N-terminal segment of the protein contains two nuclear localization signals and two acidic regions, the host range region, and all of the 11 phosphorylation sites. The highly conserved C-terminal segment contains a potential leucine zipper and zinc finger motifs. These sequence features were mapped onto a predicted secondary structure of the Ad.2 DBP.

Adenoviridae↗
PubMed1995

Can virus therapy of human cancer be improved by apoptosis induction?

Direct virus inoculations and viral oncolysates may induce temporary remissions and prolong life with reduced tumor burden, or decrease relapse rates but fall short of curing human cancers. We propose: (i) investigations of Cassel's 73-T, an Ehrlich's mouse ascites carcinoma-adapted Newcastle disease virus (NDV) strain that so effectively reduced relapse rates in malignant melanoma if it is an admixture or a recombinant with a murine parvovirus; (ii) transfection of prostatic carcinoma cells with the TRMP gene; (iii) transfection of sarcoma cells with the fas gene followed by treatment with anti-fas monoclonal antibodies, and (iv) treatment of metastatic tumors with a parvovirus incorporating the apoptosis-inducer Ad5 E1A gene.Thus, replicating virions and haphazard generation of cytokines in the inoculated host could be replaced with transfection of single genes of well-defined, limited but selected efficacy.

Adenovirus E1A Proteins↗
PubMed1995

A baboon (Papio hamadryas) model of insulin-dependent diabetes.

Over a period of four years, streptozocin has been used to induce diabetes in 10 baboons, all of whom are insulin dependent. We describe our experience with their husbandry, induction of diabetes, insulin therapy, metabolic control and growth rate. Streptozocin dosage of 60 mg/kg readily induces hyperglycemia with minimal hepatic or renal toxicity. Using a once daily injection of mixed short and intermediate acting insulins at a dosage of 2-4 U/kg, it is possible to maintain a degree of metabolic control similar to that attained in patients.

Aging↗
PubMed1994

High dose rate afterloading intraluminal brachytherapy in malignant airway obstruction of lung cancer.

PURPOSE: This is a retrospective study to review the palliation rate, survival rate and complications of high dose rate (HDR) intraluminal brachytherapy in the treatment of malignant airway obstruction of lung cancer. METHODS AND MATERIALS: A total of 225 high dose rate (HDR) brachytherapy treatments were delivered to 76 patients with symptomatic malignant airway obstruction by remote afterloading technique. An average of 7 Gy at a radius of 1 cm from the center of the source was delivered by Iridium-192 (Ir-192) sources. The majority of the patients received 3 fractions at 2 week intervals. Fifty-four patients received HDR brachytherapy as part of their initial treatment; 20 patients presented as symptomatic endobronchial recurrence. Two patients received YAG laser photoresection to open up the obstruction to allow insertion of the brachytherapy catheter. Fifty-nine patients received concurrent external beam irradiation. Forty-two patients were given 60-70 Gy in 6-7 weeks with curative intent. Seventeen patients were given 20-59 Gy in 2-5 weeks as a palliative measure. Nine patients received a radiosensitizer. One patient received concurrent chemotherapy. RESULTS: The symptomatic response rates are as follows: dyspnea had an 87% response rate (59% partial response, 28% complete response), cough had a 79% response rate (47% partial response, 32% complete response), hemoptysis had a 95% response rate (38% partial response, 57% complete response), and postobstructive pneumonia had an 88% response rate (53% partial response, 35% complete response). Sixty-six patients had follow up endoscopic examination (1-3 months after brachytherapy). Their total response rate was 87% (52% partial response and 35% complete response). There were four acute complications: three cases of massive hemoptysis and one of mild hemoptysis. There are five late complications: three cases of radiation pneumonitis and two of esophagitis. At the time of this study, 55 patients have died with the maximum survival duration 113 months (9.4 years) from diagnosis date and 18 months from first HDR treatment. Twenty-one patients are still alive with a mean follow-up duration of 20 months from diagnosis date and 7.8 months from the first HDR treatment. CONCLUSION: HDR brachytherapy is an excellent modality for palliating symptomatic malignant airway obstruction with an acceptable complication rate; however, no definitive increase of survival rate was observed. Prospective clinical trials are needed to better define its merit regarding survival. This paper also includes a literature review and discussion of HDR brachytherapy on bronchogenic cancer.

Adenocarcinoma↗
PubMed1994

Clinical aspects of the interactions between human immunodeficiency virus and the hepatotropic viruses.

The hepatitis viruses A through D are prevalent among patients at risk for human immunodeficiency virus (HIV) infection. The courses of hepatitis B, C, and D are modified by HIV infection. With hepatitis B, increased carriage rates, increased viral replication, and milder liver injury are seen. The degree of HIV-induced immunosuppression does not correlate well with liver injury or amount of hepatitis B viral replication. With progression to AIDS, surface antibody titers can decline, resulting in reactivation of latent hepatitis B virus or reinfection with another subtype. hepatitis B virus may enhance progression to AIDS. Preliminary data suggest that HIV infection can prolong or increase hepatitis C or D viremia and decrease the accuracy of tests for hepatitis C. Interferon may have efficacy against hepatitis C but rarely against hepatitis B in patients who are coinfected with HIV. Zidovudine, ganciclovir, and foscarnet also may be active against these hepatotropic viruses.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Work-site cholesterol screening and dietary intervention: the Staff Healthy Heart Project. Steering Committee.

OBJECTIVES: The Staff Healthy Heart Project was established to run a work-site cholesterol screening project and a randomized controlled trial of dietary interventions. METHODS: Screening was offered to all staff at six Australian hospitals. Participants with blood cholesterol of 5.2 mmol/L (200 mg/dL) or above were randomly allocated to receive screening only (control group), a self-help package, or a nutrition course. Participants were seen 3 and 6 months after intervention to measure blood cholesterol and dietary changes. RESULTS: Eighty percent of available staff (n = 2638) were screened. Of those eligible, 67% (n = 683) entered the trial. Follow-up measures of blood cholesterol and dietary intake were obtained for 63% and 38% of trial participants, respectively. A reduction in reported dietary fat was found for all groups, but there were no significant differences between groups. Reported dietary fiber rose by 0.6 g/MJ/day for those in the nutrition course. There were no changes in total blood or high-density lipoprotein cholesterol. CONCLUSIONS: Cholesterol reduction was not demonstrated, but this result is difficult to interpret given the poor ongoing participation rates. Strategies to improve ongoing participation in work-site projects are needed to achieve adequate assessment of dietary interventions used in cholesterol screening.

Adolescent↗
PubMed1994

Adoptive immunotherapy with activated peripheral blood lymphocytes.

Adoptive immunotherapy is used to treat malignant tumors resistant to conventional therapeutic modalities. Patients with metastatic melanoma, renal cell carcinoma or mesothelioma are most likely to benefit from this treatment. Tumor infiltrating lymphocytes (TIL) contain tumor specific killer cells and are found to be the most effective. When TIL is not available or until it can be produced in sufficient amount, autologous activated lymphocytes (AAL) are an alternative. AAL are leukapheresed lymphocytes, activated by conditioned medium from OKT3 stimulated autologous lymphocytes. Subcutaneous IL-2 and oral cimetidine are also administered to support the reinfused AAL and to inhibit activation of CD8+ suppressor cells, respectively. To improve the yield and activation of reinfused lymphocytes, addition of IL-2 to the culture medium was tested in different time intervals after the onset of the culture. Interleukin-2 added in the first or second day i) improved the yield of activated lymphocytes; ii) increased the expression of activation markers CD25 (IL-2 receptor) and HLA-DR and iii) augmented killing of tumor cells. Later addition of IL-2 had no or negative effects. In vitro priming of peripheral blood mononuclear cells with autologous or allogeneic but histologically identical tumors was used to increase tumor-specificity of AAL. Autologous serum, containing antibodies specific to tumor cells, facilitated antigen presentation and yielded cytotoxic lymphocytes capable of efficiently killing tumor cells.

Humans↗
PubMed1994

Human cancer vaccines.

Immune T cells recognize peptide antigens presented to them within self-MHC molecules. Thus auto-tumor reactive lymphocyte populations can be generated. Antigenic expression can be modified and intensified and reactive lymphocyte populations can be expanded. Active immunization of the tumor-bearing human host can induce immune reactions of tumor rejection strength. Frequently, micrometastases can be eliminated and occasionally partial or complete remissions of gross metastases can be induced.

BCG Vaccine↗
PubMed1994

Apoptosis by genetic engineering.

Apoptotic cell death is physiological. Malignant cells often escape programmed cell death. Many genes that promote (p53) or antagonize (bcl-2, fes) apoptosis have been recognized. Apoptosis promoter genes can be activated by growth factor or hormone withdrawal in growth factor- or hormone-dependent tumor cells. Malignant cells acquiring apoptosis-resistance, still can be killed by cytotoxic lymphocytes releasing lymphotoxins. This phenomenon gives further support to the therapeutic use of activated and expanded lymphocyte populations and/or apoptosis-inducing cytokines. Chemotherapeutic agents (esp. topoisomerase inhibitors) frequently kill tumor cells by activating programmed cell death (PCD). Biologicals and chemotherapeutics may synergize in evoking apoptosis. We propose the cloning of apoptotic genes and their transfer by transfection in vivo into tumor cells. While transfection of genes into tumor cells in vitro is widely practiced, the lack of proper technology for transfection in vivo and the unknown aspects of apoptotic cell death are recognized.

Animals↗
PubMed1993

New developments in the virus therapy of cancer: a historical review.

Since the 1920s, viruses had been used for oncolysis. Natural human viral infections can rarely induce remissions of leukemias or lymphomas. Inoculation of tumor-bearing patients with live viruses very seldom resulted in durable complete remissions. Genetically engineered or tumor-adapted virus strains may perform better. Virally modified tumor cell membrane vaccines can induce in the host rejection strength antitumor immunity. Modern technology and much more work is needed before the optimal procedures for viral oncolysis or active antitumor immunization with virally modified tumor cell vaccines are learned and can be implemented in the clinical practice. Laboratory monitoring of the host's immunological reactions accompanying failure and success of tumor rejection is essential for the recognition and duplication of the successful and for the avoidance of the unsuccessful interventions.

Genetic Engineering↗
PubMed1993

Infection in the transplanted and native lung after single lung transplantation.

OBJECTIVE: To analyze a single-center experience with infectious complications of single lung transplantation (SLT) with special emphasis on risk factors for infection in the transplanted and native lung. DESIGN: Consecutive case series. SETTING: University teaching hospital. PATIENTS: Fifteen consecutive SLT recipients (mean age, 43 years; 9 men and 6 women). Mean follow-up was 337 days. RESULTS: Fifteen patients had 24 infectious episodes (1.6 per patient) of which 83 percent were life-threatening, 79 percent involved the lung, airway, or pleural space, and 79 percent occurred in the first 4 months after transplantation. Despite this high infectious morbidity, there were no infectious deaths. The most important infections were bacterial pneumonia (n = 10), cytomegalovirus (CMV) pneumonia (n = 5), and bronchial anastomotic infections (n = 3). Significant risk factors for bacterial pneumonia were a diagnosis of primary or secondary pulmonary hypertension (p < 0.05) and the presence of airway complications of stenosis or dehiscence (p < 0.05). No risk factors for overall lung infections were identified. The native lung was involved in 6 of 16 lung infections and was the exclusive site of infection in 4 cases. Underlying disease in the native lung may have predisposed to infection at that site by a mechanism of inadequate blood flow or impaired ventilation. Three bronchial anastomotic infections (Pseudomonas, Candida, Aspergillus) occurred, all with dehiscence of the anastomosis. These were highly morbid but resolved with antibiotics, stent placement, and surgical retention in two of the three cases. The five episodes of CMV pneumonia caused mild (four patients) or moderate (one patient) dysfunction and responded to antiviral agents without relapse. CONCLUSION: The frequency, complexity, and morbidity of infections after SLT were great, but most infections were manageable and good outcomes were achieved. A pretransplant diagnosis of pulmonary hypertension or posttransplant occurrence of bronchial stenosis or dehiscence were associated with a higher rate of bacterial pneumonia. The underlying disease in the native lung may predispose to infection at that site.

Adolescent↗
PubMed1993

Cytotoxic human lymphocytes: from in vitro testing (1970s) to immunotherapy (1990s).

The senior author was the recipient of a contract (1-CP3-3292) from the National Cancer Institute, USA (NCI) in the early 1970s. The aim of NCI's targeted research program was the establishment of a tumour-specific human lymphocyte-mediated cytotoxicity assay. Neither lymphocyte growth factors nor monoclonal antibodies for lymphocyte typing were available. Tumour-specific populations of lymphocytes could not be maintained but their presence in ficoll-hypaque preparations of blood buffy coats or in primary cultures of tumours was clearly recognized. Another indiscriminately cytotoxic population of lymphocytes had usually overridden the tumour-specific population. In contradistinction to the ruling doctrine of the era, indiscriminately cytotoxic lymphocytes were readily found in the blood of tumour-bearing patients and healthy individuals (the senior author's lymphocytes were shown to practice indiscriminate cytotoxicity in 1971, an observation first interpreted as "immune surveillance at work" in an individual daily exposed to patients with metastatic cancers). Instead of converting the subject matter of the contract from a tumour-specific to a non-specific cytotoxicity assay, the NCI prematurely "phased it out" (but continued the project as intramural research). Nevertheless, many functions of cytotoxic lymphocytes that had become by now well established were foreshadowed during the early 1970s with the limited support of that NCI contract and funds from other sources. Here we recount those early observations; present the outlines of adoptive immunotherapy with various autologous lymphocyte populations and in a separate report in this volume give a technical description how these lymphocyte populations are prepared in the laboratory for therapeutic reinfusions into the patient.

Animals↗
PubMed1992

Adenovirus transformation revertant resistant to retransformation by E1 but not by SV40-T and HPV16-E7 oncogenes.

We have previously described a revertant cell line which expresses a dominant tumor suppressor phenotype to E1 but not to heterologous oncogenes such as c-myc, N-ras, or polyoma middle t (Sircar et al. (1988) Oncogene 3, 725-728). DNA tumor virus oncogenes have been suggested to transform cells via the common mechanism of sequestering the Rb-105 antioncoprotein. This paradigm would predict that our revertant cell line, which is resistant to retransformation by E1a, should also be resistant to the other members of the Rb-105 binding family of oncogenes. To test this hypothesis we transfected the revertant cell line with plasmids bearing SV40-T or the HPV16-E7 oncogenes. Because transformation was obtained by both oncogenes at efficiencies similar to the transformation of a related revertant cell line, the results suggest that the resistance phenotype is specific to E1a. This specificity was further confirmed by cell fusion experiments.

Adenoviridae↗