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Biomedical subjects

S Thaler

Publications and source records attributed to S Thaler.

At least 19 recordsLinked to original sources
PubMed2005

Inhibitors of apoptosis confer resistance to tumour suppression by adoptively transplanted cytotoxic T-lymphocytes in vitro and in vivo.

Deregulation of apoptosis signalling is commonly found in cancer and results in resistance to cytotoxic therapies. Immunotherapy is a promising strategy to eliminate resistant cancer cells. The transfer of T-lymphocytes during allogeneic stem cell transplantation is clinically explored to induce a 'graft-versus-tumor' effect (GvT). Cytotoxic T-lymphocytes (CTL), which are major effectors of GvT, eliminate cancer cells by inducing apoptosis via multiple parallel pathways. Here, we study in vitro and in vivo the susceptibility of murine cancer cells engineered to express single antiapoptotic genes to CTL-mediated cytotoxicity. Interestingly, we find that single inhibitors of caspase activation, such as BCL-XL or dominant-negative mutants of FADD and caspase-9, protect cancer cells against antigen-specific CTL in vitro. Moreover, expression of BCL-XL impairs the growth suppression by adoptively transplanted CTL of established tumours in vivo. Hence, apoptosis defects that provide protection to cytotoxic cancer therapies can confer crossresistance to immunotherapy by tumour-reactive CTL.

Adoptive Transfer↗
PubMed2001

A packaging cell line generating CD4-specific retroviral vectors for efficient gene transfer into primary human T-helper lymphocytes.

Murine leukemia virus (MuLV) can be pseudotyped with a variant of the human immunodeficency virus (HIV) envelope gene encoding the surface glycoprotein gp120-SU and a carboxy-terminally truncated transmembrane (TM) protein with only seven cytoplasmic amino acids. MuLV/HIV-1 pseudotyped retroviral vectors selectively target gene transfer to human cells expressing both CD4 and CXCR4. To apply this vector system to gene therapy of human diseases, we generated a stable packaging cell line, FLY-HIV-87, expressing the MuLV gag and pol genes and the C-terminally truncated variant of the HIV-1 envelope gene, but no retroviral vector genome. Production of infectious vector particles was tested after the introduction of different vector genomes and was in the range of 5x10(5) IU/ml. The vector particles could be concentrated up to 25-fold. Specific and efficient gene transfer into CD4/CXCR4 expressing cell lines and stimulated primary human CD4+ peripheral blood lymphocytes was achieved. Thus the packaging cell line FLY-HIV-87 is highly suitable for gene therapy of disorders of human T-helper cells.

CD4 Antigens↗
PubMed2001

The Interdisciplinary Generalist Curriculum Project at the University of Wisconsin Medical School: the Generalist Partners Program.

The Generalist Partners Program (GPP) provides all University of Wisconsin Medical School students with a comprehensive generalist core curriculum through early clinical experiences, interactive faculty presentations, and small-group discussions during the first two years of medical school. The GPP is the first component of a comprehensive, longitudinal generalist curriculum offered during all four years of medical education. Faculty members from family medicine, general internal medicine, and general pediatrics work together to develop the learning goals and provide the curriculum for the GPP courses. Each of the 145 entering first-year medical students is matched with a community-based physician, the generalist practice partner, and the students participate in early clinical experiences at this site throughout their first two years of medical education. Students' clinical experiences are presented and discussed in case-based small-group sessions led by the school's generalist faculty. A core lecture series on professionalism, communication skills, evidence-based medicine, and the organization of the health care system supplements the early clinical experiences.

Curriculum↗
PubMed2001

Membrane-anchored peptide inhibits human immunodeficiency virus entry.

Peptides derived from the heptad repeats of human immunodeficiency virus (HIV) gp41 envelope glycoprotein, such as T20, can efficiently inhibit HIV type 1 (HIV-1) entry. In this study, replication of HIV-1 was inhibited more than 100-fold in a T-helper cell line transduced with a retrovirus vector expressing membrane-anchored T20 on the cell surface. Inhibition was independent of coreceptor usage.

Amino Acid Sequence↗
PubMed2000

Comparison of two different time interval protocols for central venous catheter dressing in bone marrow transplant patients: results of a randomized, multicenter study. The Italian Nurse Bone Marrow Transplant Group (GITMO).

BACKGROUND AND OBJECTIVE: Care of central venous catheter (CVC) in patients undergoing bone marrow transplantation (BMT) raises significant problems related to the high risk of local infections due to the immunodeficient status, which in itself is a predisposing factor for systemic blood-stream infections. Although frequent changes of CVC dressing might theoretically reduce the incidence of infections, they are also accompanied by significant skin toxicity and patient discomfort. No study has yet addressed these points. The objective of this study was to compare two different time interval protocols for CVC dressing in order to assess the effects on local infections and toxicity. DESIGN AND METHODS: In a multicenter study, 399 bone marrow transplant (BMT) patients with a tunneled CVC (Group A, 230 pts) or a non-tunneled one (Group B, 169 pts) were randomly allocated to receive CVC dressing changes every 5 or 10 days, if belonging to Group A, or 2 or 5 days, if in Group B. Transparent, impermeable polyurethane dressings were used for all patients. The rate of local infections at the site of CVC insertion was assessed by microbiological assays every 10 days, while the severity of skin toxicity was measured according to the ECOG scale. RESULTS: Sixty-five per cent of enrolled patients were finally evaluable. Patients (in both Groups) receiving CVC dressing changes at longer intervals did not show a significant increase in the rate of local infections, while those who received dressing every 2 days had a significant increase in local skin toxicity. Longer intervals were accompanied by a reduction in costs. INTERPRETATION AND CONCLUSIONS: The results of this study demonstrate that the increase in time interval between CVC dressing changes in BMT patients did not raise the risk of local infections, while significantly reducing patient discomfort and costs.

Bone Marrow Transplantation↗
PubMed1999

Truncation of the human immunodeficiency virus-type-2 envelope glycoprotein allows efficient pseudotyping of murine leukemia virus retroviral vector particles.

The incorporation of human immunodeficiency virus-type-2 (HIV-2) envelope glycoprotein into murine leukemia virus (MuLV) particles was studied in a transient transfection packaging cell system. We observed that wild-type HIV-2 envelope protein or a frameshift mutant with 187 unrelated carboxyl-terminal residues did not allow the formation of infectious retroviral particles. In view of recent findings that an HIV-1 envelope protein variant with a shortened cytoplasmic domain was incorporated into MuLV particles, we constructed carboxyl-terminal truncations of the HIV-2 envelope protein. An envelope variant with 18 cytoplasmic amino acids formed only very few viral pseudotypes. The further removal of an additional 11 amino acids allowed the efficient pseudotyping of MuLV particles. As with the HIV-1 envelope protein, an HIV-2 envelope variant with 7 cytoplasmic amino acids was incorporated into functional MuLV particles. The pseudotyped vectors obtained are able to infect human CD4/CXCR4-expressing cells. Cell lines expressing human CD4 and other coreceptors could not be infected. This retroviral vector will prove useful for the study of HIV infection events mediated by the HIV-2 envelope glycoproteins, as well as for the targeting of CD4+ cells in the context of gene therapy of AIDS.

Animals↗
PubMed1997

Suppression of smooth-muscle alpha-actin expression by platelet-derived growth factor in vascular smooth-muscle cells involves Ras and cytosolic phospholipase A2.

Platelet-derived growth factor (PDGF), which is a potent mitogen for vascular smooth-muscle cells (VSMC), also inhibits the expression of specific smooth-muscle proteins, including smooth-muscle alpha-actin (SM-alpha-actin), in these cells. The goal of this study was to identify signalling pathways mediating these distinct effects. In rat aortic VSMC, PDGF caused a rapid activation of Ras and Raf, leading to the activation of mitogen-activated protein kinases (ERKs). Cells stably transfected with constitutively active Ras (H-Ras) expressed low levels of SM-alpha-actin protein. Arginine vasopressin, which stimulated SM-alpha-actin promoter activity in wild-type cells or controls (Neo; transfected with a plasmid lacking an insert), failed to do so in cells transiently expressing H-Ras. The effects of Ras on suppression of SM-alpha-actin expression were not mediated by the Raf/ERK pathway, since cells stably expressing constitutively active Raf (BxB-Raf) had normal levels of SM-alpha-actin protein, and stimulation of SM-alpha-actin promoter activity by vasopressin was unaffected in cells transiently expressing BxB-Raf. Furthermore a specific inhibitor of ERK activation had no effect on SM-alpha-actin expression. Exposure of wild-type VSMC to PDGF, or stable expression of Ras but not Raf, also resulted in constitutive increases in prostaglandin E2 production and cytosolic phospholipase A2 (cPLA2) activity, which was mediated by an increased expression of cPLA2 protein. Transient expression of cPLA2 in wild-type VSMC inhibited the stimulation of SM-alpha-actin promoter activity by vasopressin. These results suggest that PDGF-induced inhibition of SM-alpha-actin expression is mediated through a Ras-dependent/Raf independent pathway involving the induction of cPLA2 and eicosanoid production.

Actins↗
PubMed1997

Induction of cytosolic phospholipase A2 by oncogenic Ras in human non-small cell lung cancer.

Mutations in Ras family members that confer oncogenic potential are frequently observed in specific human cancers. We report that human non-small cell lung cancer (NSCLC) lines that harbor oncogenic mutations in Ki-Ras (H460, A549, H2122) synthesized high levels of prostaglandin E2 (PGE2) compared with NSCLC lacking Ras mutations or non-transformed lung epithelial cells (BEAS-2B). This increased PGE2 production was mediated by constitutively high expression of 85-kDa cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (COX-2). The increased expression of cPLA2 protein was mediated through elevated mRNA levels and activation of the cPLA2 promoter. Induction of cPLA2 promoter activity was blocked by expression of dominant-negative forms of Ras. Inhibition of Ras by the farnesyltransferase inhibitor BZA-5B inhibited prostaglandin synthesis in H2122 cells by decreasing expression of both cPLA2 and COX-2. Finally, inhibitors of eicosanoid synthesis blocked anchorage-independent growth of NSCLC lines exhibiting Ki-Ras mutations. These results identify cPLA2 as a novel Ras-inducible regulator of eicosanoid synthesis that participates in cellular transformation.

Carcinoma, Non-Small-Cell Lung↗
PubMed1994

Effect of electromagnetic stimulation with different waveforms on cultured chick tendon fibroblasts.

An energy efficient electromagnetic stimulator device for fracture healing was compared to a commercially available device in stimulating cell growth in tissue cultures. The energy efficient device, which conserves energy by using a bidirectional time-dependent magnetic wave form, and the commercially available stimulator, which uses a unidirectional time-dependent magnetic wave form, were tested on chick tendon fibroblasts in primary culture. Comparing non-stimulated control and cells electromagnetically stimulated with unidirectional and bidirectional waveforms showed that at the growth phase between days 2 and 3, both electrical stimulation techniques increased cell division as measured by DNA synthesis. When cells were dividing rapidly, collagen synthesis was reduced. When the cells reached the confluence there was no difference among the groups (control, unidirectionally stimulated, and bidirectionally stimulated) in terms of number of cells or collagen produced.

Animals↗
PubMed1992

A portable pulsed electromagnetic field (PEMF) device to enhance healing of recalcitrant venous ulcers: a double-blind, placebo-controlled clinical trial.

A prospective, randomized, double-blind, placebo-controlled multicentre study assessed the clinical efficacy and safety of pulsed electromagnetic limb ulcer therapy (PELUT) in the healing of recalcitrant, predominantly venous leg ulcers. The portable device was used at home for 3 h daily during this 8-week clinical trial as an adjunct to a wound dressing. Wound surface area, ulcer depth and pain intensity were assessed at weeks 0, 4 and 8. At week 8 the active group had a 47.7% decrease in wound surface area vs. a 42.3% increase for placebo (P < 0.0002). Investigators' global evaluations indicated that 50% of the ulcers in the active group healed or markedly improved vs. 0% in the placebo group, and 0% of the active group worsened vs. 54% of the placebo group (P < 0.001). Significant decreases in wound depth (P < 0.04) and pain intensity (P < 0.04) favouring the active group were seen. Patients whose ulcers improved significantly after 8 weeks were permitted to continue double-blind therapy for an additional 4 weeks. Eleven active and one placebo patient continued therapy until week 12, with the active treatment group continuing to show improvement. There were no reports of adverse events attributable to this device. We conclude that the PELUT device is a safe and effective adjunct to non-surgical therapy for recalcitrant venous leg ulcers.

Adult↗
PubMed1976

Delayed hypersensitivity and local control of patients treated by radiotherapy for head and neck cancer.

Delayed hypersensitivity of sixty-three patients with head and neck cancer treated by radiotherapy was correlated with short-term tumor control. Of eighteen patients with early disease, sixteen were DNCB-reactive and all were controlled and one of the two nonreactors was controlled. Thirty-three of forty-five patients with advanced tumors were reactive and nineteen were controlled. Only two of the twelve nonreactors were controlled.

Adult↗
PubMed1976

Hepatoma induced by thorium dioxide.

A 74-year-old man complained of anorexia and weight loss. Twenty-six years earlier he had received an injection of Thorotrast. A needle biopsy of the liver showed thorium dioxide granules and periportal fibrosis. On laparotomy, a hepatoma of the left lobe of the liver was discovered. Hepatic malignancy should be suspected in any patient with abnormal results of liver function tests, particularly an elevated level of alkaline phosphatase, who previously has had an injection of Thorotrast.

Aged↗