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  • 1
    Abstract: Bacterial cytosine deaminase (CD) converts the non-toxic prodrug 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU), which is toxic for mammalian cells. Therefore, the CD gene is used in cancer gene therapy to achieve high local concentration of a toxic metabolite without significant systemic toxicity. To allow the detection of CD expression at the protein level, we raised both polyclonal rabbit antisera and a monoclonal antibody (mAb) against a histidine-tagged CD fusion protein. The specificity of the polyclonal antisera and the mAb was confirmed by immunohistochemistry, immunoblot analysis, and immunoprecipitation using CD-expressing tumor cell lines. Furthermore, the antibodies can be used for ELISA assays and flow cytometry. Finally, the CD protein could be demonstrated in frozen tissue sections of CD-modified tumors in a rat tumor model using the anti-CD serum. With these antibodies, CD expression can now be monitored throughout in vitro and in vivo gene transfer studies, including clinical protocols relying on the CD suicide gene strategy.
    Type of Publication: Journal article published
    PubMed ID: 9295134
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  • 2
    Abstract: Colorectal cancer is considered a non-immunogenic malignany. One strategy to augment the immunogenicity of such tumours is represented by the expression of costimulatory molecules by gene transfer. Using transfected variants of the human colorectal cancer cell line SW480 we tested various costimulatory molecules (CD80, CD86, CD54) and a class II major histocompatibility complex (MHC) allele (HLA-DR3) alone or in combination on their ability to support primary T-lymphocyte activation in vitro. Expression of CD80 or CD86 similarly as the combination of both was not sufficient to induce proliferation of human allogeneic T cells. Expression of CD54 together with CD80 strongly augmented the costimulatory function of CD80, as observed in the presence of a CD3 monoclonal antibody (mAb), but did not lead directly to a T-cell response against modified tumour cells. Importantly, SW480 cells coexpressing CD54, CD80 and the HLA-DR3 allele effectively promoted T-lymphocyte proliferation. Moreover, the use of such CD54+/CD80+/HLA-DR3+ SW480 variants for repetitive stimulations resulted in the generation of T-cell lines predominantly composed of CD8+ T cells exhibiting class I MHC restricted cytolytic activity towards untransfected SW480 tumour cells. This demonstrates that the generation of immunogenic tumour cell variants, i.e. for the use as cellular vaccines, requires multiple genetic alterations in the case of non-immunogenic human tumours cells, such as colorectal cancer cells.
    Type of Publication: Journal article published
    PubMed ID: 9640250
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  • 3
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; SURVIVAL ; tumor ; carcinoma ; CELL ; Germany ; MODEL ; THERAPY ; TOOL ; GENE ; GENES ; MONOCLONAL-ANTIBODY ; MICE ; MECHANISM ; MARKER ; VARIANTS ; BREAST-CANCER ; antibodies ; antibody ; GLYCOPROTEIN ; TARGET ; MOUSE ; PROGRESSION ; METASTASIS ; MONOCLONAL-ANTIBODIES ; CARCINOMAS ; MOUSE MODEL ; L1 ; CELL-ADHESION MOLECULE ; expression profiling ; EFFECTOR ; FEATURES ; ONCOLOGY ; PROGRAM ; VARIANT ; TUMOR-GROWTH ; HUMAN TUMORS ; DEPLETION ; MOTILITY ; L1 CD171 ; METASTATIC COLORECTAL-CANCER ; PROMOTE
    Abstract: Recent work has identified L1CAM (CD171) as a novel marker for human carcinoma progression. Functionally, L1CAM promotes tumor cell invasion and motility, augments tumor growth in nude mice, and facilitates experimental tumor metastasis. These functional features qualify L1 as an interesting target molecule for tumor therapy. Here, we generated a series of novel monoclonal antibodies (mAb) to the L1CAM ectodomain that were characterized by biochemical and functional means. All novel mAbs reacted specifically with L1CAM and not with the closely related molecule CHL1, whereas antibodies to the COOH terminal part of L1CAM (mAb2C2, mAb745H7, pcytL1) showed cross-reactivity. Among the novel mAbs, L1-9.3 was selected and its therapeutic potential was analyzed in various isotype variants in a model of SKOV3ip cells growing i.p. in CD1 nude mice. Only therapy with the IgG2a variant efficiently prolonged survival and reduced tumor burden. This was accompanied by an increased infiltration of F4/80-positive monocytic cells. Clodronate pretreatment of tumor-bearing animals led to the depletion of monocytes and abolished the therapeutic effect of L1-9.3/IgG2a. Expression profiling of tumor-derived mRNA revealed that L1-9.3/IgG2a therapy induced altered expression of cellular genes associated with apoptosis and tumor growth. Our results establish that anti-L1 mAb therapy acts via immunologic and nonimmunologic effector mechanism to block tumor growth. The novel antibodies to L1CAM could become helpful tools for the therapy of L1-positive human carcinomas.
    Type of Publication: Journal article published
    PubMed ID: 20215505
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  • 4
    ISSN: 1433-7347
    Keywords: Key words High tibial osteotomy ; Distal fibular osteotomy ; Neurovascular complications ; Common peroneal nerve
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Sports Science
    Notes: Abstract Based on our clinical experience and an anatomical study, we examined the conditions under which injury to the popliteal artery, tibial nerve or peroneal nerve and its branches may occur during high tibial osteotomy. In 250 high tibial osteotomies performed in our department, we observed the following intraoperative complications. (1) The popliteal artery was severed in 1 patient and repaired by the same surgical team using a microsurgical technique. (2) A tibial nerve paresis also occurred in 1 patient. (3) In 3 patients, temporary palsy of the anterior tibialis muscle was documented. (4) In 4 other patients, palsy of the extensor hallucis longus occurred. To investigate the causes of these complications in the popliteal artery, tibial nerve and branches of the peroneal nerve, we dissected the neurovascular structures surrounding the area of the osteotomy in 10 cadaveric knees and performed a high tibial osteotomy in another 13 cadaveric knees. We concluded the following. (1) The popliteal artery and tibial nerve are protected, at the level of the osteotomy, behind the popliteus and tibialis posterior muscles. Damage can occur only by placing the Hohman retractor behind the muscles. The insertion of the muscles is very close to the periosteum and can be separated only with a scalpel. (2) The tibialis anterior muscle is innervated by a group of branches arising from the deep branch of the peroneal nerve. In two-thirds of the dissected knees, we found a main branch close to the periosteum, which can be damaged by dividing the muscle improperly or due to improper placement and pressure of the Hohman retractor. This may explain the partially reversible muscle palsy. (3) The extensor hallucis longus is also innervated by 2–3 thin branches, arising from the deep branch of the peroneal nerve, but in 25% of the specimens, only one large branch was found. This branch is placed under tension by manipulating the distal tibia forward. Thus, it may be damaged by the Hohman retractor during distal screw fixation, tensioned by hyperextension or directly injured during midshaft fibular osteotomy.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 0014-4827
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1433-7347
    Keywords: Key words Carpal tunnel ; Nerve ; compression ; Open release ; Endoscopy ; Two small incisions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Sports Science
    Notes: Abstract In reporting on the preliminary results of our series of 76 patients, this paper aims to identify potentially complicating aspects of endoscopic carpal tunnel release (ECTR) using the two-portal Chow technique, and to recommend solutions, based on our early experience, which enhance the ease and safety of this minimally invasive technique. Of the first 24 patients, 16 cases required conversion to an open procedure. Based on these initial cases, we developed certain modifications of the Chow technique which precluded any need for open conversion in the 60 remaining cases. During a follow-up interval ranging from 4 to 24 months, there was no recurrence of carpal tunnel symptoms, and the average time to resumption of work activity was 14 days. The complication rate was 5% and included one case of transient hypesthesia, one case of extended hematoma, and one hypersensitive scar. All complications resolved at subsequent follow-up. In our experience, correct positioning of the hand, proper injection of local anesthetic, use of magnifying loupes, and correct use of instruments are essential for a safe and successful procedure.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 0022-4731
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1440
    Keywords: Interleukin-2 ; Colorectal neoplasms ; Gene therapy ; Adoptive cellular immunotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract One aim of the genetic modification of tumor cells is the generation of immunogenic variants that can be used for the induction of immune responses against tumors. We engineered the human colorectal carcinoma cell line SW480 by means of plasmid transfection to secrete interleukin (IL)-2. Transfection of SW480 cells resulted in stable IL-2 secretion at 5–30 ng/ml per 105 cells in 24 h and, unexpectedly, in CD54 expression on the cell surface. SW480 variants expressing IL-2 and CD54 were tested for their capacity to induce T lymphocyte activation in vitro in comparison to untransfected and CD54 transfected cells. The cytolytic effector function of a class I MHC restricted CD8+, peptide antigen specific T cell clone was augmented following expression of CD54. IL-2 secreting SW480 variants did not further increase antigen-dependent cytolysis. Primary activation of resting T lymphocytes was assessed following allogeneic stimulation. When compared with unmodified SW480 cells, CD54 expressing variants did not initiate T cell proliferation. In contrast, IL-2 secreting SW480 cells strongly promoted primary T cell proliferation. Similarly, exogenous IL-2 and SW480 cells induced T cell pro liferatiowhich was not only due to IL-2 but was depen dent on tumor cells. However, following the initial wave of cell growth in response to IL-2 secreting SW480 cells T lymphocytes could not be restimulated with SW480 or IL-2 secreting variants and could not be further expanded. T cells initially activated by IL-2 secreting SW480 cells exhibited cytolytic activity towards SW480 cells. This reactivity, however, was transient and completely blocked by K562 cells, suggesting MHC-unrestricted, nonspecific cytotoxicity. We conclude that endogenous IL-2 secretion by the colorectal carcinoma cell line SW480 does not result in the activation of MHC restricted specific T lymphocytes but predominantly induces lymphokine-activated killer cells. Considering that tumor cell vaccines are aimed at inducing tumor-specific immune responses, our in vitro observation would rather argue against the in vivo application of such a tumor cell modification in colorectal cancer.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1437-1596
    Keywords: Key words Trauma ; Calcification ; Bone ; Embolism ; Autopsy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Law
    Notes: Abstract Embolism of bone marrow to the lungs is a quite frequent finding after trauma but transport and deposition of solid bone is rarely seen, which may simply be because pulmonary calcifications are not recognized as bone fragments. We report on three patients with embolism of bone spicules to small lung arteries of about 0.5 mm in diameter which were plentiful in two of the patients on postmortem examination. However, the true nature of the emboli was only recognizable after decalcification of lung tissues. It appears that trauma occurring in a septic bone lesion has the greatest chance to provoke bone embolism. The bone spicules do not usually occlude vessel lumina and thus do not severely disturb the blood circulation in the lungs. The bone fragments become covered by endothelium and can remain recognizable for months or even years.
    Type of Medium: Electronic Resource
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