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Biomedical subjects

C Renner

Publications and source records attributed to C Renner.

At least 55 records · Page 3Linked to original sources
PubMed2000

Immune recruitment by bispecific antibodies for the treatment of Hodgkin disease.

For the treatment of Hodgkin lymphoma, bispecific monoclonal antibodies (bi-mAbs) were established which recognize the Hodgkin-associated CD30 antigen with one arm and the CD3 or CD28 antigen on T lymphocytes or the CD16 antigen on natural killer (NK) cells with the second arm. The NK cell-activating alpha-CD16/CD30 antibody was able to retarget human NK cells toward CD30- target cells and induce their lysis. Sixty percent of Hodgkin tumor-bearing severe combined immunodeficient mice responded to a combined treatment with bi-mAb and human NK cells, leading to a final cure rate of 20%. T cell-activating bi-mAbs were more effective, resulting in the cure of all mice treated. The in vivo administration of both alpha-CD3/CD30 and alpha-CD28/CD30 antibodies resulted in the specific activation of resting human T cells infiltrating the CD30+ Hodgkin tumors. Tumor-infiltrating lymphocytes in the group of mice treated with both T cell-activating bi-mAbs expressed high levels of cytokines and cytotoxic molecules such as perforin and the cytotoxic serine esterases granzyme A and B. More importantly, activated T cells did not home to CD30 tissue and did not enter the circulation. Encouraged by these preclinical data, 15 patients with treatment-refractory Hodgkin lymphoma were included in a phase I/II dose-escalation study and treated four times every 3 or 4 days with increasing doses of the alpha-CD16/CD30 bi-mAb ranging from 1 mg/m2 to 128 mg/m2. No dose-limiting toxicity occurred even at the highest doses. Of these 15 patients, one had a complete response, one a partial response, three a mixed response, two stable disease, and eight patients had progressive disease. Treatment with immunological effector cell-recruiting bi-mAbs is a promising new approach to the treatment of Hodgkin disease refractory to standard therapy.

Animals↗
PubMed2000

Initiation of humoral and cellular immune responses in patients with refractory Hodgkin's disease by treatment with an anti-CD16/CD30 bispecific antibody.

Fifteen patients with refractory Hodgkin's disease were treated in a dose-escalation trial with the bispecific monoclonal antibody (bi-mAb) HRS-3/A9, which is directed against the Fc gamma receptor III (CD16 antigen) and the Hodgkin's-associated CD30 antigen. Treatment consisted of four cycles of four bi-mAb infusions given over 1 h every 3-4 days at different dose levels ranging from 1 mg/m2 to 64 mg/m2. Measurable serum levels (above 0.1 microgram/ml) of circulating bi-mAb could be detected in patients treated with doses above 4 mg/m2, reaching peak levels of 9.5 micrograms/ml immediately after the end of antibody infusion on the highest dose level. Bi-mAb elimination corresponded to second-order kinetics with a terminal half-life time (t1/2, beta) of 28-32 h. Bi-mAb treatment induced the occurrence of human anti-(mouse Ig) antibodies (HAMA) in 6 out of 13 patients initially testing negative. All 6 patients not only developed anti-isotypic anti-(mouse Ig) but also anti-idiotypic and anti-anti-idiotypic antibodies. While no consistent changes of peripheral blood cell counts, or of any lymphocyte subpopulation including natural killer (NK) cells, has been observed, 4 out of 6 evaluable patients treated with doses of at least 4 mg/m2 showed an increase of NK cell activity within 2 weeks after treatment, which lasted for a maximum of 12 weeks. Circulating amounts of soluble CD30 antigen could be detected in the serum of 6 patients. However, like the results and time courses of all the other immunological parameters evaluated, this was not predictive for treatment outcome.

Animals↗
PubMed2000

Tumour vaccines: a new immunotherapeutic approach in oncology.

Substantial progress has been made in vaccine development in recent years for the treatment of malignant diseases. New technologies have fostered the identification of potentially immunogenic tumour antigens that can be used to activate the patient's immune system to specifically recognize and destroy human tumour cells. More detailed insights into the process of intracellular protein degradation, processing and cell surface presentation have allowed immunogenic peptide domains to be identified that can be used in vaccine trials. Still a matter of intensive debate is the question of the most optimal presentation of tumour-derived proteins or peptides to the immune system to achieve a maximum response. In this area, major progress has been made by using dendritic cell or even naked DNA-based vaccines. The generation of new tools such as HLA-tetramer complexes now allows researchers to monitor more closely the expansion of peptide-specific T cells under the process of vaccination. On the basis of these advances, a couple of vaccine trials have been performed that have increased our knowledge of vaccine development and provided indications that the concept of tumour-specific vaccination might be valid. However, we are still at the beginning of this process and should always remember that only well-designed, prospective clinical trials can define the optimal use of tumour vaccines in oncology.

Cancer Vaccines↗
PubMed2000

Gene-modified spontaneous Epstein-Barr virus-transformed lymphoblastoid cell lines as autologous cancer vaccines: mutated p21 ras oncogene as a model.

The transfer of genes coding for tumor antigens (Ags) into Ag-presenting cells is a promising strategy to develop cancer vaccines for patients not limited by major histocompatibility complex restriction. To test whether autologous lymphoblastoid cell lines (LCL) can be used as an alternative to dendritic cells for Ag presentation, we established LCL by spontaneous growth in cyclosporin-containing medium in vitro (SP-LCL). SP-LCL, which have an advantage over B95-8-transfected LCL in that they carry no risk of introducing a new infectious agent when used for vaccination, served as a permanent source for transfection with an episomal Epstein-Barr virus-based expression vector encoding the Ki-ras p21 oncogene carrying a point mutation at codon 12 (muRas) as a model tumor Ag. The ability of muRas-transfected SP-LCL (muRas-LCL) to induce immunoreactivity was determined in vitro. After electroporation with an optimized protocol, muRas-LCL expressed mutated ras peptides for a considerable period of time (at least 8 weeks) on the cell surface. The transfection procedure did not affect the expression of the costimulatory molecules B7.1, intercellular adhesion molecule-1, and leukocyte function associated Ag-3 by SP-LCL. muRas-LCL were able to induce muRas-specific cytotoxic T lymphocytes from three of three healthy donors and one of one patient with pancreatic carcinoma. Our results suggest that the gene transfer of muRas sequences to SP-LCL leads to an endogenous processing of this Ag in the major histocompatibility complex class I pathway and to functional presentation of antigenic peptides to CD8+ T lymphocytes. Autologous SP-LCL can serve as an unlimited renewable source for autologous cellular vaccines and appear to be good candidates as presenters for a wide range of human tumor Ags.

B7-1 Antigen↗
PubMed1999

Preferred conformation of endomorphin-1 in aqueous and membrane-mimetic environments.

The newly discovered endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) are potent opioid peptides with the highest affinity and selectivity for the mu receptor among all known endogenous ligands. To investigate a possible correlation between these biological properties and the conformational preferences of the small peptides, a comparative structural analysis was performed of endomorphin-1 in aqueous buffer and in membrane-mimicking SDS and AOT normal and reverse micelles by the use of CD, FT-IR, fluorescence and(1)H-NMR spectroscopy. It is well established for opioid peptides that, independently of the receptor selectivity, the Tyr1 residue plays the role of the primary pharmacophore and that the orientation of the second aromatic pharmacophore relative to the tyrosine side-chain dictates the mu or delta-receptor selectivity. By varying the environment of endomorphin-1 from water to the amphipathic SDS micelles and even more efficiently to the AOT reverse micelles, the display of the aromatic side-chains changes from an interaction of the Tyr1 and Phe4 residues to a switch of the Trp3 indole group into close contact with the phenolic moiety to prevent this type of interaction and to force an orientation of the Phe4 side-chain into the opposite direction. This conformational switch is accompanied by a stabilization of the cis -Pro2 isomer and the resulting spatial array of the pharmacophoric groups correlate well with the structural model of mu receptor-bound opioid peptides. The results indicate that AOT reverse micelles with a woof 10, where almost exclusively ordered water is secluded in the cavity, constitute with their electrostatic and hydrophobic potential an excellent mimetic of amphipathic surfaces as present on lipid bilayers and on ligand-recognition and ligand-binding sites of proteins.

Circular Dichroism↗
PubMed1999

Immunotherapy of human tumors with T-cell-activating bispecific antibodies: stimulation of cytotoxic pathways in vivo.

Bispecific monoclonal antibodies (Bi-mAbs) specific for a tumor-associated antigen and the CD3 or CD28 antigen on T lymphocytes represent one of the most successful experimental strategies for the immunotherapy of cancer. We report that the in vivo administration of both alpha-CD3/CD30 and alpha-CD28/CD30 Bi-mAbs results in the specific activation of xenotransplanted, resting human T cells infiltrating the CD30-positive Hodgkin's tumor. Bi-mAb treatment resulted in enhanced expression of cytokines such as interleukin 1beta, interleukin 2, tumor necrosis factor type alpha, and activation markers including Ki-67, CD25, and CD45RO in tumor-infiltrating lymphocytes. This antigen-dependent, local T-cell stimulation led to the activation of the cytolytic machinery in T lymphocytes, determined by the up-regulation of mRNA-encoding perforin and the cytotoxic serine-esterases granzymes A and B. The Bi-mAb-induced generation of CTLs depended on the presence of the CD30 antigen and the combined application of both Bi-mAbs. Our findings suggest that the combined application of T-cell-activating Bi-mAbs is able to achieve a tumor site-specific activation of the T-cell cytolytic machinery in vivo. The fact that these cytotoxic cells do not home in tumor-associated antigen-negative tissue and do not enter circulation might explain our previous observations (C. Renner et al., Blood, 87: 2930-2937, 1996) of a high cure rate in preclinical models even at an advanced stage of disease.

Animals↗
PubMed1999

EB/RP gene family encodes tubulin binding proteins.

Mutations in the adenomatous polyposis coli (APC) gene are linked to the dysplastic transformation of colorectal polyps and represent an early step in the development of colorectal tumors. Ninety-four percent of all mutations result in the expression of a truncated APC protein lacking the C-terminal region. The C-terminal region of the APC protein may have a tumor suppressor function as its absence appears to be linked to the development of dysplastic lesions. Recently, we discovered and characterized a protein called RP1 which binds specifically to the C-terminal region of the APC protein. We show now that RP1 and the other known members of the EB/RP family (EB1 and RP3) also bind directly to tubulin, both in vitro and in vivo. Immunohistochemical analyses reveal a distinct staining pattern during interphase as well as an association of RP1/EB1 with mitotic microtubule structures. The previously described puncta of the APC protein at the leading edge of membrane protrusions contact microtubule fibers that contain RP1 or EB1.

Adenomatous Polyposis Coli↗
PubMed1999

Geometry of laparoscopic suturing and knotting techniques.

BACKGROUND: Spatial limitation, together with a fixed trocar position, restricted handling, and movement of the instruments, is inevitably associated with reconstructive laparoscopy and retroperitoneoscopy. This problem includes not only suturing technique and instruments but also geometric factors of endoscopic reconstruction, such as optimal distances between the working trocars, length of instruments, and angles between the instruments and the object. We present an experimental access to determine the specific impact of these factors on reconstructive laparoscopy. MATERIALS AND METHODS: In an in vitro model, end-to-end anastomoses of porcine intestine were performed using a standardized intracorporeal suturing technique. Suturing was performed without and after training in reconstructive surgery with variation of the following geometric factors: (1) the distance between the working trocars (between 6 and 12 cm); (2) the position of the object (lateral right, medially, lateral left); (3) the camera position (medially, lateral right, lateral left); (4) the angle between the instruments and a horizontal line (15 degrees , 55 degrees, 90 degrees); (5) the intracorporeal length of instruments (between 10 and 25 cm); and (6) narrowed space available for the instruments (between 4 and 25 cm). RESULTS: Continual training decreased the time required for suturing between 30% to 50%. Training decreased the time required for nonsuturing activities between 50% and 70% but the time required for suturing activities only between 20% and 45%. If the space between instruments and camera was limited, shifting the camera into a lateral position simplified the procedure of intracorporeal suturing. Angles of <55 degrees between instruments and the horizontal line simplified laparoscopic suturing, as did angles of <45 degrees between the instruments. In cases of maximally narrowed space (diameter of 4 cm), a suture filament length of <10 cm decreased the time required by 30%. CONCLUSION: We suggest an isosceles triangle between the instruments with an angle between 25 degrees and 45 degrees and an angle of <55 degrees between the instruments and the horizontal line as the optimal geometry for intracorporeal suturing. These data should be considered when planning a reconstructive laparoscopic procedure (i.e., alignment of trocars, table position). However, further studies are required to confirm these preliminary results.

Anastomosis, Surgical↗
PubMed1999

Treatment of Peyronie's disease by extracorporeal shockwave therapy: evaluation of our preliminary results.

BACKGROUND: Peyronie's disease is an idiopathic disorder of the penis that produces erectile dysfunction. It affects mainly the tunica albuginea. We describe our preliminary results with extracorporal shockwave therapy (ESWT) as a new noninvasive modality for the treatment of Peyronie's disease. PATIENTS AND METHODS: In this study, 24 patients aged 36 to 67 years were treated with ESWT on the Lithostar overhead-module (Siemens). All our patients had unsuccessful medical treatment before ESWT. The average plaque was 7x15 mm. The number of shockwaves ranged from 15,000 to 25,000 (18-21 kV) delivered in four to ten sessions. Most patients needed local anesthesia before therapy. RESULTS: Four patients (17%) showed marked improvement and complete remission of the penile deviation. Six patients (25%) showed partial remission with painless erections after treatment. Four patients had painless erections after treatment but still had some penile deviation. In 10 patients (41%), ESWT failed, necessitating subsequent penile surgery. CONCLUSIONS: Our preliminary results with a response rate of 59% with ESWT for Peyronie's disease, including a 17% complete remission rate, is encouraging. However, further multicenter studies will have to prove if ESWT is a real therapeutic option for this disease.

Adult↗
PubMed1999

Outsourcing to increase service capacity in a New Zealand hospital.

Service firms manage variability using both demand-side tactics (levelling customer demand), and supply-side tactics (increasing available capacity). One popular way of increasing available capacity is the outsourcing of non-core services. This article uses a case study to examine the impact of an outsourced non-core service on a hospital's overall service system. Findings show that the outsourced service provides access to more sophisticated technology, increases in-house capacity and saves capital expenditure. However, the outsourcing also increases the scheduling problems that the hospital faces. These problems are largely due to communication delays from the involvement of more than one organisation. These delays decrease the response time available to match changes in demand for the outsourced service. Given the obvious benefits of such outsourcing, the article concludes that management should pay close attention to the communication pathways between organisations, in order to minimise the end effects identified in this study.

Cost-Benefit Analysis↗
PubMed1999

Treatment of renal stones by extracorporeal shock wave lithotripsy.

Based on an extensive review of the literature and our own clinical experience, this article attempts to present clear guidelines for the management of various kidney stones that will be acceptable to clinical urologists and their patients. Regarding our own patients, we compared different studies and discussed the results concerning the anatomical kidney situation, stone size, stone localization and observation time. Stone-free rates of patients with calyceal diverticula calculi range from 4 to 58%, with an increase after longer follow-up periods. According to the importance of residual fragments following extracorporeal shock wave lithotripsy (ESWL), we have to distinguish between clinical insignificant residual fragments and clinical significant residual fragments. 24 months following ESWL, stone passage occurs as a continuous process, and if there are no clinical symptoms, any endoscopic procedure should be considered as over-treatment. Newer ESWL technology has increased the percentage of clinically insignificant residual fragments. We consider percutaneous nephrolithotripsy in most of the patients with renal calculi smaller than 30 mm in diameter only as second-line therapy.

Humans↗
PubMed1998

Structure of the IGF-binding domain of the insulin-like growth factor-binding protein-5 (IGFBP-5): implications for IGF and IGF-I receptor interactions.

Binding proteins for insulin-like growth factors (IGFs) IGF-I and IGF-II, known as IGFBPs, control the distribution, function and activity of IGFs in various cell tissues and body fluids. Insulin-like growth factor-binding protein-5 (IGFBP-5) is known to modulate the stimulatory effects of IGFs and is the major IGF-binding protein in bone tissue. We have expressed two N-terminal fragments of IGFBP-5 in Escherichia coli; the first encodes the N-terminal domain of the protein (residues 1-104) and the second, mini-IGFBP-5, comprises residues Ala40 to Ile92. We show that the entire IGFBP-5 protein contains only one high-affinity binding site for IGFs, located in mini-IGFBP-5. The solution structure of mini-IGFBP-5, determined by nuclear magnetic resonance spectroscopy, discloses a rigid, globular structure that consists of a centrally located three-stranded anti-parallel beta-sheet. Its scaffold is stabilized further by two inside packed disulfide bridges. The binding to IGFs, which is in the nanomolar range, involves conserved Leu and Val residues localized in a hydrophobic patch on the surface of the IGFBP-5 protein. Remarkably, the IGF-I receptor binding assays of IGFBP-5 showed that IGFBP-5 inhibits the binding of IGFs to the IGF-I receptor, resulting in reduction of receptor stimulation and autophosphorylation. Compared with the full-length IGFBP-5, the smaller N-terminal fragments were less efficient inhibitors of the IGF-I receptor binding of IGFs.

3T3 Cells↗
PubMed1998

Structure of reduced DsbA from Escherichia coli in solution.

The three-dimensional structure of reduced DsbA from Escherichia coli in aqueous solution has been determined by nuclear magnetic resonance (NMR) spectroscopy and is compared with the crystal structure of oxidized DsbA [Guddat, L. W., Bardwell, J. C. A., Zander, T., and Martin, J. L. (1997) Protein Sci. 6, 1148-1156]. DsbA is a monomeric 21 kDa protein which consists of 189 residues and is required for disulfide bond formation in the periplasm of E. coli. On the basis of sequence-specific 1H NMR assignments, 1664 nuclear Overhauser enhancement distance constraints, 118 hydrogen bond distance constraints, and 293 dihedral angle constraints were obtained as the input for the structure calculations by simulated annealing with the program X-PLOR. The enzyme is made up of two domains. The catalytic domain has a thioredoxin-like fold with a five-stranded beta-sheet and three alpha-helices, and the second domain consists of four alpha-helices and is inserted into the thioredoxin motif. The active site between Cys30 and Cys33 is located at the N terminus of the first alpha-helix in the thioredoxin-like domain. The solution structure of reduced DsbA is rather similar to the crystal structure of the oxidized enzyme but exhibits a different relative orientation of both domains. In addition, the conformations of the active site and a loop between strand beta5 and helix alpha7 are slightly different. These structural differences may reflect important functional requirements in the reaction cycle of DsbA as they appear to facilitate the release of oxidized polypeptides from reduced DsbA. The extremely low pKa value of the nucleophilic active site thiol of Cys30 in reduced DsbA is most likely caused by its interactions with the dipole of the active site helix and the side chain of His32, as no other charged residues are located next to the sulfur atom of Cys30 in the solution structure.

Amino Acid Sequence↗