Biomedical subjects

C Hess

Publications and source records attributed to C Hess.

At least 19 recordsLinked to original sources

PubMed2001

Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth.

The vascular endothelial growth factor (VEGF) receptor is a major target for anti-angiogenesis-based cancer treatment. Here we report the treatment effect of ionizing radiation in combination with the novel orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on endothelial cell proliferation in vitro and with tumour xenografts in vivo. Combined treatment of human umbilical vein endothelial cells with increasing doses of PTK787/ZK222584 and ionizing radiation abrogated VEGF-dependent proliferation in a dose-dependent way, but inhibition of endothelial cell proliferation was not due to apoptosis induction. In vivo, a combined treatment regimen of PTK787/ZK222584 (4 x 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 x 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-dysfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells while each treatment modality alone had only a minimal effect on tumour size and neovascularization. SW480 tumours from animals that received a combined treatment regimen, displayed not only an extended tumour growth delay but also a significant decrease in the number of microvessels in the tumour xenograft. These results support the model of a cooperative anti-tumoral effect of angiogenesis inhibitor and irradiation and show that the orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 is suitable for combination therapy with irradiation.

Adenocarcinoma↗

PubMed2001

Novel surface vibrational spectroscopy: infrared-infrared-visible sum-frequency generation.

A novel type of surface vibrational sum-frequency generation spectroscopy is presented that enables a highly specific measurement of the coupling of molecules on surfaces. With this doubly vibrationally resonant technique, two-dimensional vibrational spectroscopy of molecules on surfaces becomes possible. The technique is demonstrated for the C-O stretch vibration of CO on a ruthenium (001) surface. It allows for the determination of the intermolecular coupling strength of dipole-coupled CO molecules on the surface.

Journal Article↗

PubMed2001

Key targets for the execution of radiation-induced tumor cell apoptosis: the role of p53 and caspases.

In many human hematologic and solid malignancies, intrinsic or acquired treatment resistance remains a major obstacle for successful cancer therapy. The molecular understanding of how tumor cells respond to chemotherapy and ionizing radiation is rapidly evolving. Induction of programmed cell death, apoptosis, is one important strategy for successful cancer therapy. This has been shown convincingly for oncogene-transformed normal cells as well as tumor cells of lymphoid origin. However, the relevance of apoptosis in solid human malignancies is less clear. Loss of apoptosis might be linked to specific mutations in the often tissue-specific apoptotic pathways due to aberrations in the stress-related signal transduction cascades. Restoration of a dysfunctional apoptotic program in cancer tissue where apoptosis has been identified as an important mechanism for tissue homeostasis is one rational approach for innovative cancer therapy. In this review, we focus on the relevance of the tumor suppressor p53 for apoptosis-induction and successful cancer therapy outlining the importance of an intact caspase machinery for apoptosis execution. Strategies are discussed to overcome treatment resistance and a high apoptotic threshold in human malignancies where apoptosis is the dominant mode of cell death and the status of p53 is an important determinant for apoptosis induction.

Adenoviridae↗

PubMed2001

Adjuvant versus neoadjuvant radiochemotherapy for locally advanced rectal cancer. A progress report of a phase-III randomized trial (protocol CAO/ARO/AIO-94).

AIM: The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy is recommended for patients with advanced disease (pT3/4 or pN+). In recent years, encouraging results of preoperative radiotherapy have been reported. This prospective randomized phase-III trial (CAO/ARO/AIO-94) compares the efficacy of neoadjuvant radiochemotherapy to standard postoperative radiochemotherapy. We report on the design of the study and first results with regard to toxicity of radiochemotherapy and postoperative morbidity. PATIENTS AND METHODS: Patients with locally advanced operable rectal cancer (uT3/4 or uN+, Mason CS III/IV) were randomly assigned to pre- or postoperative radiochemotherapy: A total dose of 50.4 Gy (single dose 1.8 Gy) was applied to the tumor and the pelvic lymph nodes. 5-FU (1,000 mg/m2/d) was administered concomitantly in the first and fifth week of radiation as 120-h continuous infusion. Four additional cycles of 5-FU chemotherapy (500 mg/m2/d, i.v. bolus) were applied. Radiochemotherapy was identical in both arms except for a small-volume boost of 5.4 Gy in the postoperative setting. Time interval between radiochemotherapy and surgery was 4-6 weeks in both arms. Techniques of surgery were standardized and included total mesorectal excision. In addition, stratification according to surgeons involved has been provided for. Primary endpoints of the study are 5-year overall-survival, local and distant control, secondary endpoints include rate of curative (R0) resections and sphincter saving procedures, toxicity of radiochemotherapy, surgical complications and quality of life. RESULTS: As of 15th November 2000, 628 patients were randomized from 26 participating institutions: 310 patients were randomized to postoperative radiochemotherapy, 318 patients to preoperative radiochemotherapy. Acute toxicity (WHO) of radiochemotherapy was low, with less than 15% of patients experiencing Grade 3 or higher toxicity: The principal toxicity was diarrhea, with 12% in the postoperative radiochemotherapy arm and 10% in the preoperative radiochemotherapy arm having Grade-3, and 1% in either arm having Grade-4 diarrhea. Erythema, nausea and leukopenia were the next common toxicities, with less than 3% of patients in either arm suffering Grade 3 or greater leukopenia or nausea. Postoperative complication rates were similar in both arms, with 12% (postoperative radiochemotherapy) and 13% (preoperative radiochemotherapy) of patients, respectively, suffering from anastomotic leakage, 4% (postoperative radiochemotherapy) and 3% (preoperative radiochemotherapy) from postoperative bleeding, and 6% (postoperative radiochemotherapy) and 5% (preoperative radiochemotherapy) from delayed wound healing. CONCLUSION: The patient accrual of our trial is satisfactory, neoadjuvant radiochemotherapy is well tolerated and bears no higher risk for postoperative morbidity.

Adult↗

PubMed2001

Melatonin protects SHSY5Y neuroblastoma cells from cobalt-induced oxidative stress, neurotoxicity and increased beta-amyloid secretion.

Heavy metals are increasingly being implicated as causative agents in neurodegenerative diseases such as Alzheimer's disease (AD). Cobalt, a positively charged transition metal, has previously been shown to be in elevated levels in the brain of AD patients compared with age-matched controls. In this study, we investigate the effects of cobalt as an inducer of oxidative stress/cell cytotoxicity and the resultant metabolic implications for neural cells. We show that cobalt is able to induce cell cytotoxicity (reduced MTT metabolism) and oxidative stress (reduced cellular glutathione). The pre-treatment of cells with the pineal indoleamine melatonin, prevented cell cytotoxicity and the induction of oxidative stress. Cobalt treatment of SHSY5Y cells increased the release of beta-amyloid (Abeta) compared with untreated controls (ratio Abeta 40/42). Melatonin pre-treatment reversed the deleterious effects of cobalt. These findings are significant as cobalt is an essential nutritional requirement, usually bound to cobalamin (vitamin B12), for all animals which in the unbound form could lead to neurotoxicity.

Alzheimer Disease↗

PubMed2001

The first activating TSH receptor mutation in transmembrane domain 1 identified in a family with nonautoimmune hyperthyroidism.

Sporadic and familial nonautoimmune hyperthyroidism are very rarely occurring diseases. Within the last years constitutively activating TSH receptor mutations were identified as one possible pathomechanism. Except for S281N in the extracellular N-terminal domain, all other germline mutations are located in the transmembrane domains 2, 3, 5, 6, and 7 of the TSH receptor, whereas no mutation was reported in transmembrane domains 1 and 4 to date. Here we report the first family with a constitutively active TSHR mutation in transmembrane domain 1 resulting in a substitution of the conserved Gly(431) for Ser. This mutation was found in the investigated patient, his father, and the paternal grandmother. As known from other familial cases of nonautoimmune hyperthyroidism, the age of onset of the disease was variable, ranging from early childhood in the patient and his father to adolescence in the grandmother. Functional characterization of this mutation showed a constitutive activation of the G(s)/adenylyl cyclase system. Moreover, this germline mutation also activates the G(q/11)/phospholipase C pathway. The importance of Gly(431) for receptor quiescence is supported further by introduction of other mutations at this position, all leading to constitutive receptor activity. Our data show now that constitutively activating mutations can be found in the entire transmembrane domain region of the TSH receptor, indicating the important role of all parts of the transmembrane domain region for maintaining the inactive receptor conformation.

Adenylyl Cyclases↗

PubMed2000

Direct observation of vibrational energy delocalization on surfaces: CO on Ru(001)

We report the experimental observation of the gradual transition from a local oscillator to a two-dimensional delocalized phonon, observed for the CO-stretch vibration of carbon monoxide adsorbed on a Ru(001) surface by means of broadband-infrared saturation sum-frequency spectroscopy. The data are theoretically reproduced by an exchange model with residence times of the excitation down to 2.5 ps.

Journal Article↗

PubMed2000

Induction of neutrophil responsiveness to myeloperoxidase antibodies by their exposure to supernatant of degranulated autologous neutrophils.

Antibodies against myeloperoxidase (MPO) and proteinase 3 (PR3) are the predominant autoantibodies present in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Their binding to the corresponding antigen on the surface of polymorphonuclear neutrophils (PMNs) is believed to trigger the disease process. Cytokines released during an inflammatory reaction are thought to prime resting PMNs, making them responsive to autoantibodies. In the present study we found that MPO but not PR3 could be detected on the cell surface of unstimulated PMNs after incubation with the supernatants of activated autologous PMNs. MPO was shown to be acquired from these supernatants, because PMNs did not express MPO when the supernatants were specifically MPO-depleted. In addition, purified soluble MPO bound to unstimulated PMNs. Unstimulated PMNs that had passively acquired MPO released oxygen radicals when incubated with monoclonal antibody anti-MPO or the immunoglobulin G fraction of a patient with MPO-ANCA. The data presented here suggest that, in ANCA-associated vasculitis, soluble MPO released by activated PMNs may bind to unstimulated PMNs, thereby making them reactive to anti-MPO antibodies. This mechanism of dispersing PMN activation would be specific for MPO-ANCA and may explain differences in the pathologic and clinical expression of MPO-ANCA versus PR3-ANCA vasculitis. (Blood. 2000;96:2822-2827)

Adsorption↗

PubMed2000

[Adolescent crisis with cyclic abdominal complaints and regressive behavior].

In this 18 year old female patient with adolescent crisis, psychic regression and cyclic abdominal pain, the diagnosis of an acute intermittent porphyria was made by positive urine finding of porphobilinogen, by low serum measurement of the enzyme urosynthase and the positive genetic mutation of this enzyme. The article gives a brief report of the pathogenesis, clinical findings, diagnostic tests and the current therapies being undertaken. Further, a list of medications which are indicated or contraindicated relating to the patient with acute intermittent porphyria is noted.

Abdominal Pain↗

PubMed2000

Femtosecond surface vibrational spectroscopy of CO adsorbed on Ru(001) during desorption

Using time-resolved sum-frequency generation spectroscopy, the C- O stretch vibration of carbon monoxide adsorbed on a single-crystal Ru(001) surface is investigated during femtosecond near-IR laser excitation leading to desorption. A large transient redshift, a broadening of the resonance, and a strong decrease in intensity are observed. These originate from coupling of the C- O stretch to low-frequency modes, especially the frustrated rotation, that are highly excited in the desorption process.

Journal Article↗

PubMed2000

Thermal and electronic transport properties and two-phase mixtures in La(5/8-x)Pr(x)Ca(3/8)MnO3

We measured thermal conductivity kappa, thermoelectric power S, and electric conductivity sigma of La(5/8-x)Pr(x)Ca(3/8)MnO3, showing an intricate interplay between metallic ferromagnetism (FM) and charge ordering (CO) instability. The change of kappa, S, and sigma with temperature (T) and x agrees well with the effective medium theories for binary metal-insulator mixtures. This agreement clearly demonstrates that with the variation of T as well as x, the relative volumes of FM and CO phases drastically change and percolative metal-insulator transition occurs in the mixture of FM and CO domains.

Journal Article↗

PubMed2000

Molecular analysis of hemolysin-mediated secretion of a human interleukin-6 fusion protein in Salmonella typhimurium.

Previously, we reported a plasmid-bearing Salmonella typhimurium strain capable of secreting human interleukin-6 (hIL-6) when genetically fused to the Escherichia coli hemolysin transport signal (HlyA(S)). Stationary phase culture supernatants of this strain revealed three major forms of hIL-6-HlyA(S) fusion protein (apparent molecular masses 32.4, 30.3, 27.0 kDa), at which the largest protein presumably represented full-length hIL-6-HlyA(S). The biological activity of the hIL-6-HlyA(S) protein mixture was similar to that of mature hIL-6. Accumulation of hIL-6-HlyA(S) in the culture supernatant occurred only during the initial growth phase, whereas in stationary phase and under in vitro conditions successive cleavage into the two truncated forms was observed. On the other hand, in whole cell lysates only full-length hIL-6-HlyA(S) could be detected, accounting for more than 50% of the totally synthesized protein. Upon cell fractionation, cellular hIL-6-HlyA(S) was exclusively found in the membrane fraction. These results suggest, that in S. typhimurium production and secretion of hIL-6-HlyA(S) is restricted to growing cells. A specific processing by a Salmonella-derived protease did not affect the biological activity of the fusion protein.

Animals↗

PubMed2000

Textured-surface saline-filled silicone breast implants for augmentation mammaplasty.

The earliest silicone breast implants were smooth-surface, silicone rubber devices filled with either silicone gel or saline. Because of persistent problems with capsular contracture, polyurethane-covered silicone implants were developed as an alternative. Particularly in the short run, these alternatives proved highly successful at reducing the incidence of capsular contracture. By 1990, polyurethane-covered implants were rapidly becoming the preferred implant choice of many plastic surgeons, but for legal, regulatory, financial, and safety reasons they were withdrawn from the market by Bristol-Myers in 1991. Meanwhile, during the late 1980s, surface texturing and improved materials became available on other silicone breast implants and expanders. Most studies suggest that textured-surface silicone gel-filled implants, saline-filled implants, and tissue expanders have less frequent capsular contracture than their smooth-surface counterparts.

Breast Implants↗

PubMed1999

Monomeric complement-activating IgG paraproteins.

Three patients presented a unique syndrome of recurrent panniculitis with an IgGkappa paraprotein and depletion of the early components of the classical pathway of complement. The IgGkappa paraproteins were monomers with a normal structure, and with no evidence for aggregation, as assessed by electron microscopy and ultracentrifugation. Both heavy and light chains were of normal molecular size (SDS-PAGE), and the paraproteins were not heavily glycosylated. However, the paraproteins from all three patients had unusual features that included abnormal behavior on gel filtration chromatography and a heavy chain of high pI. When analyzed by fast protein liquid chromatography (Superdex 200), elution of the paraproteins was retarded, particularly when the ionic strength was increased. This retardation was partially reversed in 20% alcohol, and fully reversed in 6 M guanidine-HCl. Neither anti-C1 inhibitor nor anti-C1q autoantibodies were found in any of the patients' sera. However, the paraproteins bound to the globular heads of C1q at normal ionic strength. They activated C4 in normal human serum, but not in C1q-deficient serum. Activation led to the formation of C1s-C1 inhibitor complexes. Taken together, the data suggest that the unusual paraproteins have the capacity to bind C1q, which then leads to activation of C1. The ability of these paraproteins to activate C1, in spite of their being soluble monomers, is likely to be related to their unique physicochemical features.

Chromatography, Gel↗

PubMed1999

Ectosomes released by human neutrophils are specialized functional units.

Here we show that human polymorphonuclear leukocytes (PMN) release ectosomes independently of complement attack during their activation both in vitro and at the site of inflammation in vivo. Patterns of biotinylated proteins on the surface of PMN and on PMN-derived ectosomes indicated a specific sorting of cell surface proteins into and out of ectosomes. Ectosomes expressed clusters of complement receptor 1 (CR1), which allowed them to bind efficiently to opsonized bacteria. Myeloperoxidase and human leukocyte elastase, both stored within the azurophilic granules of PMN, were found to colocalize on ectosomes with CR1. Furthermore, myeloperoxidase colocalized with human leukocyte elastase. In contrast, not present on CR1-expressing ectosomes were CD63, a selective marker for the azurophilic granules, and CD14, which is located within the same granules and the secretory vesicles as CR1. Of the other complement regulatory proteins expressed by PMN, only CD59 colocalized with CR1, while CD55 and CD46 were almost absent. Ectosomes released by activated PMN at the site of inflammation may function as a well organized element (ecto-organelle), designed to focus antimicrobial activity onto opsonized surfaces.

Animals↗

PubMed1999

Phonon- versus electron-mediated desorption and oxidation of CO on Ru(0001)

Heating of a ruthenium surface on which carbon monoxide and atomic oxygen are coadsorbed leads exclusively to desorption of carbon monoxide. In contrast, excitation with femtosecond infrared laser pulses enables also the formation of carbon dioxide. The desorption is caused by coupling of the adsorbate to the phonon bath of the ruthenium substrate, whereas the oxidation reaction is initiated by hot substrate electrons, as evidenced by the observed subpicosecond reaction dynamics and density functional calculations. The presence of this laser-induced reaction pathway allows elucidation of the microscopic mechanism and the dynamics of the carbon monoxide oxidation reaction.

Journal Article↗

PubMed1999

Elastase and metalloproteinase activities regulate soluble complement receptor 1 release.

Complement receptor 1 (CR1) is cleaved from the surface of polymorphonuclear cells (PMN) in the membrane-proximal region to yield a soluble fragment (sCR1) that contains the functional domains. The enzymes involved in this cleavage are produced by the PMN itself, since in vitro stimulation of purified PMN is followed by sCR1 release. Purified human neutrophil elastase (HNE) cleaved CR1 from erythrocytes and urinary vesicles originating from podocytes and enhanced tenfold the cleavage of CR1 from activated PMN. The largest fragment released from PMN by HNE was identical in size to CR1 shed spontaneously. The CR1 fragments cleaved from erythrocytes were functional. The shedding of sCR1 by activated PMN was inhibited by phenylmethylsulfonyl fluoride (80 +/- 10%), alpha1-antiprotease (50 +/- 5%) and elafin (60 +/- 5%). Furthermore the cleavage was blocked by the metalloprotease inhibitor 1,10-phenanthroline (70 +/- 6 %) as well as by a monoclonal antibody against human neutrophil collagenase MMP8 (40 +/- 10%). Maximal inhibition of sCR1 shedding was obtained by a combination of 1,10-phenanthroline with elafin (86 +/- 6%). These inhibitors had no effect on L-selectin shedding, indicating that the cleavage of CR1 was specific. In conclusion, elastase or elastase-like activity may be responsible for the shedding of functional sCR1 in vivo, and this activity is controlled by the local release of PMN metalloproteases and alpha1antiprotease.

Complement C3b↗

PubMed1998

[Complement and its role in immune response].

The complement system as a part of innate immunity is considered to provide rapid tough incomplete antimicrobial activity. However, besides providing a first-line defence, innate immunity plays additional important roles: it initiates and improves the slower, but more specific, acquired immune response. The recognition and destruction of noxious substances, as well as initiation of the acquired immune response, are accompanied by potentially hazardous inflammation. The inflammatory process has thus to be tightly regulated. In this overview, innate immunity and its interactions with acquired immunity are discussed with the main focus on the complement system. Our scientific interests are integrated into the discussion on complement.

Animals↗