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Biomedical subjects

Rudolf M Huber

Publications and source records attributed to Rudolf M Huber.

16 recordsLinked to original sources
PubMed2006

IL-13Ralpha2 reverses the effects of IL-13 and IL-4 on bronchial reactivity and acetylcholine-induced Ca+ signaling.

BACKGROUND: The interleukins IL-4 and IL-13 play a key role in the pathophysiology of asthma. The interleukin receptor IL-13Ralpha2 is believed to act as a decoy receptor, but until now, the functional significance of IL-13Ralpha2 remains vague. METHODS: Bronchial reactivity was quantified in murine lung slices by digital video microscopy and acetylcholine (ACH)-induced Ca(2+) signaling was measured in human airway smooth muscle cells (ASMC) using fluorescence microscopy. RESULTS: IL-4 or IL-13 up to 50 ng/ml induced bronchial hyperreactivity. But after incubation with 100 ng/ml this effect was lost and bronchial responsiveness was again comparable to the control level. The effects of IL-4 and IL-13 on bronchial reactivity were paralleled by the effects on ASMC proliferation. Fifty nanograms per milliliter of IL-4 and IL-13 increased the Ca(2+) response of human ASMC to ACH. At 100 ng/ml, however, the effects of the cytokines on the Ca(2+) response were no longer evident. The expression of IL-13Ralpha2 increased with increasing concentrations of IL-4 or IL-13, reaching its maximum at 100 ng/ml. Blocking IL-13Ralpha2, the loss of the effect of IL-4 and IL-13 at 100 ng/ml on human ASMC proliferation and the ACH-induced Ca(2+) response were no longer present. CONCLUSIONS: IL-4 and IL-13 induce bronchial hyperreactivity by changing the Ca(2+) homeostasis of ASMC. These effects are counteracted by IL-13Ralpha2. The biological significance of IL-13Ralpha2 might be a protective function by regulating IL-13- and IL-4-mediated signal transduction and thereby limiting pathological alterations in Th2-mediated inflammatory diseases.

Acetylcholine↗
PubMed2006

Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group.

PURPOSE: The aim of this study was to examine whether, after preceding induction chemotherapy, simultaneous chemoradiotherapy is superior to radiotherapy alone. PATIENTS AND METHODS: Patients with non-small-cell lung cancer in inoperable stage IIIA or IIIB received induction chemotherapy with two cycles of paclitaxel 200 mg/m2 and carboplatin area under the curve 6 every 3 weeks. Patients without progression at restaging after induction chemotherapy were randomly assigned to radiotherapy (60 Gy) or chemoradiotherapy (paclitaxel 60 mg/m2 weekly). The primary end point was overall survival; secondary end points were time to progression, response, and toxicity. RESULTS: Three hundred three patients entered the study, and 276 completed induction chemotherapy. Two hundred fourteen patients were randomly assigned (radiotherapy alone: n = 113; simultaneous chemoradiotherapy: n = 101). Median follow-up time of all randomly assigned patients was 13.6 months (interquartile range [IQR], 6.4 to 29.0 months), and median follow-up time of the subgroup of censored patients (n = 52) was 37.4 months (IQR, 5.9 to 57.0 months; maximum, 76.1 months). Toxicities during the induction phase were mild. During radiotherapy, overall toxicity rates were not significantly different between the two arms. Median survival times in the radiotherapy group and chemoradiotherapy group were 14.1 months (95% CI, 11.8 to 16.3 months) and 18.7 months (95% CI, 14.1 to 23.3 months; difference not statistically significant, P = .091). Median time to progression significantly favored simultaneous chemoradiotherapy (11.5 months; 95% CI, 8.3 to 14.7 months) versus radiotherapy alone (6.3 months; 95% CI, 5.0 to 7.6 months; P < .001, log-rank test). CONCLUSION: Induction chemotherapy followed by chemoradiotherapy with weekly paclitaxel is feasible. Response, time to progression, and survival favor chemoradiotherapy compared with radiotherapy alone.

Aged↗
PubMed2006

Oral vinorelbine and cisplatin with concomitant radiotherapy in stage III non-small cell lung cancer (NSCLC): a feasibility study.

BACKGROUND: Concurrent chemoradiotherapy has improved survival in inoperable stage III non-small cell lung cancer (NSCLC). This phase I trial was performed in order to establish a dose recommendation for oral vinorelbine in combination with cisplatin and simultaneous radiotherapy. PATIENTS AND METHODS: Previously untreated patients with stage IIIB NSCLC received concurrent chemoradiotherapy with 66 Gy and 2 cycles of cisplatin and oral vinorelbine which was administered at 3 different levels (40, 50 and 60 mg/m2). This was to be followed by 2 cycles of cisplatin/ vinorelbine oral consolidation chemotherapy. The study goal was to determine the maximal recommended dose of oral vinorelbine during concurrent treatment. RESULTS: 11 stage IIIB patients were entered into the study. The median radiotherapy dose was 66 Gy. Grade 3-4 toxicity included neutropenia, esophagitis, gastritis and febrile neutropenia. The dose-limiting toxicity for concurrent chemoradiotherapy was esophagitis. 9 patients received consolidation chemotherapy, with neutropenia and anemia/thrombocytopenia grade 3 being the only toxicities. The overall response was 73%. CONCLUSION: Oral vinorelbine 50 mg/m2 (days 1, 8, 15 over 4 weeks) in combination with cisplatin 20 mg/m2 (days 1-4) is the recommended dose in combination with radiotherapy (66 Gy) and will be used for concurrent chemoradiotherapy in a forthcoming phase III trial testing the efficacy of consolidation chemotherapy in patients not progressing after chemoradiotherapy.

Administration, Oral↗
PubMed2006

Ca2+-signaling in airway smooth muscle cells is altered in T-bet knock-out mice.

BACKGROUND: Airway smooth muscle cells (ASMC) play a key role in bronchial hyperresponsiveness (BHR). A major component of the signaling cascade leading to ASMC contraction is calcium. So far, agonist-induced Ca2+-signaling in asthma has been studied by comparing innate properties of inbred rat or mouse strains, or by using selected mediators known to be involved in asthma. T-bet knock-out (KO) mice show key features of allergic asthma such as a shift towards TH2-lymphocytes and display a broad spectrum of asthma-like histological and functional characteristics. In this study, we aimed at investigating whether Ca2+-homeostasis of ASMC is altered in T-bet KO-mice as an experimental model of asthma. METHODS: Lung slices of 100 to 200 microm thickness were obtained from T-bet KO- and wild-type mice. Airway contraction in response to acetylcholine (ACH) was measured by video-microscopy and Ca2+-signaling in single ASMC of lung slices was assessed using two-photon-microscopy. RESULTS: Airways from T-bet KO-mice showed increased baseline airway tone (BAT) and BHR compared to wild-type mice. This could be mimicked by incubation of lung slices from wild-type mice with IL-13. The increased BAT was correlated with an increased incidence of spontaneous changes in intracellular Ca2+-concentrations, whereas BHR correlated with higher ACH-induced Ca2+-transients and an increased proportion of ASMC showing Ca2+-oscillations. Emptying intracellular Ca2+-stores using caffeine or cyclopiazonic acid induced higher Ca2+-elevations in ASMC from T-bet KO- compared to wild-type mice. CONCLUSION: Altered Ca2+-homeostasis of ASMC contributes to increased BAT and BHR in lung slices from T-bet KO-mice as a murine asthma model. We propose that a higher Ca2+-content of the intracellular Ca2+-stores is involved in the pathophysiology of these changes.

Animals↗
PubMed2006

Acute effects of hemodialysis on lung function in patients with end-stage renal disease.

Impaired lung function in hemodialysis patients may be caused by an underlying pulmonary disease; however, the impact of uremia and the effects of dialysis treatment are not well understood. Our investigation aimed to characterize the acute effects of bicarbonate hemodialysis using membranes differing in biocompatibility on various parameters of lung function in unselected uremic patients maintained on regular hemodialysis. Fourteen clinically stable hemodialysis patients without acute lung disease were included in the study. Restrictive lung disease was present in eight of 14 cases and obstructive lung disease in one patient. A cellulose dialyzer membrane and a synthetic high-flux dialyzer membrane were each tested twice (two sessions one week apart). Spirometry (VCmax, FEV1, FEF(25-75%), PEF) was carried out before and after hemodialysis. Resistance was determined with the interrupter technique and with the impulse oscillation system (R5Hz, R20Hz) before, during and after hemodialysis. Our comparative investigation of two dialyzer membranes found that bioincompatibility of dialysis had no acute adverse effects on lung function in our heterogeneous population of dialysis patients. None of our patients experienced bronchoconstriction or aggravation of obstructive lung disease as a result of poor biocompatibility of the dialyzer membrane. Spirometric data and resistance measurements by two different methods showed no relevant changes during the dialysis procedure. There was no correlation between lung function parameters and interdialytic changes in body weight or duration on hemodialysis. Regardless of the membrane used, the hemodialysis procedure does not acutely affect lung function in uremic patients on maintenance hemodialysis. Hemodialysis is a safe procedure even in uremic patients with pre-existing lung disease.

Adult↗
PubMed2006

Topotecan therapy in patients with relapsed small-cell lung cancer and poor performance status.

PURPOSE: Topotecan is generally well tolerated and active in patients with relapsed small-cell lung cancer (SCLC) and poor performance status (PS). In this study, we investigated whether treatment with topotecan is associated with improvement in PS as measured by the rate of conversion from PS 2 to PS 0/1. PATIENTS AND METHODS: A retrospective analysis of data from 7 clinical trials (N = 795) investigating topotecan in patients with relapsed SCLC was performed. All patients received topotecan 1.25-1.5 mg/m2 daily on days 1-5 of a 21-day cycle. Demographics were similar for patients with PS 2 and PS 0/1. A total of 152 patients with PS 2 at baseline received 502 cycles (median, 2 cycles; range, 1-14 cycles) of therapy, and 32 (21%) experienced PS improvement to PS 0/1 that lasted for > or = 2 cycles. RESULTS: Overall, 50% of patients who experienced PS conversion also exhibited an objective antitumor response, compared with 8% of patients with PS 2 who had no improvement in PS and achieved a response. Similarly, median overall survival was longer for patients with PS improvement (37 weeks; 95% confidence interval, 29.6-49.4 weeks) compared with patients with PS 2 who had a response but no PS improvement (10.4 weeks; 95% confidence interval, 8.7-13.6 weeks). A substantial proportion of patients with PS 2 and relapsed SCLC experienced PS improvement during topotecan treatment. These patients had a substantially longer median survival and a higher response rate compared with the overall trial population. CONCLUSION: Improvement in PS appears to be a good indicator of benefit from topotecan therapy.

Adult↗
PubMed2004

The use of mini-organ cultures of human upper aerodigestive tract epithelia in ecogenotoxicology.

The carcinogenic potential of xenobiotics and possible confounders are often difficult to differentiate in in vivo studies. In contrast, in vitro studies allow investigation of the impact of carcinogens on human target cells under standardized conditions. The aim of the present study is to demonstrate whether three-dimensional mini organ-cultures (MOCs) of human inferior nasal turbinate epithelia may represent a useful model to study genotoxic effects of xenobiotics in vitro. Culture of mini organs was performed by cutting 1mm3 pieces from fresh specimens of inferior nasal turbinates. After a period of 5-6 days the specimens were fully covered with epithelium. On days 7, 9, and 11 of culture, intact MOCs from 25 tissue donors were incubated with dimethyl sulfoxide (DMSO) as a negative control, or with mono(2-ethylhexyl) phthalate (MEHP), benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). On days 7 and 11, MOCs were analyzed by the alkaline Comet assay to detect DNA-single-strand breaks, alkali-labile sites and incomplete excision-repair sites. DNA migration after single exposure of non-cultivated fresh specimens was also analyzed. In order to detect regimen-specific effects, DNA fragmentation after single exposure of intact MOCs was compared with that of cells after separation of MOCs on day 7 of culture and consecutive exposure of individual cells. Significant DNA migration as a measure of DNA single-strand breaks, alkali-labile sites and incomplete excision repair sites, was found after electrophoresis due to single and triple exposure of MOCs to MEHP, BPDE and MNNG. Triple exposure of MOCs compared to single exposure revealed no difference after exposure to DMSO or MEHP, and an increased migration after exposure to BPDE and MNNG. When single exposure of isolated cells from fresh specimens was compared with that of intact MOCs, DMSO and MNNG had no significantly different effect, whereas exposure to MEHP or BPDE caused a reduced migration in cells from MOCs. When exposure of isolated cells harvested from MOCs was compared with exposure of intact MOCs, MEHP and BPDE caused a significantly lower DNA migration in intact MOCs. MOCs provide an in vitro model suitable for the assessment of genotoxic effects of environmental pollutants both after single or repetitive exposure. Due to the intact structure of the exposed mucosa this model may be a helpful tool in mimicking the in vivo situation in ecogenotoxicology studies.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2004

MUC5AC and MUC5B Mucins Are Decreased in Cystic Fibrosis Airway Secretions.

Cystic fibrosis (CF) is characterized by progressive airway obstruction. Although it has been postulated that this is due in part to mucus hypersecretion, there are no published data showing an increase in the gel-forming mucins MUC5AC or MUC5B in CF secretions. We used confocal microscopy to assess the amount of mucin-like glycoprotein and DNA in CF sputum and found more mucin in bronchitis sputum and a much greater amount of DNA in CF sputum. We then used antibodies to MUC5AC and MUC5B with Western gels and dot-blot to quantify mucin in sputum from 12 patients with CF and 11 subjects without lung disease. There was a 70% decrease in MUC5B and a 93% decrease in MUC5AC in CF sputum (P < 0.005 for both). We conclude that the vol/vol concentration of MUC5AC and MUC5B are decreased in the CF airways relative to normal mucus. This may be due to a relative increase in other components of sputum in the CF airway or to a primary defect in mucin secretion in CF.

Adolescent↗
PubMed2004

Improvement of alveolar glutathione and lung function but not oxidative state in cystic fibrosis.

Chronic neutrophilic inflammation leads to oxidative damage, which may play an important role in the pathogenesis of cystic fibrosis lung disease. Bronchoalveolar lavage levels of the antioxidant glutathione are diminished in patients with cystic fibrosis. Here we evaluated the effects of glutathione aerosol on lower airway glutathione levels, lung function, and oxidative status. Pulmonary deposition of a radiolabeled monodisperse aerosol generated with a Pari LC Star nebulizer (Allergy Asthma Technology, Morton Grove, IL) connected to an AKITA inhalation device (Inamed, Gauting, Germany) was determined in six patients. In 17 additional patients bronchoalveolar lavage fluid was assessed before and after 14 days of inhalation with thrice-daily doses of 300 or 450 mg of glutathione. Intrathoracic deposition was 86.3 +/- 1.4% of the emitted dose. Glutathione concentration in lavage 1 hour postinhalation was increased three- to fourfold and was still almost doubled 12 hours postinhalation. FEV(1) transiently dropped after inhalation but increased compared with pretreatment values after 14 days (p < 0.001). This improvement was not related to the lavage content of oxidized proteins and lipids, which did not change with treatment. These results show that, using a new inhalation device with high efficacy, glutathione treatment of the lower airways is feasible. Reversion of markers of oxidative injury may need longer treatment, higher doses, or different types of antioxidants.

Adolescent↗
PubMed2003

Combination therapy with single inhaler budesonide/formoterol compared with high dose of fluticasone propionate alone in patients with moderate persistent asthma.

BACKGROUND: The efficacy and safety of Symbicort (budesonide and formoterol in a single inhaler) were compared with those of a high dose of the commonly used corticosteroid fluticasone propionate in patients with moderate persistent asthma. METHODS: This randomized, double-blind, double-dummy, parallel-group study involved 373 patients with asthma (mean age 42 years; FEV(1) 78% of predicted; reversibility 21%). After a 2-week run-in period, during which patients received budesonide 200 microg twice daily, they were randomly assigned to treatment with either Symbicort Turbuhaler (budesonide/formoterol 160/4.5 microg, one inhalation twice daily) or Flovent/Flixotide Diskus (fluticasone propionate 250 microg twice daily) for 12 weeks. RESULTS: Significantly greater increases in morning PEF, the primary efficacy variable, were observed in patients treated with budesonide/formoterol compared with fluticasone propionate (27.4 L/min vs 7.7 L/min; p < 0.001). Evening PEF and clinic FEV(1) also favored budesonide/formoterol compared with fluticasone propionate (p < 0.001), as did use of reliever medication (p = 0.04) and the proportion of reliever-free days (p < 0.001). There were also numerical improvements in symptom-free days (60.4% vs 55.5%), night-time awakenings (7.9% vs 9.6%) and asthma-control days (57.8% vs 52.4%) in favor of budesonide/formoterol. The risk of an exacerbation was reduced by 32% in the budesonide/formoterol group compared with the fluticasone propionate group (p < 0.05). Both treatments were well tolerated. CONCLUSION: Symbicort (budesonide/formoterol in a single inhaler) was more effective than a high dose of fluticasone propionate in improving lung function, reducing use of reliever medication and improving control of moderate persistent asthma.

Administration, Inhalation↗
PubMed2002

Combined transcriptome and genome analysis of single micrometastatic cells.

In human cancer, early systemic spread of tumor cells is recognized as a leading cause of death. Adjuvant therapies are administered to patients after complete resectioning of their primary tumors to eradicate the few residual and latent metastatic cells. These therapeutic regimens, however, are currently designed without direct information about the presence or nature of the latent cells. To address this problem, we developed a PCR-based technique to analyze the transcriptome of individual tumor cells isolated from the bone marrow of cancer patients. From the same cells, genomic aberrations were identified by comparative genomic hybridization. The utility of this approach for understanding the biology of occult disseminated cells and for the identification of new therapeutic targets is demonstrated here by the detection of frequent extracellular matrix metalloproteinase inducer (EMMPRIN; CD147) expression which was verified by immunostaining.

Cell Cycle↗