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Biomedical subjects

C Huber

Publications and source records attributed to C Huber.

At least 37 records · Page 2Linked to original sources
PubMed2003

Safety and feasibility of CHOP/rituximab induction treatment followed by high-dose chemo/radiotherapy and autologous PBSC-transplantation in patients with previously untreated mantle cell or indolent B-cell-non-Hodgkin's lymphoma.

Patients with no prior chemotherapy and with advanced and progressive follicular lymphoma (FCL) or mantle cell lymphoma (MCL) were enrolled into a treatment protocol combining CHOP/rituximab-CHOP therapy with subsequent consolidation high-dose therapy (HDT) to evaluate the safety and feasibility of this treatment. Overall, 15 patients were enrolled and 13 patients completed the entire treatment protocol without major toxicities or increased infectious complications. One patient withdrew consent after achieving complete remission (CR) prior to HDT. One patient was taken off study with signs of disease progression after induction treatment. All patients showed stable engraftment after HDT. Response rates appear to be favorable, indicating an additional effect of rituximab and HDT. Overall, 12 of 13 patients achieved CR/CRu and one patient partial remission. Follow-up of immune reconstitution displayed transient severe combined immunodeficiency with slow normalization of the cellular and humoral compartments without a significant increase of infectious complications. Taken together, high-dose chemotherapy can be safely given following treatment with CHOP+rituximab. Efficacy in this small cohort of patients was encouraging with sustained remissions in both FCL and MCL patients. Upfront HDT should be considered as a therapeutic option especially in young and/or high-risk patients.

Adult↗
PubMed2003

In BCR-ABL-positive cells, STAT-5 tyrosine-phosphorylation integrates signals induced by imatinib mesylate and Ara-C.

In BCR-ABL-positive cells, the transcription factor STAT-5 is constitutively activated by tyrosine phosphorylation. STAT-5 activation results in upregulation of bcl-X(L) and increased resistance to induction of apoptosis. Here, we investigated the effects of imatinib mesylate and cytosine arabinoside (Ara-C) on STAT-5 tyrosine-phosphorylation, cellular proliferation and induction of apoptosis in cell lines and primary hematopoietic cells. Imatinib mesylate treatment strongly suppressed STAT-5 tyrosine-phosphorylation in K562 and primary CML blasts. In contrast to JAK-2 and PI-3-kinase inhibition, exposure of K562 cells to imatinib mesylate resulted in obvious suppression of proliferation. Reduced cell growth was due to specific induction of caspase activation followed by apoptotic cell death. In addition, we investigated the effects of Ara-C on STAT-5 tyrosine-phosphorylation. Exposure to Ara-C resulted in significant downregulation of STAT-5 tyrosine-phosphorylation and inhibition of DNA binding. Treatment of K562 cells with Ara-C in combination with imatinib mesylate revealed synergistic effects at the level of STAT-5 tyrosine-phosphorylation and DNA binding, Hck tyrosine-phosphorylation, cell growth and induction of apoptosis. Overall, in this report we demonstrate that STAT-5 tyrosine-phosphorylation is a specific target of imatinib mesylate and Ara-C. Our results suggest that, in combination therapy, inhibition of STAT-5 tyrosine-phosphorylation may be responsible for synergistic or additive effects on BCR-ABL-positive cells.

Antineoplastic Agents↗
PubMed2002

Prospective randomized trial to evaluate two delayed granulocyte colony stimulating factor administration schedules after high-dose cytarabine therapy in adult patients with acute lymphoblastic leukemia.

In acute lymphoblastic leukemia (ALL), treatment with granulocyte colony stimulating factor (G-CSF) during remission induction shortens granulocytopenia and may decrease morbidity due to infections. However, the optimal timing of G-CSF administration after chemotherapy is not known. In a prospective randomized multi-center study, adult ALL patients were treated with high-dose ARA-C [HDAC, 3 g/m(2) bid (1 g/m(2) bid for T-ALL) days 1-4] and mitoxantrone (MI 10 mg/m(2) days 3-5). They were randomized to receive recombinant human G-CSF (Lenograstim) 263 micro g/day SC starting either from day 12 (Group 1) or day 17 (Group 2). Fifty-five patients (41 male, 14 female) with a median age of 34 years (range: 18-55 years) were enrolled into the study; 50 patients were evaluable. The median duration of neutropenia <500/ micro l after HDAC/MI was 12 days (range: 7-22 days) in the early G-CSF Group 1 and also 12 days (range: 4-22 days) in the late G-CSF Group 2; this was shorter than in the historical control group (15 days, range: 4-43 days, n=46) where the patients received identical cytotoxic treatment without G-CSF. Seventeen infections were observed in 14 patients in Group 1 (47%) and 13 infections in 10 patients in Group 2 (50%) compared to 27 infections in 49 patients of the historical control (54%). In Group 1, the patients received a median of 11 injections with G-CSF (range: 7-22) compared to 7 injections (range: 4-19) in Group 2. The total administered dose of G-CSF in Group 2 was significantly reduced by 40% ( P<0.0001). The delayed start of G-CSF after HDAC/MI in ALL achieves the same clinical benefit compared to the earlier initiation of G-CSF. The reduction of treatment costs by reducing the total G-CSF dose may be important in future treatment with this hematopoietic growth factor.

Adolescent↗
PubMed2002

On-line determination of oxygen isotope ratios of water or ice by mass spectrometry.

Oxygen isotope ratio determination on any of the water phases (water vapor, water, ice) is of great relevance in different research fields such as climate and paleoclimate studies, geological surveys, and hydrological studies. The conventional technique for oxygen isotope measurement involves equilibration with carbon dioxide gas for a given time with a subsequent isotope determination. The equilibration technique is available in different layouts, but all of them are rather time-consuming. Here we report a new on-line technique that processes water samples as well as ice samples. The same principal, CO2 hydration, is used but speeded up by (i) a direct injection and full dissolution of CO2 in the water, (ii) an increased isotope exchange temperature at 50 degrees C, and (iii) a rapid gas extraction by means of an air-permeable membrane into a continuous helium flux supplying the isotope ratio mass spectrometer with the sample gas. The precision is better than 0.1/1000 which is only slightly larger than with the conventional equilibration technique. This on-line technique allows analysis of 1 m of ice with a resolution of 1-3 cm, depending on the meltwater flux, within 1 h. Similarly, continuous and fast analysis can be performed for aqueous samples for hydrological, geological, and perhaps medical applications.

Journal Article↗
PubMed2002

Rituximab in vivo purging is safe and effective in combination with CD34-positive selected autologous stem cell transplantation for salvage therapy in B-NHL.

The purpose of this study was to evaluate feasibility and efficacy of Rituximab included into a sequential salvage protocol for CD20(+) B-NHL in relapse or induction failure. Twenty-seven patients with CD20(+) B-NHL in relapse or induction failure received Rituximab combined with DexaBEAM (R-DexaBEAM) for stem cell mobilization. Additional ex vivo selection of CD34-positive cells was performed using the CliniMacs device. Two doses of Rituximab were included in the high-dose therapy regimen (HDT). R-DexaBEAM was well tolerated and 26 of 27 patients mobilized sufficient numbers of CD34(+) blood stem cells. Application of R-DexaBEAM resulted in significant depletion of peripheral B cells. No treatment-related deaths occurred after HDT and all patients showed stable engraftment of hematopoesis. Combined immunodeficiency was observed post HDT and eight patients developed CMV antigenemia. Remission rate post HDT was 96% (CR, 24/26; PR, 1/26). Overall and progression-free survival (PFS) at 16 months post HDT (range 6-27) is 95% and 77%, respectively. With regard to histology, PFS was 71% in aggressive lymphoma (n = 11), 74% in indolent FCL (n = 10) and 100% in MCL (n = 5). The treatment protocol has proven feasible, with high purging efficiency and encouraging remission rates.

Adult↗
PubMed2002

Generating p53-specific cytotoxic T lymphocytes by recombinant adenoviral vector-based vaccination in mice, but not man.

Mutations and aberrant expression of the p53 tumor suppressor protein are the most frequent molecular alterations in human malignancy. Peptides derived from the wild-type (wt) p53 protein and presented by major histocompatibility complex (MHC) molecules for T lymphocyte recognition are believed to serve as universal tumor-associated antigens for cancer immunotherapy. We studied the immunogeneicity of a recombinant replication-defective adenoviral vector encoding human full-length wt p53 (rAd/hup53) in human leukocyte antigen (HLA)-A2K(b)-transgenic (Tg) mice and man. The generation of p53 epitope-specific cytotoxic T lymphocytes (CTLs) in p53-proficient and p53-deficient A2K(b)-Tg mice was affected by self-tolerance and a selective inability of rAd/hup53 to induce p53.264-272 peptide-reactive effector cells. To extend this study into a pilot clinical trial, six advanced-stage cancer patients received sequential injections of rAd/hup53. The treatment was well tolerated. To date, no evidence for objective tumor responses was observed. An amplification of humoral and cellular anti-adenoviral immune responses was demonstrated in all patients following rAd/hup53 vaccination. However, p53-reactive antibodies and HLA-A*0201 (A2.1)-restricted CTLs specific for wt p53 epitopes were not generated. Tailoring p53-based cancer immunotherapy thus requires the interference with p53-specific self-tolerance and the induction of the entire repertoire of p53-reactive T lymphocytes.

Adenoviridae↗
PubMed2002

Safety and efficacy of STI-571 (imatinib mesylate) in patients with bcr/abl-positive chronic myelogenous leukemia (CML) after autologous peripheral blood stem cell transplantation (PBSCT).

We examined safety and efficacy of STI-571 in 24 bcr/abl-positive patients with CML post PBSCT. At start of STI-571 therapy, nine patients presented in blast crisis (BC) or in accelerated phase (AP), and 15 in chronic phase (CP). Patients were evaluated for hematologic, cytogenetic and molecular response, survival and toxicity. In general, STI-571 was well tolerated in this heavily pretreated group of patients with a non-hematologic and hematologic toxicity profile similar to that observed in a previous phase I trial at comparable doses. Five of nine patients with CML in transformation (AP, BC) were evaluable for hematologic response. Two of five patients had transient reductions in WBC and blasts, and three patients achieved a sustained hematologic response (>4 weeks). Cytogenetic analysis in these patients revealed numerical and/or structural responses. In CML chronic phase, STI-571 induced complete hematologic responses in all patients and major cytogenetic responses in 61% of patients with a complete cytogenetic response rate of 46%. This report indicates that STI-571 is a safe and effective drug in heavily pretreated patients. No apparent additional side-effects were noted in this patient cohort. The high rate of complete hematologic and complete cytogenetic responses in CP patients is remarkable, as intensive treatment approaches plus IFN-alpha failed to be efficient in achieving long-term stabilization of CML in this patient cohort.

Adult↗
PubMed2002

Partial antagonism of tiletamine-zolazepam anesthesia in cheetah.

This study evaluated partial antagonism of tiletamine-zolazepam (TZ) anesthesia in cheetahs (Acinonyx jubatus) and differences between two benzodiazepine antagonists, flumazenil and sarmazenil, in this species. Four cheetahs were anesthetized three times at an interval of 14 days with an average intramuscular dose of 4.2 mg/kg TZ. In trials 2 and 3 flumazenil at 0.031 mg/kg and sarmazenil at 0.1 mg/kg, respectively, were applied intramuscularly 30 min after initial TZ injection. There was a highly significant difference between the duration of TZ anesthesia with and without antagonist. Use of the antagonists significantly shortened duration and recovery and eliminated excitatory behavior during the recovery phase. No significant differences could be determined between the two antagonists. We recommend the use of sarmazenil and flumazenil to antagonize TZ anesthesia in cheetahs.

Acinonyx↗
PubMed2001

Immune escape of melanoma: first evidence of structural alterations in two distinct components of the MHC class I antigen processing pathway.

Sequence analyses of the transporter associated with antigen processing (TAP) in tumor cell lines with deficient MHC class I surface expression identified a bp deletion at position 1489 near the ATP-binding domain of Tap1, causing a frameshift in one melanoma cell line. The impaired TAP1 protein expression was associated with deficient TAP2 protein expression, peptide binding, translocation, and MHC class I surface expression. Stable TAP1 gene transfer reconstitutes the described defects, whereas lysis by HLA-A2-restricted CTLs was still abrogated. This was attributable to a 2-bp insertion at position 890 in the HLA-A2 gene and was corrected after HLA-A2 cotransfection. This study describes for the first time mutations in two distinct components of the MHC class I antigen processing pathway, suggesting an immune selection against CTLs recognizing both TAP-dependent and -independent T-cell epitopes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Regeneration of mature Norway spruce stands: early effects of selective cutting and clear cutting on seepage water quality and soil fertility.

The cutting of trees influences element turnover in the forest ecosystem. The reduction of plant uptake, as well as an increased mineralization and nitrification due to higher soil temperature and soil moisture, can lead to considerable losses of nutrients from the main rooting zone. This may result in a reduced soil fertility and a decrease in drinking water quality due to high nitrate concentrations in the seepage water. In Bavaria (Germany) selective cutting is preferred to clear cutting when initiating the regeneration of Norway spruce stands with European beech. This paper summarizes the early effects of both forest management practices on soil fertility and seepage water quality for three different sites. Shown are the concentrations of nitrogen and base cations in the seepage water as well as the water and ion fluxes during the first year after tree cut. Nutrient inputs decreased on thinned plots and even more at clear-cuts. Nitrate concentrations in the seepage water are hardly affected by moderate thinning; however, on clear-cuts, the nitrate concentration increases significantly, and base cations are lost from the upper mineral soil. This effect is less obvious at sites where a dense ground vegetation, which is able to take up excess nitrogen, exists.

Anions↗
PubMed2001

Complexation of unsaturated carbon-carbon bonds in pi-conjugated polymers with transition metals.

The present paper explores the possibility of preparing pi-conjugated organometallic polymer hybrid systems based on a poly(p-phenylene ethynylene) (PPE) derivative, in which the ethynylene moieties of the polymer are coordinated to platinum(II) centers. The use of the "bifunctional" [Pt-(mu-Cl)Cl(PhCH=CH(2))](2) (2) allows, under appropriate conditions, the formation of three-dimensionally cross-linked, conjugated PPE-platinum(II) networks. The synthesis of [Pt-(mu-Cl)Cl(PhC(triple bond)CPh)](2), as a model compound, and a series of model reactions of 2 with diphenylacetylene (3) have enabled an NMR study which has revealed a number of equilibria, and suggests a mixed Pt-styrene-acetylene complex as a key structure. As expected, the coordination of Pt markedly influences the photophysical characteristics of the PPE. The photoluminescence is efficiently quenched, and the absorption maximum in the visible regime experiences a hypsochromic shift upon complexation with 2.

Journal Article↗
PubMed2001

Dual lifetime referencing as applied to a chloride optical sensor.

A membrane with an optical response to chloride has been developed that contains two luminophores that display two largely different decay times. The first luminophore (the "reference") is a chloride-insensitive ruthenium metal-ligand complex possessing a decay time in the microsecond range. The second luminophore is the short-lived chloride-quenchable fluorescent probe lucigenin. Both are contained in a hydrogel matrix and are excited by a blue LED emitting sinusoidally modulated light. Under these conditions, the chloride-dependent fluorescence intensity of lucigenin can be converted in an analyte-dependent fluorescence phase shift that depends on the ratio of the two luminescence intensities and can be measured at modulation frequencies of typically 45 kHz. The dynamic range of this sensor can be adjusted by either varying the ratio of the two luminophores or selecting a particular optical filter combination.

Acridines↗
PubMed2001

Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study.

PURPOSE: To study the additional benefit from adenoviral p53 gene therapy in patients undergoing first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-five patients with nonresectable NSCLC were enrolled in an open-label, multicenter phase II study of three cycles of regimen A, carboplatin (area under the curve, 6; day 1) plus paclitaxel (175 mg/m(2), day 1), or regimen B, cisplatin (100 mg/m(2), day 1) plus vinorelbine (25 mg/m(2), days 1, 8, 15, and 22) in combination with intratumoral injection of 7.5 x 10(12) particles of SCH 58500 (rAd/p53, day 1). Responses of individual tumor lesions were assessed after each cycle, and gene transfer was examined in posttreatment tumor biopsies using reverse transcriptase polymerase chain reaction. RESULTS: There was no difference between the response rate of lesions treated with p53 gene therapy in addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy alone (48% objective responses). Subgroup analysis according to the chemotherapy regimens revealed evidence for increased mean local tumor regressions in response to additional p53 gene therapy in patients receiving regimen B, but not in patients receiving regimen A. There was no survival difference between the two chemotherapy regimens, and the median survival of the cohort was 10.5 months (1-year survival, 44%). Transgene expression was confirmed in tumor samples from 68% of patients, and toxicities attributable to gene therapy were mild to moderate. CONCLUSION: Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.

Adenoviridae↗
PubMed2001

Characterization of the major histocompatibility complex class I deficiencies in B16 melanoma cells.

The murine B16 melanoma system represents an important in vivo model for the evaluation of T cell-based immunization and vaccination strategies, although deficient MHC class I surface expression has been identified in these cells. We postulate here that the MHC class I-deficient phenotype of B16 melanoma cells is attributable to down-regulation or the loss of the expression and function of multiple components of the MHC class I antigen-processing pathway, including the peptide transporter associated with antigen processing, the proteasome subunits LMP2, LMP7, and LMP10, PA28alpha and -beta, and the chaperone tapasin. In contrast, calnexin, calreticulin, ER60, and protein disulfide isomerase expression are unaltered or only marginally suppressed in these cells. The level of down-regulation of the components of the antigen-processing pathway is either transcriptionally or posttranscriptionally controlled and could be corrected in all cases by IFN-y treatment, which also reconstituted MHC class I surface expression. Thus, B16 melanoma cells can be used as a model for the characterization of the mechanisms underlying the coordinated dysregulation of the antigen-processing components, which should provide new insights into the development of tumors and the factors controlling this process.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Allelic and nonallelic heterogeneity in dyschondrosteosis (Leri-Weill syndrome).

Dyschondrosteosis (DCS) is an autosomal dominant form of mesomelic dysplasia that has been recently ascribed to large-scale deletions and nonsense mutations of the SHOX gene on the pseudoautosomal region of chromosome X and Y [Belin et al., 1998: Nat Genet 19:67-69; Shears et al., 1998: Nat Genet 19:70-73]. Here, we report the molecular analysis of a total of 23 DCS families including 16 previously reported pedigrees [Belin et al., 1998: Nat Genet 19:67-69; Huber et al., 2001: J Med Genet 38:281-284] and 7 novel DCS families. Linkage analyses in 21 of 23 families were consistent with linkage to the pseudoautosomal region. However, in 2 of 23 families, linkage studies excluded SHOX as the disease-causing gene, suggesting that this condition is genetically heterogeneous.

Alleles↗
PubMed2001

Downregulation of the constitutive tapasin expression in human tumor cells of distinct origin and its transcriptional upregulation by cytokines.

Human tumor cells frequently exhibit abnormalities in the major histocompatibility complex (MHC) class I surface expression which can be due to structural alterations and/or dysregulation of various components of the MHC class I antigen processing machinery, such as HLA class I heavy and light chains, the peptide transporter and the proteasome subunits. Although several cofactors critical for proper MHC class I assembly have been identified, their contribution to the immune escape phenotype of tumor cells has not been analyzed. In order to determine whether tapasin deficits are an integral part of immune escape mechanisms of human tumors, we studied the constitutive and cytokine-regulated expression pattern of tapasin in malignant cells of distinct histology. Heterogeneous and reduced expression levels of tapasin were found in small-cell lung carcinoma, pancreatic carcinoma, colon carcinoma, head an neck squamous cell carcinoma and renal cell carcinoma cell lines. Tapasin downregulation was also prominent in surgically removed tumor lesions when compared to normal controls. The impaired tapasin expression is often associated with low MHC class I cell surface expression. In addition, various cytokines, including interferon (IFN)-alpha, IFN-gamma, tumor necrosis factor (TNF)-alpha and interleukin (IL)-4, but not granulocyte-macrophage colony stimulating factor (GM-CSF), transcriptionally upregulate to a distinct extent and in a time-dependent manner tapasin expression in tumor cells. Thus, deficient tapasin expression appears to be a frequent event in human tumor cells. Its restoration by cytokines further suggests that impaired tapasin expression in tumors is rather due to dysregulation than to structural alterations.

Antiporters↗
PubMed2001

Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer.

We identified a tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the widely expressed human MDM2 oncoprotein and were able to bypass self-tolerance to this tumor antigen in HLA-A*0201 (A2.1) transgenic mice and by generating A2.1-negative, allo-A2.1-restricted human T lymphocytes. A broad range of malignant, as opposed to nontransformed cells, were killed by high-avidity transgenic mouse and allogeneic human CTLs specific for the A2.1-presented MDM2 epitope. Whereas the self-A2.1-restricted human T cell repertoire gave rise only to low-avidity CTLs unable to recognize the natural MDM2 peptide, human A2.1+ T lymphocytes were turned into efficient MDM2-specific CTLs upon expression of wild-type and partially humanized high-affinity T cell antigen receptor (TCR) genes derived from the transgenic mice. These results demonstrate that TCR gene transfer can be used to circumvent self-tolerance of autologous T lymphocytes to universal tumor antigens and thus provide the basis for a TCR gene transfer-based broad-spectrum immunotherapy of malignant disease.

Animals↗