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Biomedical subjects

D Pink

Publications and source records attributed to D Pink.

14 recordsLinked to original sources
PubMed2006

Phase 1 European Organisation for Research and Treatment of Cancer study determining safety of pegylated liposomal doxorubicin (Caelyx) in combination with ifosfamide in previously untreated adult patients with advanced or metastatic soft tissue sarcomas.

This phase I study evaluated the toxicity of first-line combined pegylated liposomal doxorubicin (Caelyx) and ifosfamide in patients with advanced and/or metastatic soft tissue sarcomas. Five dose levels (L) were studied: Caelyx 30 mg/m2 (L1-4) or 40 mg/m2 (L5) 1-h infusion d 1 q 3 weeks + ifosfamide and mesna at X g/m2/4 h d 1-3 q 3 weeks at five doses: L1: X = 1.7 g; L2: X = 2 g; L3: X = 2.5 g; L4 and L5: X = 3 g. Cohorts of 3 patients were entered at each level unless a dose-limiting toxicity (DLT) occurred. In case of DLT in 1 of 3 patients a new cohort was added. Toxicity was evaluated by Common Toxicity Criteria (CTC). A total of 28 patients was included: 4 at dose L1, 8 at L2, 3 at L3, 6 at L4, and 7 at L5. Median age was 60 years (range 29-69 years). Male/female ratio was 12/16. Seventy-five percent of patients had a performance status of 1.0 and 36% had leiomyosarcomas. No DLT was observed at dose L1-4. Six patients developed a DLT at dose L5, and thus the recommended dose is level 4 (i.e. Caelyx 30 mg/m2/1 h d 1+ifosfamide at 3 g/m2/4 h d 1-3 q 3 weeks). Few haematological and biochemical events were observed and the principal toxicities were granulocytopaenia and leucopaenia. Five patients discontinued therapy because of toxicity, 4 of them at dose level 5. Non-haematological toxicities > grade 2 were also few. Palmar-plantar erythrodysesthesia (PPE) > grade 1 was not seen. Two patients obtained partial response (PR) and 13 stable disease (SD). Median overall survival (OS) was 333 d and median progression-free survival (PFS) 174 d. In conclusion, this seems to be a feasible combination in patients with advanced soft tissue sarcomas, allowing ifosfamide to be given in a dosage similar to that used when given alone. The recommended dose for future studies is Caelyx 30 mg/m2/1 h d 1+ifosfamide 3 g/m2/4 h d 1-3 q 3 weeks.

Adolescent↗
PubMed2004

[Gastrointestinal stromal tumors (GIST)].

The vast majority of mesenchymal tumors originating from the GI tract consists of gastrointestinal stromal tumors (GIST), an entity just recently defined. The incidence is estimated to be around 10 - 20/1000000, the median age at diagnosis has been reported to be 55 to 65 years. GISTs most commonly occur in the stomach or duodenum, followed by the small intestine. About half of the patients present with metastatic disease at first diagnosis, predominantly in the liver or periteneum. GISTs are strongly and uniformly positive for CD117 (c-kit), a type III receptor-tyrosine kinase. Kit mutations, mostly in exon 11, leading to ligand independent constitutive activation are supposed to play a major role in the pathogenesis of GIST. Until recently no active systemic treatment was available for advanced gastrointestinal stromal tumors. Imatinib (STI571 = Glivec) is a rationally designed, orally available phenylaminopyrimidin analogue. The mechanism of action consists of a competitive interaction with the ATP-binding pocket of specific tyrosine kinases. Early results from clinical trials with response rates around 60 % and progression arrest in more than 80 % of patients resulting in fast relief of symptoms, confirm the high activity of this novel treatment. The role of adjuvant treatment after potentially curative resection of GIST is currently evaluated in ongoing clinical trials. Patients with progressive disease while under treatment with Imatinib should be enrolled in studies testing novel treatment strategies as RAD001, PKC412 or SU11 248.

Antineoplastic Agents↗
PubMed2004

Molecular response of gastrointestinal stromal tumour after treatment with tyrosine kinase inhibitor imatinib mesylate.

Bleeding from the tumour site is not uncommon during the treatment of gastrointestinal stromal tumours with imatinib mesylate. It might represent an early reaction of highly vascularised tumour tissue to receptor blockade. Although often requiring emergency surgery, this is not necessarily a deleterious sign. Slow tumour regression and cystic tissue alteration may follow. Using immunohistochemistry and consecutive resection specimens, it was shown that the number of mitoses decreased significantly and MIB-1 as a marker of cell proliferation could no longer be detected. In the few tumour cells still present, the magnitude of expression of the pathognomonic marker CD117 remained unchanged. Decreases in the size of tumours responding to imatinib mesylate cannot be expected to meet the World Health Organisation or RECIST (response evaluation criteria in solid tumours) criteria. This underlines the necessity of functional imaging by positron emission tomography, contrast enhanced magnetic resonance imaging, or magnetic resonance spectroscopy to assess the response to treatment.

Adult↗
PubMed2003

Chemotherapy in alveolar soft part sarcomas. What do we know?

Alveolar soft part sarcoma (ASPS) is a rare tumour. Published series about treatment and outcome are scarce. Conclusive data about the response to chemotherapy are not available. The aim of this study was to analyse the efficacy of palliative chemotherapeutic treatment options and the incidence and mode of presentation of brain metastases. We retrospectively analysed our own sarcoma data-base and reviewed the literature. From our registry containing 757 patients, we identified 8 patients with ASPS. From the literature, 47 cases of adult patients and 13 children with sufficient data about chemotherapy were identified. Response to first-line chemotherapy in 68 patients was: complete remission (CR) 4%, partial remission (PR) 3%, stable disease (SD) 41%, progressive disease (PD) 51%. 285 patients with stage IV disease were evaluable for the analysis of metastatic sites. The incidence of brain metastases was 30.5% (87/285). Brain metastases were detected at a median interval of 48 months (range 0-396 months) after the primary diagnosis. Median survival after the diagnosis of brain metastases was 12 months. The median survival for patients with stage IV disease treated by chemotherapy was 36+ months (range 10-132 months) (31 patients evaluable) with a median follow-up of 46 months (range 10-135 months). ASPS shows a high incidence of brain metastases, at least 3 times higher than that of other soft tissue sarcomas. Chemotherapeutic regimens used for the treatment of other soft tissue sarcomas lack efficacy in ASPS. Staging investigations for ASPS should routinely include imaging of the brain. ASPS patients should not be treated with chemotherapy outside of controlled clinical trials. New targets for specific biologically-directed therapies need to be developed.

Adult↗
PubMed2003

[Morphology of gastrointestinal stromal tumors in advanced stages of the disease: baseline findings before chemotherapy with imatinib].

PURPOSE: Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal tract with an increasing detection rate due to improved differentiating methods in current diagnostic pathology. This study evaluates the radiologic characteristics of these neoplasms to discover specific signs leading to an earlier diagnosis. MATERIALS AND METHODS: As part of a randomized phase III clinical trial of the European Organization for Research and Treatment of Cancer (EORTC), 72 patients with advanced stage GIST were treated with the selective tyrosine-kinase-inhibitor imatinib (Glivec, Novartis, Switzerland). For initial staging, 60 patients underwent MRI and 12 patients underwent CT. RESULTS: GISTs are mesenchymal tumors that grow submucosally and exophytically and become multiple, nodular or ovoid in the advanced stage. The predominant findings are peripheral solid structures with strong contrast enhancement and a central necrosis. Metastases are primarily located in the liver, where they appear as oval or round, sharply delineated solitary lesions with central necrosis. CT demonstrates the primary tumors and local recurrences as nearly isodense with the liver. On MRI, the lesions are hypointense on T 1 -weighted sequences and hyperintense on T 2 -weighted sequences, compared to the liver. CONCLUSION: Immunopathology now enables the exact histologic separation of GISTs from other mesenchymal tumors. The radiological morphology is not sufficiently specific to differentiate GISTs from other mesenchymal tumors. In view of new therapeutic options, cognizance of their typical manifestations is of increasing importance for radiologists.

Adult↗
PubMed2002

Oral trofosfamide: an active and well-tolerated maintenance therapy for adult patients with advanced bone and soft tissue sarcomas. Results of a retrospective analysis.

OBJECTIVES: Aim of this study was to evaluate the feasibility and toxicity of oral trofosfamide given as maintenance therapy to adult patients with bone and soft tissue sarcomas following first or later line induction chemotherapy, and to determine the clinical efficacy in terms of impact on progression-free and overall survival. PATIENTS AND METHODS: 49 patients with locally advanced or metastatic high-grade soft tissue and bone sarcomas were identified retrospectively according to the inclusion criteria of the analysis. They were treated with oral trofosfamide at a dose of 100-150 mg per day continuously. All patients were pretreated with one or more lines of chemotherapy resulting in partial remission or stable disease. Patients were treated until progression of disease or unacceptable toxicity occurred. Progression- free and overall survival were measured from the beginning of maintenance therapy. RESULTS: Median follow-up for all patients was 33 months (range 10-98). Toxicity was mild and predominantly hematologic. Only 1 patient had to stop treatment due to renal toxicity. The median progression-free survival was 7 months with 27% of patients continuing maintenance treatment at 1 year. Median overall survival is 14 months. Patients with metastatic disease showed a median survival of 23 months from diagnosis of metastases. 3 patients with stable disease following induction chemotherapy reached partial remission while under trofosfamide maintenance. CONCLUSION: Oral maintenance therapy with trofosfamide is well-tolerated and seems to prolong progression-free and overall survival compared to the course of advanced soft tissue and bone sarcomas without maintenance chemotherapy.

Administration, Oral↗
PubMed2000

Elasticity of the rod-shaped gram-negative eubacteria.

We report a theoretical calculation of the elasticity of the peptidoglycan network, the only stress-bearing part of rod-shaped Gram-negative eubacteria. The peptidoglycan network consists of elastic peptides and inextensible glycan strands, and it has been proposed that the latter form zigzag filaments along the circumference of the cylindrical bacterial shell. The zigzag geometry of the glycan strands gives rise to nonlinear elastic behavior. The four elastic moduli of the peptidoglycan network depend on its stressed state. For a bacterium under physiological conditions the elasticity is proportional to the bacterial turgor pressure. Our results are in good agreement with recent measurements.

Cell Membrane↗
PubMed2000

Angiotensin II directly increases transforming growth factor beta1 and osteopontin and indirectly affects collagen mRNA expression in the human heart.

OBJECTIVES: Angiotensin II (Ang II) induces fibroblast proliferation and collagen synthesis in the myocardium, but its precise mechanisms of action in human hearts are still unknown. Therefore, we investigated whether Ang II directly affects the collagen mRNA content in the human myocardium and in isolated human cardiac fibroblasts or whether the growth factors TGFbeta-1 and osteopontin are involved in this process. METHODS AND RESULTS I: In a first set of experiments, the direct effect of Ang II on collagen I, TGFbeta-1 and osteopontin mRNA content in fresh samples of human atrial myocardium was determined by the use of a short stimulation period. After 4 h, Ang II-stimulated atrial samples gave a significantly higher expression of both TGFbeta-1 (183+/-21% of control, p<0.05) and osteopontin mRNA (275+/-58%, p<0.02) than the controls. In contrast, the expression of collagen I mRNA was unchanged (95+/-8%). Stimulation with TGFbeta-1 led to an increase in collagen I and III mRNA (127+/-10%, p<0.05; 140+/-15%, p<0.02). METHODS AND RESULTS II: In a second protocol, to assess the effects of longer stimulation periods, we determined the effects of Ang II and its potential mediator TGFbeta-1 on collagen I, III and fibronectin mRNA expression and on proliferation of cultured human cardiac fibroblasts. Ang II caused a dose-dependent stimulation of proliferation but did not affect collagen I, II or fibronectin mRNA content after 24 h. In contrast, TGFbeta-1 stimulation significantly increased collagen I and III mRNA expression (124+/-5% and 128+/-5%, p<0.002). CONCLUSIONS: In the human heart, Ang II does not directly increase collagen or fibronectin mRNA, but it does increase TGFbeta-1 and osteopontin mRNA expression. Since TGFbeta-1 induces collagen I and III mRNA in atrial samples and in isolated cardiac fibroblasts, it may represent a necessary mediator of the Ang II effects in the human heart.

Aged↗
PubMed2000

Insoluble condensed tannins of canola/rapeseed.

The contents of soluble, SDS-extractable, and insoluble condensed tannins were determined in canola/rapeseed hulls from several varieties by utilizing the proanthocyanidin assay. The total amount of tannins in rapeseed/canola hulls ranged from 1913 to 6213 mg per 100 g of oil-free hulls. Insoluble tannins predominated in canola/rapeseed hulls and comprised from 70 to 95.8% of total tannins present. The amounts of SDS-extractable tannins were comparable to those of soluble tannins but constituted only 4.7-14. 1% of insoluble tannins present.

Anthocyanins↗
PubMed2000

On the architecture of the gram-negative bacterial murein sacculus.

The peptidoglycan network of the murein sacculus must be porous so that nutrients, waste products, and secreted proteins can pass through. Using Escherichia coli and Pseudomonas aeruginosa as a baseline for gram-negative sacculi, the hole size distribution in the peptidoglycan network has been modeled by computer simulation to deduce the network's properties. By requiring that the distribution of glycan chain lengths predicted by the model be in accord with the distribution observed, we conclude that the holes are slits running essentially perpendicular to the local axis of the glycan chains (i. e., the slits run along the long axis of the cell). This result is in accord with previous permeability measurements of Beveridge and Jack and Demchik and Koch. We outline possible advantages that might accrue to the bacterium via this architecture and suggest ways in which such defect structures might be detected. Certainly, large molecules do penetrate the peptidoglycan layer of gram-negative bacteria, and the small slits that we suggest might be made larger by the bacterium.

Carbohydrate Conformation↗
PubMed1999

Deployment of disease resistance genes by plant transformation - a 'mix and match' approach.

Breeding for disease resistance has often resulted in the evolution of a matching virulence within the pathogen population, leading to an apparent 'breakdown' of resistance. In general, plant breeders have responded by introducing new genes for resistance, with similar consequences. This has led to 'boom-bust' cycles, where varieties possessing effective resistance are grown on an expanding acreage (boom) until matching virulence evolves and spreads within the pathogen population (bust). A variety of resistance genes have recently been identified and characterized in model systems. Together with the development of efficient plant transformation systems these genes offer an alternative means to introduce specific resistance into a crop improvement programme. However, unless the resistance genes are deployed with care, the boom-bust cycle is likely to be perpetuated.

Journal Article↗
PubMed1999

Evaluation of the quality of frozen minced red hake: use of fourier transform near-infrared spectroscopy.

The quality of frozen minced red hake was assessed by FTNIR spectroscopy in transmission mode. The region 1530-1866 nm was best correlated to dimethylamine (DMA) concentration, which is an accepted quality index for frozen gadoid fish. Partial least-squares (PLS) analysis showed that this technique predicts the DMA content sufficiently well for quality assurance (SD/SEP > 3). The PLS calibration was equally successful when five narrow spectral regions were chosen instead of the continuous spectrum, indicating that a cheap filter instrument may be developed for industrial use.

Animals↗
PubMed1999

Thickness and elasticity of gram-negative murein sacculi measured by atomic force microscopy.

Atomic force microscopy was used to measure the thickness of air-dried, collapsed murein sacculi from Escherichia coli K-12 and Pseudomonas aeruginosa PAO1. Air-dried sacculi from E. coli had a thickness of 3.0 nm, whereas those from P. aeruginosa were 1.5 nm thick. When rehydrated, the sacculi of both bacteria swelled to double their anhydrous thickness. Computer simulation of a section of a model single-layer peptidoglycan network in an aqueous solution with a Debye shielding length of 0.3 nm gave a mass distribution full width at half height of 2.4 nm, in essential agreement with these results. When E. coli sacculi were suspended over a narrow groove that had been etched into a silicon surface and the tip of the atomic force microscope used to depress and stretch the peptidoglycan, an elastic modulus of 2.5 x 10(7) N/m(2) was determined for hydrated sacculi; they were perfectly elastic, springing back to their original position when the tip was removed. Dried sacculi were more rigid with a modulus of 3 x 10(8) to 4 x 10(8) N/m(2) and at times could be broken by the atomic force microscope tip. Sacculi aligned over the groove with their long axis at right angles to the channel axis were more deformable than those with their long axis parallel to the groove axis, as would be expected if the peptidoglycan strands in the sacculus were oriented at right angles to the long cell axis of this gram-negative rod. Polar caps were not found to be more rigid structures but collapsed to the same thickness as the cylindrical portions of the sacculi. The elasticity of intact E. coli sacculi is such that, if the peptidoglycan strands are aligned in unison, the interstrand spacing should increase by 12% with every 1 atm increase in (turgor) pressure. Assuming an unstressed hydrated interstrand spacing of 1.3 nm (R. E. Burge, A. G. Fowler, and D. A. Reaveley, J. Mol. Biol. 117:927-953, 1977) and an internal turgor pressure of 3 to 5 atm (or 304 to 507 kPa) (A. L. Koch, Adv. Microbial Physiol. 24:301-366, 1983), the natural interstrand spacing in cells would be 1.6 to 2.0 nm. Clearly, if large macromolecules of a diameter greater than these spacings are secreted through this layer, the local ordering of the peptidoglycan must somehow be disrupted.

Cell Wall↗