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Biomedical subjects

P Hofman

Publications and source records attributed to P Hofman.

At least 19 recordsLinked to original sources
PubMed2006

Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126.

Current experimental and clinical knowledge supports the optimisation of endothelial cell targeting using a strategy combining anti-EGFR drugs with antivascular agents. The purpose of the present study was to examine the effects of the association of ZD6126, an antivascular microtubule-destabilising agent, with gefitinib and irradiation on the growth of six head and neck human cancer cell lines xenografted in nude mice and to study predictive and molecular factors responsible for antitumour effects. CAL33- and Hep-2-grafted cell lines were the most sensitive to ZD6126 treatment, with VEGF levels significantly higher (P=0.0336) in these tumour xenografts compared to Detroit 562- and CAL27-grafted cell lines with relatively low VEGF levels that were not sensitive to ZD6126. In contrast, neither IL8 levels nor EGFR expression was linked to the antitumour effects of ZD6126. ZD6126 in combination with gefitinib resulted in a synergistic cytotoxic interaction with greater antitumour effects than gefitinib alone. The synergistic interaction between ZD6126 and gefitinib was corroborated by a significant decrease in CD31 labelling. The present study may serve for future innovative clinical applications, as it suggests that VEGF tumour levels are possible predictors for ZD6126 antitumour efficacy. It also supports the notion of antitumour supra-additivity when combining gefitinib and ZD6126, and identifies neoangiogenesis as the main determinant of this synergistic combination.

Angiogenesis Inhibitors↗
PubMed2006

A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis.

The K562 cell line serves as a model to study the molecular mechanisms associated with leukemia differentiation. We show here that cotreatment of K562 cells with PMA and low doses of SB202190 (SB), an inhibitor of the p38 MAPK pathway, induced a majority of cells to differentiate towards the megakaryocytic lineage. Electronic microscopy analysis showed that K562 cells treated with PMA+SB exhibited characteristic features of physiological megakaryocytic differentiation including the presence of vacuoles and demarcation membranes. Differentiation was also accompanied by a net increase in megakaryocytic markers and a reduction of erythroid markers, especially when both effectors were present. PMA effect was selectively mediated by new PKC isoforms. Differentiation of K562 cells by the combination of PMA and SB required Erk1/2 activation, a threshold of JNK activation and p38 MAPK inhibition. Interestingly, higher concentrations of SB, which drastically activated JNK, blocked megakaryocytic differentiation, and considerably increased cell death in the presence of PMA. c-DNA microarray membranes and PCR analysis allow us to identify a set of genes modulated during PMA-induced K562 cell differentiation. Several gene families identified in our screening, including ephrins receptors and some angiogenic factors, had never been reported so far to be regulated during megakaryocytic differentiation.

Base Sequence↗
PubMed2005

[Flow cytometric differential gating strategy for evaluation of T-lymphocyte survival and proliferation in mixed lymphocyte reaction with dendritic cells].

Mixed lymphocyte reaction (MLC) of T-lymphocytes with dendritic cells is one of the basic tools for studying of immune reaction mechanisms. This work describes a new method of evaluation of allogeneic and autologous MLC by flow cytometry and differential gating. This method is based on fixed time acquisition of events and their sorting according to their forward and side scatter properties. Differential gating distinguishes populations of all living cells (R1), living non-proliferating cells (R2) and dead/apoptotic cells (R4). Addition of fluorescence microspheres (R3) enables the calculation of absolute number of cells in a given sample volume. Using the method of 7-AAD positive cells project into the exclusion, we have shown that approximately 90% of 7-AAD R4 gate. Moreover, there was an excellent correlation between the R1: R2 ratio and the percentage of cells positive for activation/proliferation marker CD71. The method of differential gating in its basic version does not require use of any fluorescent antibody and therefore is suitable for rapid screening of large number of samples at reasonable cost and without the use of radiolabeled nucleotides.

Adult↗
PubMed2004

Radiotherapy and hyperthermia in the treatment of patients with locally advanced prostate cancer: preliminary results.

OBJECTIVE: To report an interim clinical evaluation of combined external beam irradiation (EBRT) and interstitial or regional hyperthermia in the treatment of locally advanced prostate cancer. PATIENTS AND METHODS: From 1997 to 2001, 26 patients with T3-4/NX/0M0 prostate carcinoma were treated with a combination of conformal EBRT and hyperthermia. Fourteen patients received five weekly regional hyperthermia treatments within an optimization (phase II) study, using the coaxial transverse electrical magnetic system. Twelve patients received one interstitial hyperthermia treatment within a feasibility study (phase I), using the multi-electrode current source system. Irradiation was delivered using a conformal three-field technique, administering 70 Gy in 2-Gy fractions in 7 weeks. RESULTS: The mean initial prostate-specific antigen level was 26 ng/mL. Three patients had a T4 and 23 a T3 tumour; the tumours were classified as well (four), moderately (16) and poorly (six) differentiated. The mean follow-up was 36 months. In the combined treatments there was no toxicity of more than grade 2. In regional hyperthermia the mean index temperature (T90 and T50, i.e. exceeded by 90% and 50% of the measurements) was 40.2 degrees C and 40.8 degrees C, and for interstitial hyperthermia 39.4 degrees C and 41.8 degrees C, respectively. All patients survived; seven patients had a biochemical relapse (27%), three in the regional and four in the interstitial group. The actuarial probability of freedom from biochemical relapse was 70% at 36 months for all patients together, 79% for regional and 57% for interstitial. No factors were found that could be used to predict relapse. CONCLUSIONS: The clinical outcome in these patients with advanced localized prostate cancer seems to compare favourably with most series using irradiation alone, and the treatment caused no severe complications.

Aged↗
PubMed2004

Mucormycosis--early diagnosis and treatment.

OBJECTIVE: The aim of this retrospective study was to analyse the data of patients with rhino-orbital-cerebral mucormycosis for predisposing factors, diagnosis, treatment and survival rate. The role of frozen section in early diagnosis and use of nasal endoscopy in diagnosis, treatment and follow-up of patients has also been examined. DESIGN: Retrospective case series. SETTING: University Teaching Hospital. METHODS: The case notes of 9 patients with diagnosis of mucormycosis who presented from 1973 to 2001 were examined. The data for predisposing factors, signs/symptoms, histological diagnosis, radiological intervention, medical and surgical treatment and final outcome was analysed. RESULTS: There were 9 patients with mucormycoses. Early diagnosis was made by endoscopic examination and frozen section in 5 patients, which was later confirmed by histology. Treatment included parental and/or local amphotericin, hyperbaric oxygen and debridement either by endoscopic or external approach, with or without orbital exenteration. This resulted in an overall survival of 5 patients. CONCLUSION: Frozen section diagnosis allows for early therapy since successful treatment depends on systemic amphotericin, surgical debridement and treatment of underlying predisposing factors. Nasal endoscopy is useful in diagnosis, endoscopic debridement and follow up of patients.

Adult↗
PubMed2003

MR-imaging of the brain of neurologic asymptomatic patients with large cell or adenocarcinoma of the lung. Does it influence prognosis and treatment?

Magnetic resonance imaging (MRI) of the brain and extensive neurological examination by a neurologist was performed as part of initial staging evaluation of 91 neurologic asymptomatic patients with large cell carcinoma or adenocarcinoma of the lung. Patients were followed up for at least 6 months. Evidence of metastatic brain disease was documented in 13 (14%) patients. Two of these patients were found suspective of brain metastases (BM) by the neurologist. The detection of BM resulted in upstaging of 1 (3%) patient in stage I/II, 4 (21%) patients in stage IIIA and 2 (11%) patients in IIIB. Especially for patients in stage III this upstaging is of importance as aggressive locoregional treatment can be abandoned. Evaluation of the brain with MRI is a sensitive method of detecting BM in neurologic asymptomatic patients and is recommended as part of the initial staging of patients with large cell carcinoma or adenocarcinoma of the lung in stage III. Additional examination by the neurologist is of little value to provide information of the neurologic status.

Adenocarcinoma↗
PubMed2003

Rapid visuomotor preparation in the human brain: a functional MRI study.

An important feature of human motor behaviour is anticipation and preparation. We report a functional magnetic resonance imaging study of the neuronal activation patterns in the human brain that are associated with the rapid visuomotor preparation of discrete finger responses. Our imaging results reveal a large-scale distributed network of neural areas involved in fast visuomotor preparation, including specific areas in the frontal cortex (middle frontal gyrus, premotor and supplementary motor cortex), the parietal cortex (intra-parietal sulcus, inferior and superior parietal lobe) and the basal ganglia. Our reaction time results demonstrate that it is easier to prepare two fingers on one hand than on two hands. This hand-advantage phenomenon was associated with relatively enhanced levels of activity in the basal ganglia and relatively reduced levels of activity in the parietal cortex. These findings provide direct evidence for differential activity in a distributed brain system associated with specific neuro-computational operations subserving fast visuomotor preparation.

Adult↗
PubMed2003

Modification of gene expression induced in human osteogenic and osteosarcoma cells by culture on a biphasic calcium phosphate bone substitute.

Bone hybrids made of bioceramics seeded with mesenchymal or osteoblastic cells are very promising alternatives to autologous bone graft. Along this line, the development of in vitro models, dedicated to analyze the influence of these biomaterials on osteogenic cells, will help to improve the performance of these bone substitutes. In the present work we analyzed the effects of a macroporous biphasic calcium phosphate ceramic (BCP, Triosite) on three different human osteosarcoma cell lines and on human primary osteogenic cells and compared this culture substratum to traditional culture on plastic. We showed that all these osteoblastic cells adhere and proliferate on the trabecular BCP blocks, with a different spatial organization for osteosarcoma cells compared to normal osteogenic cells. We also demonstrated that osteoblastic marker genes such as Cbfa1, type I collagen, osteonectin, osteopontin, and osteocalcin were expressed at similar levels by these cells cultured on either substratum, suggesting that adhesion to BCP does maintain the osteoblastic phenotype of these cells. Next, we provided the first evidence of differences of cytokine expression profiles revealed on this Ca-P ceramic as compared to expression in classical culture. These modifications affected the expression of cytokines such as TGF-beta1, G-CSF, and IL-3 and were quantitatively different between osteosarcoma cells and normal osteogenic cells. Given the role of these cytokines in bone biology and in hematopoiesis, these results obtained in vitro suggest that the BCP ceramic studied here could stimulate osteogenesis in vivo by activating cellular processes during bone formation and healing. This study highlights the notion that the nature of the culture substratum must be taken into account when studying bone cell biology in vitro. Owing to the nature and spatial organization of the BCP, our hypothesis is that culture on BCP is closer to the physiological situation than culture on plastic.

Adolescent↗
PubMed2003

Usefulness of language and memory testing during intracarotid amobarbital testing: observations from an fMRI study.

BACKGROUND: Several procedures for testing language lateralization and memory function exist during the intracarotid amobarbital test (IAT). The use of functional magnetic resonance imaging (fMRI) gives the opportunity to assess the validity of some of these procedures, or at least to inspect the neuronal correlates. A comprehensive fMRI protocol was tested, aimed at addressing aspects of lateralization of language, as well as testing memory in relation to activation of mesiotemporal regions. Here we report observations with possible consequences for the current IAT procedures. MATERIALS AND METHODS: The protocol consisted of three language tasks (overt naming, semantic decision and silent word generation) and two memory tasks (encoding and retrieving visual scenes). The paradigms used a block-related procedure in nine right-handed normal volunteers. During the procedure dynamic weighted full brain images were acquired which are sensitive to the blood oxygenation activation effect. RESULTS: Encoding showed symmetrical bilateral activation in the mesiotemporal regions, specifically the hippocampus, parahippocampal gyrus and fusiform gyrus. With a retrieval task activation of the mesiotemporal areas was restricted to the posterior hippocampal area. Overt object naming showed results, similar to encoding tasks with bilateral activation of hippocampal areas. Silent word generation showed much stronger ability to lateralize than the other two language-related tasks and especially object naming. CONCLUSION: Activation revealed by fMRI activation shows that IAT procedures, using active semantic language processing or comprehensive procedures with multiple language tasks have the highest guarantee for individual activation lateralization. Simple object naming does not guarantee a lateralized language fMRI activation pattern. Of the different memory procedures during IAT, the procedures (Interview and the Montreal) demanding encoding processing will be related to larger areas of bilateral hippocampal activation than procedures (Seattle) exclusively requiring retrieval. Moreover, tasks using recognition of previously presented language items (naming objects) are equally effective for assessing hippocampal activation compared with presenting separate memory items.

Adult↗
PubMed2003

Cerebral tissue alterations and daily life stress experience in psychosis.

OBJECTIVE: To examine whether the total volumes of cerebrospinal fluid (CSF), cerebral grey matter and white matter were correlated with the experience of environmental stress in daily life situations. METHOD: Twenty-seven patients with psychosis underwent magnetic resonance imaging scanning and a random time-sampling self-assessment technique (Experience Sampling Method) to determine subjective daily life stress experiences. Total cerebral tissue volumes were derived from an automated segmentation procedure. RESULTS: CSF volume was positively associated with daily life event-related stress (beta=0.016, P=0.002), while the association with total white matter was negative (beta=-0.013, P=0.005). The effects were independent of each other and of total cerebral volume and other confounders. No large or significant association was found with grey matter volume. CONCLUSION: Subjective stress experience in daily life is associated with increased CSF and reduced white matter volumes in patients with psychosis, suggesting functional significance of these cerebral measures.

Adolescent↗
PubMed2003

Downregulation of caspases and Fas ligand expression, and increased lifespan of neutrophils after transmigration across intestinal epithelium.

During inflammatory bowel diseases, commitment of extravased polymorphonuclear leucocytes (PMN) to apoptosis is required for the resolution of inflammation. To investigate the effect of transepithelial migration on PMN apoptotic rates, PMN transepithelial migration was reproduced in vitro using T84 intestinal monolayers. Transepithelial migration was found to delay neutrophil apoptosis, and this survival effect correlated with a downregulation of the surface expression of Fas ligand (FasL) and with a decrease in both procaspases-3, and -8 mRNA and procaspases-3, -6, -7 and -8 protein levels. Moreover, neutrophil survival and FasL shedding mediated by transepithelial migration were abrogated by a broad-spectrum metalloproteinase inhibitor, BB-94. Although Erk1/2 and p38 MAPK were activated in transmigrated PMN, inhibition of these MAP kinases did not impair transmigration-induced PMN survival. Taken together, our results show that trans-epithelial migration induces the downregulation of proapoptotic proteins expression in transmigrated PMN, which results in their increased lifespan.

Apoptosis↗
PubMed2003

Pathological interactions of bacteria and toxins with the gastrointestinal epithelial tight junctions and/or the zonula adherens: an update.

Communication between bacteria and the gastrointestinal tight junctions (TJs) and zonula adherens is examined. Bacteial-epithelial TJs "crosstalk" can be mediated by many virulence factors, mainly secreted toxins, or can be induced by direct contact of the pathogen with epithelial membrane. Moreover, there are several mechanisms by which bacteria may act on gastrointestinal TJs. First, bacteria can act indirectely at the TJs level by inducing cell transepithelial migration. More particularly, neutrophil or dendritic cells can cross the epithelium by a paracellular pathway. Secondly, bacteria and/or toxins can trigger actin cytoskeleton reorganization (depolymerization or hyperpolymerization). Thirdly, some enteric pathogens are susceptible to act on TJs by activation of cellular signal transduction. Finally, cleavage or modification of TJs proteins can be used by bacteria. New therapeutic strategies may result from a deeper knowledge of the cellular and molecular processes induced by bacteria at the TJ level. Moreover, studies of action of the different bacterial virulence factors on the molecules comprising the TJs and zonula adherens allow us an interesting approach on our understanding of TJ complex regulation.

Adherens Junctions↗
PubMed2003

[Vitreous changes in Stickler syndrome].

We report the ultrastructural feature of a vitreous membrane with multiple fenestrations in a case of a 40-year-old woman with a Stickler syndrome. The left eye showed a type 2 vitreous phenotype. Vitreous abnormalities of the right eye may correspond to phenotypic conversion to a type 1 appearance of a type 2 vitreous phenotype. Fenestrated membrane may correspond to posterior hyaloid membrane in complete posterior vitreous detachment in this phenotypic conversion. Fenestrated membrane consisted of avascular fibrocellular tissue with cells arranged in a cohesive pattern around the fenestration. Ultrastructural findings of cells were characteristic of proliferative Müller cells. Ultrastructural examination of collagen fibrils showed them to be similar to normal vitreous. This finding suggests that collagen molecules are not functionally altered and are probably quantitatively insufficient during vitreous development.

Abnormalities, Multiple↗
PubMed2003

[Optic disk neovascularization in fungal endophthalmitis].

A case of optic disk neovascularization is reported in a 30-year-old female heroin addict with suspected fungal endophthalmitis treated with an intravitreal injection of amphotericin B and fluconazole (200mg/day). Membrane healing was characterized by densification and contraction leading to tractional retinal detachment; excision by vitrectomy was required. Electron microscopy analysis of the membrane removed the tenth month revealed a poorly vascularized fibrous tissue infiltrated by chronic inflammatory cells. Visual improvement was poor owing to a postoperative macular disorder and a full-thickness retinal scar.

Adult↗
PubMed2002

Developing a comprehensive presurgical functional MRI protocol for patients with intractable temporal lobe epilepsy: a pilot study.

Our aim was to put together and test a comprehensive functional MRI (fMRI) protocol which could compete with the intracarotid amytal (IAT) or Wada test for the localisation of language and memory function in patients with intractable temporal lobe epilepsy. The protocol was designed to be performed in under 1 h on a standard 1.5 tesla imager. We used five paradigms to test nine healthy right-handed subjects: complex scene-encoding, picture-naming, reading, word-generation and semantic-decision tasks. The combination of these tasks generated two activation maps related to memory in the mesial temporal lobes, and three language-related maps of activation in a major part of the known language network. The functional maps from the encoding and naming tasks showed typical and symmetrical posterior mesial temporal lobe activation related to memory in all subjects. Only four of nine subjects also showed symmetrical anterior hippocampal activation. Language lateralisation was best with the word generation and reading paradigms and proved possible in all subjects. The reading paradigm enables localisation of language function in the left anterior temporal pole and middle temporal gyrus, areas typically resected during epilepsy surgery. The combined results of this comprehensive f MRI protocol are adequate for a comparative study with the IAT in patients with epilepsy being assessed for surgery.

Adult↗
PubMed2002

The osteodystrophy of mucolipidosis type III and the effects of intravenous pamidronate treatment.

Mucolipidosis type III (ML III; McKusick 252600) is a rare lysosomal storage disease in which skeletal involvement is prominent, in particular the destruction of vertebral bodies and the femoral heads. We describe studies in two siblings with ML III that suggest the presence of a distinct metabolic bone disorder. Biochemical indices of bone turnover were increased, and transiliac bone biopsy demonstrated both trabecular osteopenia and marked subperiosteal bone resorption. Intravenous pamidronate treatment given monthly for a year was well tolerated and produced dramatic clinical effects, with reduction in bone pain and improvements in mobility, despite incomplete suppression of bone resorption as assessed by biochemical, radiographic and histological criteria. Bisphosphonate therapy may have an important role in the management of bone pain in ML III, as it does in the related lysosomal disorder of Gaucher disease.

Absorptiometry, Photon↗