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Biomedical subjects

C M Niemeyer

Publications and source records attributed to C M Niemeyer.

At least 19 recordsLinked to original sources
PubMed2006

Pyoderma gangraenosum, a rare, but potentially fatal complication in paediatric oncology patients.

Pyoderma gangraenosum (PG) is a serious chronic, ulcerative skin disorder afflicting both adults and children. As PG is often associated with systemic diseases (>50%) such as inflammatory bowel disease, rheumatoid arthritis or haematological disorders, it requires a multidisciplinary approach. This disorder is not commonly reported in paediatrics; therefore children with PG represent a particularly difficult diagnostic challenge. Clinical diagnosis is often delayed and PG is only considered after eliminating other causes of cutaneous ulcers. We report a 4-year-old boy with secondary myelodysplastic syndrome following treatment for acute lymphoblastic leukaemia who presented with a massive inflammatory, ulcerative proliferation of the lower lip which was diagnosed as PG. We have reviewed the literature with reference to diagnostic criteria and treatment options of this disorder that is particularly rare in childhood.

Administration, Topical↗
PubMed2005

Evaluation of dysplastic features in myelodysplastic syndromes: experience from the morphology group of the European Working Group of MDS in Childhood (EWOG-MDS).

In the absence of genetic abnormalities, the diagnoses of myelodysplastic syndromes (MDS) is primarily based on the presence of dysplasia in blood and marrow cells. Currently, there is no standardized approach to evaluate dysplasia. International cooperative study groups like the European Working Group on MDS in Childhood (EWOG-MDS) depend, however, on a concordance in diagnoses by their national reference centres for morphology. In EWOG-MDS, the morphological diagnoses of all cases enrolled from Scandinavia, the Netherlands, Germany, the Czech Republic, Austria and Italy are established by five experienced pathologists or hematologists cooperating in a morphology board. To study their concordance in evaluating myelodysplastic disorders, members of the morphology board initiated blinded reviews of smears of blood and bone marrow aspirates of known cases. Four features of dysplasia in granulopoiesis, erythropoiesis and megakaryopoiesis were assessed on May-Grünwald-Giemsa stained smears. In a final review of six blinded cases, good concordance for these features was achieved among the five observers. Accurately defined and restrictively applied cellular features of dysplasia are an important tool to improve and ensure the concordance in the diagnosis of MDS among investigators. For cooperative groups, agreement on the evaluation of the morphological assessment of dysplasia is a prerequisite.

Adult↗
PubMed2005

Stem cell transplantation for aplastic anemia and myelodysplastic syndrome.

SUMMARY: Stem cell transplantation (SCT) from a histocompatible sibling is treatment of choice for severe aplastic anemia. Survival rates have been reported to be as high as 90% for children. Immunosuppressive therapy (IST) is employed in patients who are not candidates for SCT due to donor unavailability. The addition of cyclosporin A to antilymphocyte globulin has improved the response rate to 70-80%, and survival at 5 years among responders is about 90%. In all, 30% of patients treated by IST suffer from relapse, but long-term prognosis does not appear to be affected by this complication. Juvenile myelomonocytic leukemia (JMML) shares both myelodysplastic and myeloproliferative features. Survival (10-year) of patients with JMML without SCT is only 6%. Children with JMML should be transplanted early in the course of their disease. Conditioning regimen composed of three alkylating agents, busulfan, cyclophosphamide and melphalan has been favored by the EWOG-MDS and EBMT-Pediatric WP in the second half of the 1990s. SCT using this conditioning regimen is capable of curing approximately 50% of patients with JMML. More than 70% of patients with refractory cytopenia and more than 50% of children with advanced MDS are cured of by the early performed allogeneic SCT.

Anemia, Aplastic↗
PubMed2005

Donor leukocyte infusion after hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative disorder of early childhood. In all, 21 patients with JMML who received donor leukocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation (HSCT) for either mixed chimerism (MC, n=7) or relapse (n=14) were studied. Six patients had been transplanted from an HLA-matched sibling and 15 from other donors. Six of the 21 patients (MC: 3/7 patients; relapse: 3/14 patients) responded to DLI. Response rate was significantly higher in patients receiving a higher total T-cell dose (> or =1 x 10(7)/kg) and in patients with an abnormal karyotype. None of the six patients receiving DLI from a matched sibling responded. Response was observed in five of six patients who did and in one of 15 children who did not develop acute graft-versus-host disease following DLI (P=0.01). The overall outcome was poor even for the responders. Only one of the responders is alive in remission, two relapsed, and three died of complications. In conclusion, this study shows that some cases of JMML may be sensitive to DLI, this providing evidence for a graft-versus-leukemia effect in JMML. Infusion of a high number of T cells, strategies to reduce toxicity, and cytoreduction prior to DLI may improve the results.

Child↗
PubMed2004

The International Prognostic Scoring System (IPSS) for childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML).

The International Prognostic Scoring System (IPSS) for myelodysplastic syndrome (MDS) is based upon weighted data on bone marrow (BM) blast percentage, cytopenia, and cytogenetics, separating patients into four prognostic groups. We analyzed the value of the IPSS in 142 children with de novo MDS and 166 children with juvenile myelomonocytic leukemia (JMML) enrolled in retro- and prospective studies of the European Working Group on childhood MDS (EWOG-MDS). Survivals in MDS and JMML were analyzed separately. Among the criteria considered by the IPSS score, only BM blasts <5% and platelets >100 x 10(9)/l were significantly associated with a superior survival in MDS. In JMML, better survival was associated with platelets >40 x 10(9)/l, but not with any other IPSS factors including cytogenetics. In conclusion, the IPSS is of limited value in both pediatric MDS and JMML. The results reflect the differences between myelodysplastic and myeloproliferative diseases in children and adults.

Child↗
PubMed2004

Semi-synthetic DNA-protein conjugates: novel tools in analytics and nanobiotechnology.

This article reports on the syntheses, characterization and applications of semi-synthetic conjugates composed of nucleic acids, proteins and inorganic nanoparticles. For example, self-assembled oligomeric networks consisting of streptavidin and double-stranded DNA are applicable as reagents in immunoassays, model systems for ion-switchable nanoparticle networks as well as nanometer-scaled 'soft material' standards for scanning probe microscopy. Covalent conjugates of single-stranded DNA and streptavidin are utilized as biomolecular adapters for the immobilization of biotinylated macromolecules at solid substrates via nucleic acid hybridization. This 'DNA-directed immobilization' allows for reversible and site-selective functionalization of solid substrates with metal and semiconductor nanoparticles or, vice versa, for the DNA-directed functionalization of gold nanoparticles with proteins, such as immunoglobulins and enzymes. This approach is applicable for the detection of chip-immobilized antigens. Moreover, covalent DNA-protein conjugates allow for their selective positioning along single-stranded nucleic acids, and thus for the construction of nanometre-scale assemblies composed of proteins and/or nanoclusters. Examples include the fabrication of functional biometallic nanostructures from gold nanoparticles and antibodies, applicable as diagnostic tools in bioanalytics.

Biotechnology↗
PubMed2003

A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases.

Myelodysplastic and myeloproliferative disorders are rare in childhood and there is no widely accepted system for their diagnosis and classification. We propose minimal diagnostic criteria and a simple classification scheme which, while based on accepted morphological features and conforming with the recent suggestions of the WHO, allows for the special problems of myelodysplastic diseases in children. The classification recognizes three major diagnostic groups: (1) juvenile myelomonocytic leukemia (JMML), previously named chronic myelomonocytic leukemia (CMML) or juvenile chronic myeloid leukemia (JCML); (2) myeloid leukemia of Down syndrome, a disease with distinct clinical and biological features, encompassing both MDS and AML occurring in Down syndrome; and (3) MDS occurring both de novo and as a complication of previous therapy or pre-existing bone marrow disorder (secondary MDS). The main subtypes of MDS are refractory cytopenia (RC) and refractory anemia with excess of blasts (RAEB). It is suggested retaining the subtype of RAEB-T with 20-30% blasts in the marrow until more data are available. Cytogenetics and serial assessments of the patients are essential adjuncts to morphology both in diagnosis and classification.

Child↗
PubMed2001

Dendrimer-activated solid supports for nucleic acid and protein microarrays.

The generation of chemically activated glass surfaces is of increasing interest for the production of microarrays containing DNA, proteins, and low-molecular-weight components. We here report on a novel surface chemistry for highly efficient activation of glass slides. Our method is based on the initial modification of glass with primary amino groups using a protocol, specifically optimized for high aminosilylation yields, and in particular, for homogeneous surface coverages. In a following step the surface amino groups are activated with a homobifunctional linker, such as disuccinimidylglutarate (DSG) or 1,4-phenylenediisothiocyanate (PDITC), and then allowed to react with a starburst dendrimer that contains 64 primary amino groups in its outer sphere. Subsequently, the dendritic monomers are activated and crosslinked with a homobifunctional spacer, either DSG or PDITC. This leads to the formation of a thin, chemically reactive polymer film, covalently affixed to the glass substrate, which can directly be used for the covalent attachment of amino-modified components, such as oligonucleotides. The resulting DNA microarrays were studied by means of nucleic acid hybridization experiments using fluorophor-labeled complementary oligonucleotide targets. The results indicate that the novel dendrimer-activated surfaces display a surface coverage with capture oligomers about twofold greater than that with conventional microarrays containing linear chemical linkers. In addition, the experiments suggest that the hybridization occurs with decreased steric hindrance, likely a consequence of the long, flexible linker chain between the surface and the DNA oligomer. The surfaces were found to be resistant against repeated alkaline regeneration procedures, which is likely a consequence of the crosslinked polymeric structure of the dendrimer film. The high stability allows multiple hybridization experiments without significant loss of signal intensity. The versatility of the dendrimer surfaces is also demonstrated by the covalent immobilization of streptavidin as a model protein.

Autoradiography↗
PubMed2001

Bioorganic applications of semisynthetic DNA-protein conjugates.

Semisynthetic DNA-protein conjugates are versatile molecular tools useful, for instance, in the self-assembly of high-affinity reagents for immunological detection assays, the fabrication of highly functionalized laterally microstructured biochips, and the biomimetic "bottom-up" synthesis of nanostructured supramolecular devices. This concept paper summarizes the current state-of-the-art concerning the synthesis, characterization, and applications of such hybrid molecules, and also draws perspectives on future developments.

Binding Sites↗
PubMed2001

Nucleic acid supercoiling as a means for ionic switching of DNA--nanoparticle networks.

Oligomeric nanoparticle networks, generated by the self-assembly of bis-biotinylated double-stranded DNA fragments and streptavidin, have been studied by scanning force microscopy (SFM). SFM imaging revealed the presence within the networks of irregular thick DNA molecules, which were often associated with distinct, Y-shaped structural elements. Closer analysis revealed that the Y structures are formed by condensation (thickening and shortening) of two DNA fragments, most likely through the supercoiling of two DNA molecules bound to adjacent binding sites of the streptavidin particle. The frequency of supercoiling was found to be dependent on the ionic strength applied during the immobilization of the oligomeric networks on mica surfaces. Potential applications of the structural changes as a means for constructing ion-dependent molecular switches in nanomaterials are discussed.

Biotinylation↗
PubMed2001

Evidence for linkage of familial Diamond-Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease.

Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia that usually presents early in infancy and is inherited in 10% to 20% of cases. Linkage analysis has shown that DBA in many of both dominant and recessive DBA families mapped to chromosome 19q13.2 leading to the cloning of a gene on chromosome 19q13.2 that encodes a ribosomal protein, RPS19. However, subsequently, mutations of the RPS19 gene have only been identified in 25% of all patients with DBA. This study analyzed 14 multiplex DBA families, 9 of which had 19q13.2 haplotypes inconsistent with 19q linkage. A genome-wide search for linked loci suggested the presence of a second DBA locus in a 26.4-centimorgan (cM) interval on human chromosome 8p. Subsequently, 24 additional DBA families were ascertained and all 38 families were analyzed with additional polymorphic markers on chromosome 8p. In total, 18 of 38 families were consistent with linkage to chromosome 8p with a maximal LOD score with heterogeneity of 3.55 at D8S277 assuming 90% penetrance. The results indicate the existence of a second DBA gene in the 26.4-cM telomeric region of human chromosome 8p23.3-p22, most likely within an 8.1-cM interval flanked by D8S518 and D8S1825. Seven families were inconsistent with linkage to 8p or 19q and did not reveal mutations in the RPS19 gene, suggesting further genetic heterogeneity. (Blood. 2001;97:2145-2150)

Chromosomes, Human, Pair 19↗
PubMed2001

Semi-synthetic nucleic acid-protein conjugates: applications in life sciences and nanobiotechnology.

Semi-synthetic conjugates of nucleic acids and proteins can be generated by either covalent coupling chemistry, or else by non-covalent biomolecular recognition systems, such as receptor-ligands of complementary nucleic acids. These nucleic acid-protein conjugates are versatile molecular tools which can be applied, for instance, in the self-assembly of high-affinity reagents for immunological detection assays, the fabrication of laterally microstructured biochips containing functional biological groups, and the biomimetic 'bottom-up' synthesis of nanostructured supramolecular devices. This review summarizes the current state-of-the-art synthesis and characterization methods of artificial nucleic acid-protein conjugates, as well as applications and perspectives for future developments of such hybrid biomolecular components in life sciences and nanobiotechnology.

Biotechnology↗
PubMed2001

Sensitivity of Ewing's sarcoma to TRAIL-induced apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to kill transformed cells. We have studied the expression and functionality of the TRAIL apoptotic pathway in Ewing's sarcoma. We demonstrate that tumors from patients with Ewing's sarcoma express receptors TRAIL-R1 and -R2. Using a panel of nine Ewing's sarcoma cell lines TRAIL could induce apoptosis in seven cell lines. Preincubation with interferon-gamma rendered the two resistant cell lines sensitive. TRAIL was the most potent inducer of apoptosis when compared to Fas ligand or TNF. TRAIL-mediated apoptosis could be inhibited by various caspase-inhibitors. No difference in the surface expression of TRAIL-receptors was observed between sensitive and resistant cell lines. Also, all cell lines had similar levels of expression of Flice-like inhibitory protein (FLIP) on immunoblot. However, the two resistant cell lines had only very low level expression of caspase 8 on RNA and protein level. In summary, we show that Ewing's sarcoma expresses receptors for TRAIL, and that cells are exquisitely sensitive to TRAIL-mediated apoptosis. These results may warrant clinical trials with TRAIL in Ewing's sarcoma once the safety of TRAIL for humans has been established.

Apoptosis↗
PubMed2001

Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group.

In the randomized trial AML-BFM 93 we compared 60 mg/m2/day daunorubicin with 12 mg/m2/day idarubicin for 3 days each, combined with cytarabine and etoposide during induction. Results showed a significant better blast cell reduction in the bone marrow on day 15 in patients of the idarubicin arm (25 of 144 = 17% of patients with > or = 5% blasts compared to 46 of 149 = 31% of patients after daunorubicin, Pchi2 = 0.01). This was, however, mainly seen in high risk patients treated with idarubicin (19% vs 38%, Pchi2 = 0.007). Cardiotoxicity, WHO grade 1-3 shortening fraction reduction after induction occurred in 6% patients in both arms. Bone marrow toxicity differed slightly with a median recovery time of neutrophils >500/microl of 25 days (daunorubicin) compared to 27 days (idarubicin), P = 0.05. In the total group of patients probabilities of 5 years event-free survival and disease-free survival were similar for patients treated with daunorubicin or idarubicin (49% +/- 4% vs 55% +/- 4% and 57% +/- 4% vs 64% +/- 4%, P logrank 0.29 and 0.15, respectively). However, in patients presenting with more than 5% blasts on day 15 there was a trend for a better outcome after treatment with idarubicin (P logrank 0.06). Together with the early effect seen for high risk patients these results indicate a better efficacy of idarubicin than of daunorubicin during induction with a similar rate of toxicity.

Antibiotics, Antineoplastic↗