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D Birnbaum

Publications and source records attributed to D Birnbaum.

At least 19 recordsLinked to original sources
PubMed2006

Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer.

Common fragile sites (CFSs) are regions of chromosomal break that may play a role in oncogenesis. The most frequent alteration occurs at FRA3B, within the FHIT gene, at chromosomal region 3p14. We studied a series of breast carcinomas for break of a CFS at 6q26, FRA6E, and its associated gene PARK2, using fluorescence in situ hybridization on tissue microarrays (TMA). We found break of PARK2 in 6% of cases. We studied the PARK2-encoded protein Parkin by using immunohistochemistry on the same TMA. Loss of Parkin was found in 13% of samples but was not correlated with PARK2 break. PARK2 break but not Parkin expression was correlated with prognosis. Alteration of PARK2/FRA6E may cause haplo-insufficiency of one or several telomeric potential tumor suppressor genes (TSG). The AF-6/MLLT4 gene, telomeric of PARK2, encodes the Afadin scaffold protein, which is essential for epithelial integrity. Loss of Afadin was found in 14.5% of cases, and 36% of these cases showed PARK2 break. Loss of Afadin had prognostic impact, suggesting that AF-6 may be a TSG. Loss of Afadin was correlated with loss of FHIT expression, suggesting fragility of FRA6E and FRA3B in a certain proportion of breast tumors.

Acid Anhydride Hydrolases↗
PubMed2006

Gene expression profiling of breast cell lines identifies potential new basal markers.

A better molecular characterization of breast cell lines (BCL) may help discover new markers to apply to tumour samples. We performed gene and protein expression profiling of 31 BCL using whole-genome DNA microarrays and immunohistochemistry (IHC) on 'cell microarrays' (CMA), respectively. Global hierarchical clustering discriminated two groups of BCL: group I corresponded to luminal cell lines, group II to basal and mesenchymal cell lines. Correlations with centroids calculated from a published 'intrinsic 500-gene set' assigned 15 cell lines as luminal, eight as basal and four as mesenchymal. A set of 1.233 genes was differentially expressed between basal and luminal samples. Mesenchymal and basal subtypes were rather similar and discriminated by only 227 genes. The expression of 10 proteins (CAV1, CD44, EGFR, MET, ETS1, GATA3, luminal cytokeratin CK19, basal cytokeratin CK5/6, CD10, and ERM protein moesin) encoded by luminal vs basal discriminator genes confirmed the subtype classification and the validity of the identified markers. Our BCL basal/luminal signature correctly re-classified the published series of tumour samples that originally served to identify the molecular subtypes, suggesting that the identified markers should be useful for tumour classification and might represent promising targets for disease management.

Biomarkers, Tumor↗
PubMed2006

Gene expression profiling identifies molecular subgroups among nodal peripheral T-cell lymphomas.

The classification of peripheral T-cell lymphomas (PTCL) is still a matter of debate. To establish a molecular classification of PTCL, we analysed 59 primary nodal T-cell lymphomas using cDNA microarrays, including 56 PTCL and three T-lymphoblastic lymphoma (T-LBL). The expression profiles could discriminate angioimmunoblastic lymphoma, anaplastic large-cell lymphoma and T-LBL. In contrast, cases belonging to the broad category of 'PTCL, unspecified' (PTCL-U) did not share a single molecular profile. Using a multiclass predictor, we could separate PTCL-U into three molecular subgroups called U1, U2 and U3. The U1 gene expression signature included genes known to be associated with poor outcome in other tumors, such as CCND2. The U2 subgroup was associated with overexpression of genes involved in T-cell activation and apoptosis, including NFKB1 and BCL-2. The U3 subgroup was mainly defined by overexpression of genes involved in the IFN/JAK/STAT pathway. It comprised a majority of histiocyte-rich PTCL samples. Gene Ontology annotations revealed different functional profile for each subgroup. These results suggest the existence of distinct subtypes of PTCL-U with specific molecular profiles, and thus provide a basis to improve their classification and to develop new therapeutic targets.

Gene Expression Profiling↗
PubMed2006

Postoperative serum proteomic profiles may predict metastatic relapse in high-risk primary breast cancer patients receiving adjuvant chemotherapy.

A total of 30-50% of early breast cancer (EBC) patients considered as high risk using standard prognostic factors develop metastatic recurrence despite standard adjuvant systemic treatment. A means to better predict clinical outcome is needed to optimize and individualize therapeutic decisions. To identify a protein signature correlating with metastatic relapse, we performed surface-enhanced laser desorption/ionization-time of flight mass spectrometry profiling of early postoperative serum from 81 high-risk EBC patients. Denatured and fractionated serum samples were incubated with IMAC30 and CM10 ProteinChip arrays. Several protein peaks were differentially expressed according to clinical outcome. By combining partial least squares and logistic regression methods, we built a multiprotein model that correctly predicted outcome in 83% of patients. The 5-year metastasis-free survival in 'good prognosis' and 'poor prognosis' patients as defined using the multiprotein index were strikingly different (83 and 22%, respectively; P<0.0001, log-rank test). In a multivariate Cox regression including conventional pathological factors and multiprotein index, the latter retained the strongest independent prognostic significance for metastatic relapse. Major components of the multiprotein index included haptoglobin, C3a complement fraction, transferrin, apolipoprotein C1 and apolipoprotein A1. Therefore, postoperative serum protein pattern may have an important prognostic value in high-risk EBC.

Adult↗
PubMed2006

[DNA microarrays for gene expression profiling of breast cancer: principles and prognostic applications].

Breast cancer is a major health problem in developed countries. Pathological and clinical heterogeneity, partly responsible of therapeutic failures, reflects its poorly documented complex and combinatory molecular basis. Thorough molecular typing could allow not only better tackling that diversity and improving the current prognostic classifications, but also could help in the identification of new molecular therapeutic targets. The recently developed DNA microarray technology allows the analysis of the RNA expression of several thousands of genes simultaneously in a sample. Recent studies have shown the promising prognostic impact of gene expression profiling in breast cancer by identifying new prognostic subclasses unidentifiable by conventional parameters.

Breast Neoplasms↗
PubMed2005

Multicolour-banding fluorescence in situ hybridisation (mbanding-FISH) to identify recurrent chromosomal alterations in breast tumour cell lines.

Recurrent chromosome breakpoints in tumour cells may point to cancer genes, but not many have been molecularly characterised. We have used multicolour-banding fluorescence in situ hybridisation (mbanding-FISH) on breast tumour cell lines to identify regions of chromosome break created by inversions, duplications, insertions and translocations on chromosomes 1, 5, 8, 12 and 17. We delineate a total of 136 regions of break, some of them occurring with high frequency. We further describe two examples of dual-colour FISH characterisation of breakpoints, which target the 1p36 and 5p11-12 regions. Both breaks involve genes whose function is unknown to date. The mbanding-FISH strategy constitutes an efficient first step in the search for potential cancer genes.

Breast Neoplasms↗
PubMed2005

Myeloproliferative disorders: the centrosome connection.

Some myeloproliferative disorders (MPD) result from a reciprocal translocation that involves the FGFR1 gene and a partner gene. The event creates a chimeric gene that encodes a fusion protein with constitutive FGFR1 tyrosine kinase activity. FGFR1-MPD is a rare disease, but its study may provide interesting clues on different processes such as cell signalling, oncogenesis and stem cell renewal. Some partners of FGFR1 are centrosomal proteins. The corresponding oncogenic fusion kinases are targeted to the centrosome. Constitutive phosphorylation at this site may perturbate centrosome function and the cell cycle. Direct attack at this small organelle may be an efficient way for oncogenes to alter regulation of signalling for proliferation and survival and get rid of checkpoints in cell cycle progression. The same effect might be triggered by other fusion kinases in other MPD and non-MPD malignancies.

Cell Cycle↗
PubMed2005

[The STEMMAT-project as part of health initiative BayernAktiv: adult stem cells from umbilical cord and cord blood as alternative to embryonic stem cell research].

Adult stem cells from umbilical cord and cord blood are an interesting alternative to embryonic stem cells because such research is commonly recognized as ethical undisputed and many aspects are still insufficiently investigated. In the context of the STEMMAT research project (STEM = Stem Cell and MAT = Material) different aspects of stem cells from umbilical cord and cord blood are investigated, to improve basic science understanding and potentially leading someday to a clinical application.

Cord Blood Stem Cell Transplantation↗
PubMed2004

[Pumpless extracorporeal lung assist using arterio-venous shunt in severe ARDS. Experience with 30 cases].

BACKGROUND: Extracorporeal lung assist has been proposed as an invasive measure in patients with acute respiratory distress syndrome (ARDS) when oxygenation is critically impaired. However, this technique generally requires high personnel and technical resources. We report on a new system, which is characterised by a short circuit arterio-venous shunt using arterio-venous pressure gradient as driving force (pumpless extracorporeal lung assist [pECLA]). PATIENTS AND METHODS: In 30 patients with ARDS due to multitrauma, pneumonia or after surgery (p(a)O(2)/F(I)O(2)-ratio 67+/-23 mmHg) pECLA was established by insertion of cannulae to the femoral artery and vein followed by connection with a membrane gas exchanger. For this system, only "low dose" continuous heparin infusion is required. RESULTS: Arterial oxygenation was acutely and significantly increased by pECLA (p(a)O(2)/F(I)O(2)=103+/-56 mmHg 2 h after begin) and carbon dioxide removal was markedly enhanced in 25 out of 30 patients (87%) allowing a lung protective ventilation strategy. The mean duration of pECLA therapy was 6.5 days, 15 patients (50%) died due to ARDS or non-ARDS related reasons. CONCLUSION: pECLA represents a feasable and effective treatment in patients with severe ARDS. Compared with pump-driven systems pECLA is characterised by low costs and reduced personnel requirements. However, mortality remains high in patients suffering from severe ARDS despite newer treatment modalities.

Adult↗
PubMed2004

Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism, cell proliferation and cell transformation.

We explored, by cDNA mini-arrays, gene expression measurements of MVLN, a human breast carcinoma cell line derived from MCF-7, after 4 days of exposure to 17beta-estradiol (E(2)) treatment, in order to extend our understanding of the mechanism of the pharmacological action of estrogens. We focused on 22 genes involved in estrogen metabolism, cell proliferation regulation and cell transformation. The specificity of the E(2) response was reinforced by comparison with 4-hydroxytamoxifen (OH-Tam), ICI 182,780 and E(2)+OH-Tam expression profiles. Real-time quantitative PCR (RTQ-PCR) confirmed the variation of expression of known (TFF1, AREG, IRS1, IGFBP4, PCNA, ERBB2, CTSD, MYC) as well as novel (DLEU2, CCNA2, UGT1A1, ABCC3, ABCC5, TACC1, EFNA1, NOV, CSTA, MMP15, ZNF217) genes. The temporal response of these gene expression regulations was then investigated after 6 and 18 h of E(2) treatment and this allowed the identification of different time-course patterns. Cycloheximide treatment studies indicated first that estrogen affected the transcript levels of ABCC3 and ABCC5 through dissimilar pathways, and secondly that protein synthesis was needed for modulation of the expression of the CCNA2 and TACC1 genes by estrogens. Western blot analysis performed on TFF1, IRS1, IGFBP4, amphiregulin, PCNA, cyclin A2, TACC1 and ABCC5 proteins confirmed the mini-array and RTQ-PCR data, even for genes harboring low variations of mRNA expression. Our findings should enhance the understanding of changes induced by E(2) on the transcriptional program of human E(2)-responsive cells and permit the identification of new potential diagnostic/prognostic tools for the monitoring of estrogen-related disease conditions such as breast cancer.

Breast Neoplasms↗
PubMed2003

Adequacy of perfusion during hypothermia: regional distribution of cardiopulmonary bypass flow, mixed venous and regional venous oxygen saturation - hypothermia and distribution of flow and oxygen.

BACKGROUND: Hypothermia during CPB is used to reduce metabolic activity, thus protecting organs and tissues. The aim of this study was to investigate the relationship between regional and mixed venous oxygen saturation and distribution of pump flow with respect to hypothermia. METHODS: Twenty-five patients undergoing a Ross procedure were included in a prospective, controlled study. During standard CPB, temperature was reduced stepwise to 28 degrees C. Blood gases (a-stat regimen) were analysed in samples from the inferior (IVC) and the superior vena cava (SVC), arterial and mixed venous blood. Flow was detected separately in the SVC, IVC, arterial, and collecting venous line. Samples were taken, and flows were measured before CPB, during hypothermia, during rewarming, and 30 min after CPB discontinuation. RESULTS: Oxygen saturation in the IVC was lower than in the SVC and in mixed venous blood at all times (max. difference - 17.3 +/- 3.0 % during hypothermia, - 23.8 +/- 2.9 % during rewarming, p < 0.01). There was a statistical correlation of mixed and IVC venous oxygen saturation (r = 0.79, p < 0.001) but not of SVC venous blood. Hypothermia had a major influence on pump flow distribution as backflow from the SVC decreased significantly in favour of IVC flow with increasing degree of hypothermia (increase of flow difference from 1.15 +/- 0.23 l/min to 1.49 +/- 0.36 l/min, p < 0.01). Temperature profiles were similar when detected in aorta, pulmonary artery, tympanum and nasopharygeum, but differed significantly from other sites. CONCLUSIONS: During hypothermic CPB, regional deoxygenation occurs in spite of normal mixed venous saturation. The level of hypothermia has a major impact on bypass flow distribution with cerebral perfusion reduction. Methods of regional oxygenation assessment are needed, and altered strategies during hypothermia have to be taken into consideration.

Adult↗
PubMed2002

[Extracorporeal lung support and endovascular stent in traumatic aortic rupture and severe lung failure].

Blunt thoracic injury in association with aortic rupture represents a life-threatening situation. Surgical repair used to be the preferred method of treatment. Because most patients are multiple trauma patients including head injuries, bone fractures and respiratory failure, urgent surgical procedures portend excessively high morbidity and mortality rates. Delay in operative management bears the risk of exsanguinating hemorrhage, secondary complications, prolonged hospital stay with increased costs. We present here an alternative treatment protocol including pumpless extracorporal lung assist and endovascular aortic stent graft placement in a 20-year old traffic accident victim. This procedure may be an especially useful treatment option in managing patients with complex lung and aortic pathology primarily not suitable for transportation or surgery.

Adult↗
PubMed2001

Coparalogy: physical and functional clusterings in the human genome.

Two rounds of large-scale duplications are thought to have occurred in early vertebrate ancestry; this is now known as the "2R hypothesis." They have led to the constitution of subfamilies of paralogous genes. Chromosomal regions that contain present-day paralogs (paralogous regions or paralogons) have been identified in mammals. We show that sets of paralogons (PGs) can be assembled in a tentative "human genome paralogy map" that includes all autosomes and X. A total of 14 PGs, containing more than 1600 genes, were assembled in this paralogy map. Genes that belong to the same PG are coparalogs. We show that identification of coparalogy can be used (i) to broaden data on gene mapping, (ii) to identify physical gene clusters that derive from early cis-duplications, and (iii) to speculate on coevolution and coregulation of genes sharing a common structure or function (functional clusters). Thus, coparalogy analyses should parallel phylogenetic analyses and can help draw hypotheses on gene and genome evolution.

Chromosome Mapping↗