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Biomedical subjects

T Braun

Publications and source records attributed to T Braun.

At least 19 recordsLinked to original sources
PubMed2001

Activation of myogenesis by the homeobox gene Lbx1 requires cell proliferation.

Myogenic differentiation can be initiated by a limited number of molecules. In this work, we analyzed the function of the homeobox gene Lbx1 in chicken embryos and explant cultures. We demonstrate that overexpression of Lbx1 in vivo and in vitro leads to a strong activation of various muscle markers. We show that cell proliferation, which is strongly stimulated by Lbx1 and Pax3, is required for Lbx1- or Pax3-dependent myogenic activation. Inhibition of cell proliferation prevents expression of muscle differentiation markers, while the activation of other putative downstream targets of Pax3 and Lbx1 is not affected. Our findings imply that a critical function of Pax3 and Lbx1 during muscle cell formation is the enlargement of muscle cell populations. The growth of the muscle precursor cell population may increase the bias for myogenic differentiation and thus enable myogenic cells to respond to environmental cues.

Animals↗
PubMed2001

Two-dimensional crystals: a powerful approach to assess structure, function and dynamics of membrane proteins.

Electron crystallography and atomic force microscopy allow the study of two-dimensional membrane protein crystals. While electron crystallography provides atomic scale three-dimensional density maps, atomic force microscopy gives insight into the surface structure and dynamics at sub-nanometer resolution. Importantly, the membrane protein studied is in its native environment and its function can be assessed directly. The approach allows both the atomic structure of the membrane protein and the dynamics of its surface to be analyzed. In this way, the function-related conformational changes can be assessed, thus providing a detailed insight on the molecular mechanisms of essential biological processes.

Cell Membrane↗
PubMed2001

Incorporating language phenotypes strengthens evidence of linkage to autism.

We investigated the effect of incorporating information about proband and parental structural language phenotypes into linkage analyses in the two regions for which we found the highest signals in our first-stage affected sibling pair genome screen: chromosomes 13q and 7q. We were particularly interested in following up on our chromosome 7q finding in light of two prior reports of linkage of this region to developmental language disorder, since one of the diagnostic criteria for autism is absent or abnormal language development. We hypothesized that if the language phenotype were genetically relevant to linkage at the chromosome 7q locus, then incorporating parents phenotypes would increase the signal at that locus, and most of the signal would originate from the subset of families in which both probands had severe language delay. The results support these hypotheses. The linkage signals we obtained on chromosome 7q as well as at least one signal on chromosome 13q are mainly attributable to the subgroup of families in which both probands had language delay. This became apparent only when the parents' history of language-related difficulties was also incorporated into the analyses. Although based on our data, we were not able to distinguish between epistasis or heterogeneity models, we tentatively concluded that there may be more than one autism susceptibility locus related to language development.

Autistic Disorder↗
PubMed2001

Evidence supporting WNT2 as an autism susceptibility gene.

We examined WNT2 as a candidate disease gene for autism for the following reasons. First, the WNT family of genes influences the development of numerous organs and systems, including the central nervous system. Second, WNT2 is located in the region of chromosome 7q31-33 linked to autism and is adjacent to a chromosomal breakpoint in an individual with autism. Third, a mouse knockout of Dvl1, a member of a gene family essential for the function of the WNT pathway, exhibits a behavioral phenotype characterized primarily by diminished social interaction. We screened the WNT2 coding sequence for mutations in a large number of autistic probands and found two families containing nonconservative coding sequence variants that segregated with autism in those families. We also identified linkage disequilibrium (LD) between a WNT2 3'UTR SNP and our sample of autism-affected sibling pair (ASP) families and trios. The LD arose almost exclusively from a subgroup of our ASP families defined by the presence of severe language abnormalities and was also found to be associated with the evidence for linkage to 7q from our previously published genomewide linkage screen. Furthermore, expression analysis demonstrated WNT2 expression in the human thalamus. Based on these findings, we hypothesize that rare mutations occur in the WNT2 gene that significantly increase susceptibility to autism even when present in single copies, while a more common WNT2 allele (or alleles) not yet identified may exist that contributes to the disorder to a lesser degree.

Amino Acid Sequence↗
PubMed2001

Partial synchronization and spontaneous spatial ordering in coupled chaotic systems.

A model of many symmetrically and locally coupled chaotic oscillators is studied. Partial chaotic synchronizations associated with spontaneous spatial ordering are demonstrated. Very rich patterns of the system are revealed, based on partial synchronization analysis. The stabilities of different partially synchronous spatiotemporal structures and some dynamical behaviors of these states are discussed both numerically and analytically.

Journal Article↗
PubMed2001

Five Nkx5 genes show differential expression patterns in anlagen of sensory organs in medaka: insight into the evolution of the gene family.

We report the identification and characterisation of five different Nkx5-related genes in medaka fish (Oryzias latipes). They constitute homologues of genes previously isolated in higher vertebrates, Nkx5--1, Nkx5--2, Hmx1/Nkx5--3 and SOHo-1, and were named accordingly: OlNkx5--1.1, OlNkx5--2, OlNkx5--3 and OlSOHo. For the Nkx5--1 gene a new, second homologue, OlNkx5--1.2, was isolated. In medaka, Nkx5 and SOHo genes are differentially expressed in three developing sensory organs: eye, ear and lateral line and later in defined brain regions. Phylogenetic analyses of the entire Nkx5 family revealed that four paralogous Nkx5 groups, Nkx5--1, Nkx5--2, Hmx1/Nkx5--3/GH6 and SOHo, are present in vertebrates. Only some of the Nkx5 family members have been identified in singular vertebrate species so far. Here we present, for the first time, the isolation of representatives of each Nkx5 subgroup in one species, the medaka fish. Based on similarities in sequence and expression patterns, and genomic organisation we propose a model of the evolutionary history of the Nkx5 family. The model predicts that the four vertebrate Nkx5 genes arose by a tandem duplication, followed by chromosomal duplication. The two Nkx5--1 genes identified so far exclusively in medaka most probably result from an additional genome duplication in the fish lineage.

Amino Acid Sequence↗
PubMed2001

FGFs control the patterning of the inner ear but are not able to induce the full ear program.

FGF2 or FGF8 applied ectopically, close to the developing otic placode enhances transcription of a subset of ear marker genes such as Nkx5-1, SOHo1 and Pax2. Other ear expressed genes (Dlx5 and BMP4) are not up-regulated by FGFs. Ectopic FGFs lead to an increase in size of the vestibulo-cochlear ganglion. This phenotypic change is due to an increased recruitment of epithelial cells to the neuronal fate rather than to an enhanced proliferation. We also observed an induction of additional, vesicle-like structures upon ectopic FGF treatment, but this induction never led to enrolment of a full ear program. We further demonstrate that FGF8 is expressed in two separate, short waves, first at the otic placode stage and later at the vesicle stage. Both activities correspond to critical morphogenetic events in ear development. We propose that FGF8 is an important regulator of otocyst patterning.

Animals↗
PubMed2001

Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.

Bardet-Biedl syndrome (BBS, MIM 209900) is a heterogeneous autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. The disorder is also associated with diabetes mellitus, hypertension, and congenital heart disease. Six distinct BBS loci map to 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although BBS is rare in the general population (<1/100,000), there is considerable interest in identifying the genes causing BBS because components of the phenotype, such as obesity and diabetes, are common. We and others have demonstrated that BBS6 is caused by mutations in the gene MKKS (refs. 12,13), mutation of which also causes McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly, and congenital heart defects). MKKS has sequence homology to the alpha subunit of a prokaryotic chaperonin in the thermosome Thermoplasma acidophilum. We recently identified a novel gene that causes BBS2. The BBS2 protein has no significant similarity to other chaperonins or known proteins. Here we report the positional cloning and identification of mutations in BBS patients in a novel gene designated BBS4.

Bardet-Biedl Syndrome↗
PubMed2001

Pathologic, immunohistochemical, and molecular features of benign and malignant phyllodes tumors of the breast.

The histologic distinction between benign and malignant Phyllodes tumors (PT) is often difficult and arbitrary. We analyzed a group of benign and malignant PT to determine whether specific histologic features and expression of Ki-67 and p53 could be useful in distinguishing benign PT from malignant tumors. We also determined whether deletions in Chromosome 3p at the FHIT and hMLH1 loci are common abnormalities in PT. Twenty PT were histologically classified as benign (7) or malignant (13). Seven of the malignant PT were low grade, and six were high grade. Ki-67 and p53 immunohistochemistry was performed on all tumors and analyzed for the stromal and for the epithelial component. PCR-based loss of heterozygosity analyses were performed with the following markers on Chromosome 3p: D3S1478 (3p21.2--21.3), D3S1289 (3p21.1--21.2), and D3S1295 (3p14.3--21.1). The distribution of immunoreactivity for Ki-67 was analyzed by quantifying the percentage of positive nuclei and expressed as the labeling index (LI). Patients' ages ranged from 13 to 71 years (median: 51 y). After a mean follow-up period of 8 years, none of the PT metastasized, whereas three recurred locally. Although malignant PT were larger than benign PT (means, 7.1 versus 4.3 cm), this difference was not statistically significant. Five tumors had infiltrating margins, and 14 were circumscribed. The Ki-67 LI in low-grade malignant PT (16 +/- 25.5) was significantly higher than that in benign PT (3.6 +/- 4.8), whereas the LI in the high-grade malignant PT group (50 +/- 21.9) was significantly higher than that in low-grade malignant tumors (P =.012). The Ki-67 LI in the three tumors that recurred was less than 10%. Two of seven (29%) benign PT were focally positive for p53, whereas four of seven (57%) low-grade malignant and three of six (50%) high-grade malignant PT were diffusely positive for p53. The three tumors that recurred initially were histologically benign, as were two of the recurrences. One recurrent tumor evolved to a high-grade malignant PT. Margins were greater than 1 cm in all tumors except four, three of which recurred locally. No allelic loss of 3p was found. In summary, Ki-67 expression may assist in distinguishing benign from malignant PT in diagnostically difficult cases. 3p deletions do not play a significant role in the development of these tumors. Neither Ki-67 nor p53 can reliably predict recurrence. Histologically high-grade malignant PT have a favorable prognosis if widely excised. We emphasize the importance of adequate margins in the treatment of benign and malignant PT.

Breast Neoplasms↗
PubMed2001

Persistent E-cadherin expression in inflammatory breast cancer.

E-cadherin is a transmembrane glycoprotein that mediates epithelial cell-to-cell adhesion. Because loss of E-cadherin expression results in disruption of cellular clusters, it has been postulated that E-cadherin functions as a tumor suppressor protein. The role of E-cadherin in inflammatory breast cancer (IBC), a distinct and highly aggressive form of breast cancer, is largely unknown. The aim of our study was to elucidate whether E-cadherin expression contributes to the development and progression of the IBC phenotype and to investigate any differences in E-cadherin expression between IBC and stage-matched non-IBC. Forty-two breast cancer cases (20 IBC and 22 non-IBC) were identified. Strict and well-accepted criteria were used for the diagnosis of IBC. Clinical and pathologic features were studied, and formalin-fixed, paraffin-embedded tissue sections were immunostained for E-cadherin, estrogen and progesterone receptors (ER and PR, respectively), and HER2/neu. Statistical analysis was performed using Fisher's exact test. All IBC uniformly expressed E-cadherin, whereas 15 of the 22 (68%) of the non-IBC expressed the protein (P = .006). Intralymphatic tumor emboli in the IBC cases were also all E-cadherin positive. Two IBC tumors demonstrated invasive lobular histology, and both cases were positive for E-cadherin. Of the non-IBC cases, three were invasive lobular carcinomas, and all were positive for E-cadherin. No association was found between E-cadherin expression and ER, PR status, or HER2/neu overexpression. Our study demonstrates that there is a strong association between E-cadherin expression and IBC and suggests that E-cadherin may be involved in the pathogenesis of this form of advanced breast cancer. In our study, we demonstrate that circulating IBC tumor cells strongly express E-cadherin, thereby providing an important exception to the positive association between E-cadherin loss and poor prognosis in breast cancer.

Breast Neoplasms↗
PubMed2001

Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma.

This study compares the probability of disease progression, progression-free survival, and overall survival between patients undergoing an allogeneic or autologous transplant for multiple myeloma using an identical preparative regimen. Patients received a preparative regimen of TBI, busulfan, and cyclophosphamide followed by an allogeneic or autologous transplant. In the allogeneic group (n = 21), six patients received bone marrow and 15 received G-CSF mobilized PBSC; all autologous patients (n = 35) received PBSC mobilized with cyclophosphamide and G-CSF. Allogeneic donors were HLA-identical (n = 20) or one-antigen mismatched (n = 1) siblings. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (n = 10), tacrolimus/methotrexate (n = 6), cyclosporine/methotrexate (n = 4), or cyclosporine (n = 1). The groups were evenly matched for gender, pretransplant therapy, disease status at time of transplant, myeloma subtype, and time from diagnosis to transplant. The median age was significantly lower in the allogeneic group (48 vs 55 years, P < 0.01). In the allogeneic group the probabilities of developing acute GVHD grade II-IV and chronic GVHD were 55% and 82%, respectively. The Kaplan-Meier probability of disease progression was significantly lower in the allogeneic group (11% vs 64%, P < 0.001) compared to the autologous group. Although progression-free (60% vs 30%, P = 0.19) and overall survival at 2 years (60% vs 42%, P = 0.39) favored the allogeneic group, this did not reach statistical significance. Within the allogeneic transplant group, patients age 50 years or under had a 3-year overall survival significantly higher when compared to older patients (79% vs 29%, P = 0.03). Using identical preparative regimens, allogeneic transplantation reduced disease progression compared to autologous transplantation for myeloma. This suggests that allogeneic transplantation induces a graft-versus-myeloma (GVM) effect.

Actuarial Analysis↗
PubMed2001

Double dose-intensive chemotherapy with autologous stem cell support for relapsed and refractory testicular cancer: the University of Michigan experience and literature review.

Testicular cancer patients refractory or in relapse after primary chemotherapy have < or =25% 5-year progression-free survival with salvage. To improve prognosis, patients entered a phase I/II tandem dose-escalation trial of carboplatin (1500-2100 mg/m(2)) and etoposide (1200-2250 mg/m(2)) with ABMT. Patients were eligible for a second cycle if disease progression was absent and performance status allowed. From August 1990 to June 1998, 29 males (25 NSGCT) were treated. At the time of ABMT, 10 were chemosensitive, four were chemoresistant, and 10 were absolutely refractory to platinum. Disease status (no. patients) at transplant: primary refractory disease (six), first relapse (10), second relapse (eight), third relapse (five). Fifteen (52%) received both transplants. Treatment-related mortality was 10%. Best response after ABMT included: two CR, one CR surgically NED, five PR, three PR surgically NED, seven SD, and eight PD. Eight (28%) patients are continuously progression-free a median 60 months (range, 31-93) from first ABMT. Three seminoma patients remain progression-free. Of five long-term NSGCT survivors, four were treated in first relapse with platinum-sensitive disease. Eighteen relapses occurred a median of 4 months after ABMT I (two late relapses at 28 and 44 months). The median PFS and OS for the whole group are 4 and 14 months, respectively. Patients with relapsed/ refractory testicular cancer benefit most from ABMT if they have platinum-sensitive disease in first relapse. Patients who do poorly despite ABMT have a mediastinal primary site, true cisplatin-refractory disease, disease progression prior to ABMT, and/or markedly elevated betaHCG at ABMT. New treatment modalities are needed for the latter group.

Adolescent↗
PubMed2001

Sonic hedgehog is a survival factor for hypaxial muscles during mouse development.

Sonic hedgehog (Shh) has been proposed to function as an inductive and trophic signal that controls development of epaxial musculature in vertebrate embryos. In contrast, development of hypaxial muscles was assumed to occur independently of Shh. We here show that formation of limb muscles was severely affected in two different mouse strains with inactivating mutations of the Shh gene. The limb muscle defect became apparent relatively late and initial stages of hypaxial muscle development were unaffected or only slightly delayed. Micromass cultures and cultures of tissue fragments derived from limbs under different conditions with or without the overlaying ectoderm indicated that Shh is required for the maintenance of the expression of myogenic regulatory factors (MRFs) and, consecutively, for the formation of differentiated limb muscle myotubes. We propose that Shh acts as a survival and proliferation factor for myogenic precursor cells during hypaxial muscle development. Detection of a reduced but significant level of Myf5 expression in the epaxial compartment of somites of Shh homozygous mutant embryos at E9.5 indicated that Shh might be dispensable for the initiation of myogenesis both in hypaxial and epaxial muscles. Our data suggest that Shh acts similarly in both somitic compartments as a survival and proliferation factor and not as a primary inducer of myogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The role of CD44 during CD40 ligand-induced dendritic cell clustering and maturation.

The interaction between CD40 on dendritic cells (DC) and its ligand CD154 has been recognized to be an important feature in the maturation of DC. Here, we were interested in the role of CD44 a surface receptor shown to mediate cell-cell adhesion and binding to Hyaluronic acid (HA). Western blot analysis of human DC stimulated for 3-12 h with CD154 revealed the rapid induction of the 85 kDa standard form of CD44 and an increased HA-binding affinity. Time-lapse video-imaging microscopy of human DC co-cultured on CD154-transfected murine fibroblasts showed that the CD44 up-regulation coincided with the rapid induction of homotypic DC clustering, which did not occur on empty vector-transfected fibroblasts. In this system, addition of anti-CD44s mAbs abrogated DC-cluster formation, thereby inhibiting further maturation, as shown by a reduced TNF-alpha production and inhibition of CD154-induced MHC class II up-regulation. However, co-incubation with HA-degrading enzymes induced no changes in the CD154-mediated DC clustering and maturation.

Animals↗