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K Hübner

Publications and source records attributed to K Hübner.

At least 19 recordsLinked to original sources
PubMed2006

Derivation of germ cells from embryonic stem cells.

Embryonic stem cells (ESCs), derivatives of cells of early mammalian embryos, have proven to be one of the most powerful tools in developmental and stem cell biology. When injected into embryos, ESCs can contribute to tissues derived from all three germ layers and to the germline. Prior studies have successfully shown that ESCs can recapitulate features of embryonic development by spontaneously forming somatic lineages in culture. Amazingly, recently it has been shown that mouse ESCs can also give rise to primordial germ cells (PGCs) in culture that are capable of undergoing meiosis and forming both male and female gametes. While the full potential of these ES-derived germ cells and gametes remains to be demonstrated, these discoveries provide a new approach for studying reproductive biology and medicine.

Animals↗
PubMed2001

Comparative analysis of human, bovine, and murine Oct-4 upstream promoter sequences.

The Oct-4 gene encodes a transcription factor that is specifically expressed in embryonic stem cells and germ cells of the mouse embryo. Cells that differentiate into somatic tissues lose Oct-4 expression. Regulation of Oct-4 gene transcription involves a TATA-less minimal promoter and two upstream elements: the proximal (PE) and distal enhancers (DE). We report here the nucleotide sequence of the 5' upstream regulatory regions of the human and murine Oct-4 genes. A comparative alignment analysis between these regions and those of the bovine Oct-4 ortholog reveals four conserved regions of homology (CR 1 to 4) between these species (66-94% conservation). The 1A sequence within the mouse PE is located approximately half-way between CR 2 and CR 3. A putative Sp1/Sp3 binding site and the overlapping hormone responsive element (HRE) in CR1 are identical in all three species. A high number of CCC(A/T)CCC motifs exhibit various levels of homology in these upstream regions. We discuss the importance of these and other sequences and present candidate factors that may bind and regulate Oct-4 gene expression.

Animals↗
PubMed2000

Tissue eosinophilia correlates strongly with poor prognosis in nodular sclerosing Hodgkin's disease, allowing for known prognostic factors.

Although eosinophilic granulocytes are frequently observed in lymphatic tissue of Hodgkin's patients, no substantial data reveal the prognostic role, if any, of tissue eosinophilia. Thus, eosinophilia was analyzed histologically in 1511 diagnostic biopsy specimens of patients treated under protocol therapy of the German Hodgkin's Lymphoma Study Group between 1988 and 1994. Prominent eosinophilia was seen in 38% of cases, which differed among the histologic types of Hodgkin's disease (HD): none in lymphocyte predominant, 14% in lymphocyte rich classical, 40% in nodular sclerosis grade 1 (NS-1), 55% in nodular sclerosis grade 2, 43% in mixed cellularity (MC), and 54% in lymphocyte depleted. In a multivariate analysis, tissue eosinophilia proved to be the strongest prognostic factor for freedom from treatment failure (P <. 001) and overall survival (P <.001) in a stage-stratified model. Among NS-1 patients, the effect was highly significant. In MC, no significant effect of eosinophilia on survival could be demonstrated. Eosinophils secrete CD30 ligand that is capable of binding to CD30 positive HD cells. The activation of TRAF2, followed by NF-kappaB, which occurs on CD30L/CD30 binding, may explain the neoplastic proliferation and apoptosis protection of HD cells. TRAF2 is also activated by EBV-LMP expression, which is detectable in the majority of MC but not NS cases. In addition to the possibility that eosinophils are only passive indicators for other unknown prognostic determinants, it may be concluded that the positive clinical outcome of eosinophilia-negative NS cases could be due to lower NF-kappaB activity. (Blood. 2000;95:1207-1213)

Adolescent↗
PubMed2000

Airway nitric oxide levels in cystic fibrosis patients are related to a polymorphism in the neuronal nitric oxide synthase gene.

Patients with cystic fibrosis (CF) have decreased concentrations of expired nitric oxide (FENO) as compared with healthy individuals. A number of factors, including viscous mucus as a diffusion barrier for airway NO, consumption of NO by bacterial enzymes, and decreased NO production have been hypothesized to account for these low levels of FENO. We examined the relationship between the size of an AAT repeat polymorphism in intron 20 of the NOS1 gene and FENO in 75 patients with CF. Mean FENO was significantly (p = 0.027) lower in CF patients who harbored two alleles with a high number of repeats (>/= 12) than in those who harbored alleles with fewer repeats at this locus (4.0 +/- 0.8 [mean +/- SEM] ppb versus 6.4 +/- 0.9 ppb). Colonization of the airways with Pseudomonas aeruginosa was significantly (p = 0.0358) more common in CF patients with high numbers of AAT repeats in the NOS1 gene. Significant differences between NOS1 genotypes were also observed among patients homozygous for the cystic fibrosis transmembrane regulator delta F508 mutation for FENO (2.3 +/- 0.4 ppb versus 5.3 +/- 0.7 ppb, p = 0.0006), and this was also true for colonization of the airways with P. aeruginosa (p = 0.0147) and Aspergillus fumigatus (p = 0.0221). These data provide evidence that the NOS1 gene is not only associated with the variability of FENO, but also with P. aeruginosa colonization of airways in CF patients.

Adolescent↗
PubMed1997

Validation of existing and development of new prognostic classification schemes in node negative breast cancer. German Breast Cancer Study Group.

Several prognostic classification schemes in node negative breast cancer are proposed, but only the Nottingham Prognostic Index (NPI) seems to be sufficiently validated. Validation, which is a prerequisite for a sensible assessment, is not published for two recent proposals according to Glick et al. [1] and Rubens [2]. The German Breast Cancer Study Group (GBSG) entered 662 eligible patients in a prospective observational study. 603 of them had complete data for seven 'standard' prognostic factors and median follow-up is about 5 years. As there is no accepted and informative measure of separation for classification schemes presently available, we propose a new one and use it additionally to the well known logrank-test and Kaplan-Meier estimates to investigate the predictive power of the three schemes. significant differences in survival and recurrence-free survival could be established for the NPI subgroups but not for others where even the ordering of the groups was different. With the Cox model and the classification and regression tree approach we develop two new proposals for the differentiation of subgroups of node negative patients. As in the NPI, tumor size and grade are the most important factors, but with a different weighting scheme. Young age (< or = 40 years) and very high estrogen receptor values (> 300 fmol) in a small subgroup of patients were associated with worse prognosis. The new proposals showed a better degree of separation, which demonstrates that an improvement seems possible using standard factors. Because the measures of separation give an overoptimistic impression for the new proposals, a validation with other studies is necessary before a general recommendation can be given.

Adult↗
PubMed1997

Lymphocyte-predominant Hodgkin's disease. An immunohistochemical analysis of 208 reviewed Hodgkin's disease cases from the German Hodgkin Study Group.

There is wide consensus that lymphocyte predominance Hodgkin's disease (LPHD) represents a distinct clinicopathological entity of B-cell origin. However, inconsistent results of immunophenotyping studies and low confirmation rates among multi-center trials pose the question of whether LPHD really expresses heterogeneous marker profiles or whether it represents a mixture of morphologically similar entities. Among 2,836 cases reviewed by the German Hodgkin Study Group, immunophenotyping was performed on 1) cases classified or confirmed as LPHD by the reference panel (n = 104) or 2) cases not confirmed as LPHD but classified as classical HD (cHD) within the reference study trial (n = 104). In most cases, immunohistochemistry revealed a phenotype either LPHD-like (CD20+, CD15-, CD30-, CD45+) or cHD-like (CD15+, CD30+, CD20-, CD45-). In 27 cases, the immunophenotype was not fully conclusive. Additional markers for Epstein-Barr virus and CD57 and in situ hybridization for mRNA light chains allowed for a more clear-cut distinction between LPHD and cHD. However, in 25 of 104 cases, immunohistochemistry disproved the morphological diagnosis of LPHD of the panel experts, whereas 13 cases originally not confirmed as LPHD showed a LPHD-like immunopattern. Immunohistochemically confirmed LPHD cases showed a significantly better freedom from treatment failure (P = 0.033) than cHD; this was not observed in the original study classification based only on morphology (P > 0.05). Significantly better survival for LPHD cases improved from P = 0.047 (original study classification) to P = 0.0071 when classified by immunohistochemistry. Our results show that LPHD is a more immunohistochemical rather than a purely morphological diagnosis. Immunophenotyping of HD biopsies suspected of being LPHD is mandatory when a modified therapy protocol, that is, one different from those used in cHD, is discussed.

Adult↗
PubMed1997

Classical Hodgkin's disease. Clinical impact of the immunophenotype.

Antibodies against CD15, -30, and -20 are often used to support morphological diagnosis of Hodgkin's Disease (HD). The classical HD, i.e., the non-lymphocyte-predominance types, are CD15+, CD30+, and CD20- in general. However, the results for CD15 are less clear-cut in many studies, showing up to 40% of classical HD that lack positivity for this maker. Little is currently known about the relevance of antigen expression in relation to clinical outcome in HD. Therefore, the three markers were analyzed in 1751 cases from the German Hodgkin Study Group, using micro-wave epitope retrieval to optimize staining sensitivity. Eighty-three percent of the cases showed a classical immunophenotype (CD15+, CD30+, CD20-), twelve percent lacked CD15 positivity (CD15-, CD30+, CD20-), and five percent showed other combinations. For 1286 cases, clinical follow-up was available, which revealed significant differences for freedom from treatment failure (P = 0.0022) and overall survival (P = 0.0001) between cases with classical immunophenotype and CD15 negativity (CD30+, CD20-). Multivariate Cox regression using the three markers, age, sex, histology, stage, B-symptoms (fever, sweats, weight loss > 10% of body weight), hemoglobin, and erythrocyte sedimentation rate as factors showed that lack of CD15 expression in classical HD is an independent negative prognostic factor for relapses (P = 0.022) and survival (P = 0.0035). In conclusion, immunohistochemistry is able to identify classical HD cases with unfavorable clinical outcome.

Adolescent↗
PubMed1997

[Computer analysis of the radiographic image of bones and joints].

Various possibility of computerized analysis of radiographic image of bone and joint are presented. The principle of digital image recording and processing are described. Practical application of computer programs of bone structure analysis and measurement of joint width using image analysis procedure are presented.

Algorithms↗
PubMed1996

Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis.

BACKGROUND: Ursodeoxycholic acid probably is not able to cure primary biliary cirrhosis. Therefore in this study ursodeoxycholic acid was administered together with prednisolone, since monotherapy with glucocorticoids has been shown to have some positive effects. METHODS: Thirty patients with primary biliary cirrhosis (stages I-III) were entered into the study. Fifteen were treated with ursodeoxycholic acid 10 mg.kg-1.day-1 and placebo (group A), 15 with ursodeoxycholic acid and 10 mg prednisolone (group B) for 9 months. Apart from the usual laboratory examinations, liver biopsies were taken from 29 patients before and after therapy. RESULTS: Liver enzymes decreased significantly compared to the initial values in both groups (p < 0.001), but in group B cholestasis-indicating enzymes and the immunoglobulins G and A improved more rapidly. Between both groups the differences for AP, GGT, IgG, IgA and gamma-globulins were significant (p < 0.05), but only for short terms. In group B, liver histology improved significantly (p < 0.003), which correlated with the decrease of IgG. Ursodeoxycholic acid became the predominant bile acid in the serum. Toxic bile acids did not increase. Bone densitometry revealed a slight deterioration of preexisting osteoporosis in one patient. CONCLUSIONS: Although combination therapy with ursodeoxycholic acid and prednisolone was not superior to monotherapy with ursodeoxycholic acid with regard to liver function tests, it had a highly beneficial influence on liver histology. In our previous trials with monotherapy histology remained unchanged. An early decrease in IgG during combination therapy seems to be an indicator of an amelioration of liver histology.

Adult↗
PubMed1996

Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells.

The totipotent stem cells of the pregastrulation mouse embryo which give rise to all embryonic somatic tissues and germ cells express Oct-4. The expression is downregulated during gastrulation and is thereafter only maintained in the germline lineage. Oct-4/lacZ transgenes were used to determine how this pattern of expression was achieved, and resulted in the identification of two separate regulatory elements. The distal element drives Oct-4 expression in preimplantation embryos, in migratory and postmigratory primordial germ cells but is inactive in cells of the epiblast. In cell lines this element is specifically active in embryonic stem and embryonic germ cells. The proximal element directs the epiblast-specific expression pattern, including downregulation during gastrulation; in cell lines its activity is restricted to epiblast-derived cells. Thus, Oct-4 expression in the germline is regulated separately from epiblast expression. This provides the first marker for the identification of totipotent cells in the embryo, and suggests that expression of Oct-4 in the totipotent cycle is dependent on a set of factors unique to the germline.

Animals↗
PubMed1996

[Spontaneous Hashimoto-like thyroiditis in cats].

A breeding line of domestic cats spontaneously developing symptoms of hypothyroidism between the 40th and 60th day of life (fur changes, loss of appetite, growth retardation), elevated levels of antibodies against microsomal structures and thyroglobulin, and lymphocytic thyroid infiltration has been recently established at our facility. Aim of our studies was to examine the effect of high iodine ingestion or prophylactic thyroid hormone therapy on functional and morphological characteristics of this Hashimoto-like thyroiditis in cat. From birth to day 80 of life cats were treated with iodine (n = 9; 0.1 mg/l) or thyroxin (n = 13; 2.0 micrograms/ kg/d) respectively. Untreated animals served as controls (n = 12). Cat-serum was tested for thyroid function (TT3, TT4). After 8 weeks the thyroid tissue was submitted to routine histological processing (H&E) and the inflammatory activity was scored. Additionally immunohistological staining was performed for MIB-1, IgG, IgM and MHCII expression. Both untreated hypothyroid (UHC) as well as iodine-treated (IC) cats revealed a significantly higher degree of thyroid inflammation and higher tissue levels of IgM as the thyroxin-substituted animals (TC). Epithelial proliferation decreased significantly in the IC and TC groups as compared to the untreated controls. No significant differences regarding IgG production and HLAII expression were detectable. Early thyroid hormone therapy significantly decreases both incidence and activity of autoimmune thyroiditis in cats as measured by inflammatory infiltration, IgM production and epithelial proliferation. Animals with excess iodide intake, however, show an aggravation of the autoimmune inflammatory activity.

Animals↗
PubMed1995

The bcl-2/JH gene rearrangement is undetectable in Hodgkin's lymphomas: results from the German Hodgkin trial.

Ninety-one Hodgkin's lymphomas (HD), 52 non-Hodgkin lymphomas (NHL) and 33 specimens of non-neoplastic lymphatic tissues were investigated by polymerase chain reaction (PCR) for the presence of the bcl-2/JH gene rearrangement. The majority of the HD cases were drawn from the files of the German Hodgkin trial where diagnoses are established by a panel of four independent histopathologists. Using the very sensitive PCR method which detected 1 positive among 10000 negative cells, the bcl-2/JH gene rearrangement was found in 7/52 NHL and 3/16 tonsils with follicular hyperplasia, but in none of the 91 HD. The bcl-2 protein, however, was expressed by malignant cells of B and T cell lymphomas and by the giant tumour cells in 2/13 HD lymphocyte predominant, 11/28 HD nodular sclerosing I, 14/17 HD nodular sclerosing II, 10/27 HD mixed cellularity and 3/3 HD lymphocyte depleted. The bcl-2/JH rearrangement is thus independent of protein over-expression, the latter being found in all types of lymphomas. Our results do not confirm the findings of others who have detected the bcl-2/JH rearrangement in HD. These discrepancies may be explained by differences in choice of material, the gene rearrangement actually occurring in bystander cells but not in Reed-Sternberg or Hodgkin cells, or by contamination.

Chromosomes, Human, Pair 18↗
PubMed1995

Alveolar macrophage TNF-alpha release and BAL cell phenotypes in sarcoidosis.

The aim of this study was to investigate the relationship between release of tumor necrosis factor-alpha (TNF-alpha) by alveolar macrophages (AM) and the phenotypic characteristics of bronchoalveolar lavage (BAL) cells in sarcoidosis. We studied the spontaneous release of TNF-alpha by AM in vitro and the phenotypic characteristics of freshly recovered BAL T-cells and AM in 31 individuals (13 with active sarcoidosis, nine with inactive sarcoidosis, and nine normal controls). TNF-alpha was measured by enzyme-linked immunosorbent assay (ELISA) in supernatants from unstimulated AM after 24 h culture. Phenotypic markers of BAL cells were determined by an immunocytochemical assay. AM of patients with active sarcoidosis released more TNF-alpha (1,355 +/- 133 pg/ml/ 10(6) AM/24 h) than those of the inactive group (651 +/- 142 pg/ml/10(6) AM/24 h) or the normal controls (425 +/- 121 pg/ml/10(6) AM/24 h), with p < 0.001 for both comparisons. The amount of TNF-alpha released correlated positively with the percentage expression of CD4 (r = 0.72) and CD25 (r = 0.70) by lymphocytes, and of CD14 (r = 0.63), VLA-4 (r = 0.59), FRD1 (r = 0.67) and 27E10 (r = 0.67) by AM, with p < 0.001 for all correlations. In conclusion, this relationship suggests that these antigens may be considered as cellular activation markers, and that some of these AM antigens may indirectly characterize the AM phenotype that is capable of producing TNF-alpha.

Adult↗
PubMed1995

[Pathogenetic role of HBV in liver cell carcinoma of Western European patients].

Tumour (n = 338) and corresponding liver tissue (n = 276) of liver cell carcinoma (LCC) patients including 31 Asiatic cases was studied with immunohistochemical methods (IHC) for the expression of HBs (7MABs and 2 PABs), HBc, HBe, HBx, and preS antigens. HBV-DNA was detected with in situ hybridisation (ISH) employing digoxigenin-labeled DNA probes. Furthermore, polymerase chain reaction (PCR) was done for a part of the X-ORF (1542+, 1746-). Tumours from the European patients were fibrolamellar (FLC; n = 8), hepatocellular (HCC; n = 260), mixed hepatocellular/cholangiocellular (HCC/CCC; n = 23), and pure cholangiocellular carcinomas (CCC; n = 16). Of the Asiatic cases, 56.5% contained HBs in liver and 64.5% in tumour tissue, of the European cases these were 21.7% and 29.6%, respectively. HBc, HBe, and preS antigens were found only in few cases. HBV positive rates with ISH were 82.6% and 87.1% for Asiatic, and 45.3% and 51.7% for European cases, respectively. Altogether, 93.6% of the Asiatic and 64.2% of the European patients were positive for HBV with IHC or ISH. HCC/CCC and CCC showed slightly lower HBV positive rates than HCC. Over 90% of the cases had HBx in liver and tumour tissue. PCR revealed HBV positive rates of 73.2% for liver and 90.1% for tumour tissue irrespective of patients descent and tumour type. Thus, HBV seems to represent a pathogenetic factor for LCC in Western European patients irrespective of the tumour type. The existence of the "mixed tumours" HCC/CCC as well as the frequent HBV-positivity of tumours with cholangiocellular differentiation document that CCC belong to the category LCC.

Animals↗
PubMed1994

[Duodenal tuberculosis. A rare cause of a covered perforation in the duodenal bulb].

Vague upper abdominal pain, weight loss (10 kg) and recurrent bouts of fever had been present for several months in a 77-year-old woman. Abdominal ultrasonography in the region of the head of the pancreas and duodenum had demonstrated several lymphomas, some of them with "air streaking". This finding suggested penetration from the duodenum to neighbouring lymph nodes. Plain film of the abdomen did not show free air, but at gastroscopy a covered perforation into the surrounding lymph nodes was found. At first lymphoma or Crohn's disease were considered in the differential diagnosis. But the finding of acid-fast bacteria in a biopsy from the pelvic crest suggested intestinal tuberculosis with dissemination. This diagnosis was confirmed by the direct demonstration of Mycobacterium tuberculosis in gastric juice. Under tuberculostatic treatment with daily 0.3 g isoniazid, 0.45 g rifampicin, 0.8 ethambutol and 1.5 g pyrazinamide, as well as 50 mg prednisolone to prevent stricture, the size of the tuberculous ulcer had markedly decreased within 2 weeks. Follow-up gastroscopy after 6 months showed almost complete healing without stricture. However rare, gastrointestinal tuberculosis should not be forgotten in the differential diagnosis because it can imitate a large variety of gastrointestinal diseases.

Aged↗
PubMed1994

T lymphocytes, CD68-positive cells and vascularisation in thyroid carcinomas.

Immunohistochemical detection and quantification of CD3- and CD45RO-positive lymphocytes and CD68-positive cells in 75 thyroid carcinomas of follicular cell origin revealed rising levels for these parameters associated with dedifferentiation. A parallel trend towards reduction of vascularisation, determined as CD31-positive blood vessels, with decreasing differentiation became evident, statistically only significant when well-differentiated follicular and anaplastic carcinomas were compared. Positive correlations could be demonstrated between the density of CD68-, CD3-, and CD45RO-positive cells as well as between the density of CD68-, and CD3-, and CD45RO-positive cells and vascularisation. These correlations were expected, as the interaction of CD68-positive cells and T lymphocytes results in the production of angiogenesis factors, ultimately leading to better vascularisation of the tumour. Nevertheless, the tumour cells themselves are variously capable of producing angiogenic substances. The obvious lack of positive correlation between the density of tumour-infiltrating cells determined in this study and vascularisation, despite reduced vascularisation in less differentiated tumours that contained increasing numbers of tumour-infiltrating cells, seems to be due to functional heterogeneity of morphologically similar tumours.

Antibodies, Monoclonal↗