Biomedical subjects

J Leers

Publications and source records attributed to J Leers.

10 recordsLinked to original sources

PubMed2005

[Symptoms in patients with adenocarcinoma of the esophagus].

INTRODUCTION: Gastroesophageal reflux (GER) is the main risk factor for the development of adenocarcinoma of the esophagus (AC). The aim of our study was to evaluate symptoms of patients with AC to identify those patients with a high risk for this tumour. PATIENTS AND METHODS: 117 consecutive patients with known AC were included. Prospectively all patients were interviewed with a standardised questionnaire comprising 120 items: social status, other diseases, risk factors, therapy of the GERD and, as a main part: current symptoms and those experienced at earlier times. RESULTS: 85 % of the patients had often or sometimes reflux symptoms. 46 % of the patients with reflux symptoms had such symptoms daily. The median time span for this symptom was 20 years with a range from 1 year to 50 years. In 21 % of the patients the reflux symptoms stopped (median) three years (range two months -- 30 years) before the diagnosis of the carcinoma. Only 55 % of all patients had one or more esophago-gastroscopy examinations before the diagnosis of AC. These patients showed significantly more often earlier tumour stages than those patients without an endoscopy before diagnosis. Heartburn was treated with medication in 78 % of the patients (67 % of all patients). No patient had previously undergone antireflux surgery. CONCLUSIONS: 15 % of the patients with adenocarcinoma of the esophagus show no, and in addition 25 % only discrete, heartburn; 1. an endoscopy due to heartburn was done in half of all cases, and 2. the medications do not fulfil the therapeutic standard; 3.patients with endoscopy had significantly more frequently an earlier tumour stage.

Adenocarcinoma↗

PubMed2004

Postoperative recovery of microcirculation after gastric tube formation.

BACKGROUND AND AIMS: The formation of a gastric tube is associated with partial devascularisation of the stomach and impaired tissue perfusion in the anastomotic region. The aim of the study was to gain data on the time interval of microcirculatory recovery of the normal gastric conduit. PATIENTS AND METHODS: Twenty-nine out of 49 consecutive patients who had undergone oesophagectomy and reconstruction with a gastric tube and intrathoracic oesophagogastrostomy were selected. Inclusion criterion was an uncomplicated postoperative course. After the patients' admission to ICU, continuous measurement of mucosal pCO(2) (pCO(2)I) was commenced, with the use of recirculating gas analysis with a TONOCAP device. pCO(2)I values (in mmHg and kPa) were recorded hourly and related to the arterial pCO(2) (DeltapCO(2) = pCO(2)I - pCO(2)a). In addition, mean arterial pressure (MAP), cardiac output (CO) and systemic vascular resistance (SVR) were measured by pulse contour analysis. RESULTS: pCO(2)I was monitored over an average period of 79 h (total 2,288 measurements). The mean DeltapCO(2) before extubation was 12.4 mmHg (1.7 kPa) +/- 8.7 SD (1.2 kPa). After extubation, there was an increase in DeltapCO(2) values in all 29 patients. The peak DeltapCO(2) of 27.4 mmHg (3.7 kPa) +/- 12.6 SD (1.7 kPa) was observed 18 h after extubation. This was followed by a steady decline in DeltapCO(2) values that almost reached baseline DeltapCO(2) values after 4 days of monitoring. Changes in DeltapCO(2) did not correlate with changes in MAP, CO and SVR. CONCLUSIONS: High levels of pCO(2)I indicate an impaired postoperative microcirculation in normal gastric tubes. After initial deterioration, gastric microcirculation takes approximately 4 days to recovery. These data are important for the implementation of ischaemic conditioning prior to gastric tube formation and gastric pull-up.

Adult↗

PubMed2001

Differential recruitment of the mammalian mediator subunit TRAP220 by estrogen receptors ERalpha and ERbeta.

Estrogen receptors (ERs) associate with distinct transcriptional coactivators to mediate activation of target genes in response to estrogens. Previous work has provided multiple evidence for a critical role of p160 coactivators and associated histone acetyltransferases in estrogen signaling. In contrast, the involvement of the mammalian mediator complex remains to be established. Further, although the two subtypes ERalpha and ERbeta appear to be similar in regard to principles of LXXLL-mediated coactivator binding to the AF-2 activation domain, there are indications that the context-dependent transcriptional activation profiles of the two ERs can be quite distinct. Potentially, this could be attributed to differences with regard to coregulator recruitment. We have here studied the interactions of the nuclear receptor-binding subunit of the mammalian mediator complex, referred to as TRAP220, with ERalpha and ERbeta. In comparison to the p160 coactivator TIF2, we find that TRAP220 displays ERbeta preference. Here, we show that this is a feature of the binding specificity of the TRAP220 LXXLL motifs and demonstrate that the ER subtype-specific F-domain influences TRAP220 interaction. Such differences with regard to coactivator recruitment indicate that the relative importance of individual coregulators in estrogen signaling could depend on the dominant ER subtype.

Amino Acid Motifs↗

PubMed2001

Coincidence of nutritional habits and esophageal cancer in Germany.

INTRODUCTION: The incidence rates for adenocarcinoma (AC) of the esophagus have risen rapidly in Western nations, whereas the incidence rates for esophageal squamous cell carcinoma (SCC) have remained nearly stable. There are studies about body mass index, smoking, alcohol, and development of AC or SCC. The aim of this study was to evaluate differences in nutritional habits of patients with AC or SCC compared with the population in Cologne. PATIENTS AND METHODS: From January 1, 1997 to December 31, 1998, 85 patients with esophageal cancer (SCC n = 45, AC n = 40) were interviewed about their nutritional habits using a computerized program (EBIS). By random sample, 100 citizens of Cologne who were similar of age, residence, and nationality were chosen as healthy control group (CG) and were also interviewed with EBIS. RESULTS: The known risk factors, alcohol and tobacco for SCC as well as alcohol and a high body mass index for AC, were confirmed in this study. The CG had a higher daily intake of calcium, magnesium and iron compared to patients with esophageal cancer (p < 0.05). In addition, the tumor group had a significant lower daily supply of carbohydrates, fruits, and dietary fiber (p < 0.001). About 80% of the patients ate more than 100 g meat/day in comparison to 50% of participants in the CG. Patients with AC consumed more magnesium, milk, and animal protein than patients with SCC or the participants of the CG. CONCLUSION: There are differences in nutrition between healthy controls and patients with esophageal cancer and between patients with SCC and AC. Patients with cancer of the esophagus had a nutritonal deficit in fresh fruit, vegetables, dietary fiber, and carbohydrates. Compared with the other groups, patients with AC had a higher intake of protein, fat, and milk.

Adenocarcinoma↗

PubMed2000

The Hairy and Enhancer of Split homologue-1 (HES-1) mediates the proliferative effect of 17beta-estradiol on breast cancer cell lines.

The mechanism behind hormone dependent growth of breast cancer is presently not well understood. We show that the HES-1 protein level in the breast cancer cell lines T47D and MCF-7 is down regulated by 17beta-estradiol treatment. This regulation could be reversed by addition of the anti-estrogens 4OH tamoxifen, raloxifen and Imperial Chemical Industries (ICI) 182,780. In T47D cells with inducible exogenous HES-1 expression, induced expression of HES-1 protein prevented the proliferative effect of 17beta-estradiol and subsequent up regulation of proliferating cell nuclear antigen (PCNA). An inverse correlation between the HES-1 and PCNA protein levels respectively was found in colon cancer cell lines. These findings point to a potential role of HES-1 as a tumor suppressor in epithelial cells, and as a mediator of 17beta-estradiols proliferative effect on breast cancer cells.

Basic Helix-Loop-Helix Proteins↗

PubMed1999

Competition between thyroid hormone receptor-associated protein (TRAP) 220 and transcriptional intermediary factor (TIF) 2 for binding to nuclear receptors. Implications for the recruitment of TRAP and p160 coactivator complexes.

Transcriptional activation by nuclear receptors (NRs) involves the concerted action of coactivators, chromatin components, and the basal transcription machinery. Crucial NR coactivators, which target primarily the conserved ligand-regulated activation (AF-2) domain, include p160 family members, such as TIF2, as well as p160-associated coactivators, such as CBP/p300. Because these coactivators possess intrinsic histone acetyltransferase activity, they are believed to function mainly by regulating chromatin-dependent transcriptional activation. Recent evidence suggests the existence of an additional NR coactivator complex, referred to as the thyroid hormone receptor-associated protein (TRAP) complex, which may function more directly as a bridging complex to the basal transcription machinery. TRAP220, the 220-kDa NR-binding subunit of the complex, has been identified in independent studies using both biochemical and genetic approaches. In light of the functional differences identified between p160 and TRAP coactivator complexes in NR activation, we have attempted to compare interaction and functional characteristics of TIF 2 and TRAP220. Our findings imply that competition between the NR-binding subunits of distinct coactivator complexes may act as a putative regulatory step in establishing either a sequential activation cascade or the formation of independent coactivator complexes.

Animals↗

PubMed1998

Mechanistic principles in NR box-dependent interaction between nuclear hormone receptors and the coactivator TIF2.

Nuclear hormone receptors exert transcriptional activation of target genes upon hormone induction via interactions with the basal transcription machinery. This interaction is mediated by cofactors which physically bind to receptors, thereby acting as coactivators or corepressors leading to activation or repression, respectively. Here we report the screening for and cloning of a peroxisome proliferator receptor-interacting protein, the rat homolog of TIF2. By sequence comparison with the related coactivator SRC-1, we identified three short conserved motifs (NR boxes) in both proteins which are the putative binding sites of TIF2 to nuclear hormone receptors. We demonstrate here by generation of amino acid exchanges within the NR boxes that all three boxes located in the receptor interaction domain of TIF2 are necessary and sufficient for interaction. The three boxes individually can bind to hormone receptors but display preferences in binding for certain receptors. In addition, we show that the interaction domain of TIF2 can compete with other AF-2-dependent cofactors for binding to receptors. Finally, we demonstrate cooperative binding of two TIF2 molecules to a heterodimeric nuclear receptor complex even in the presence of only one cognate ligand, indicating an allosteric effect on the heterodimeric partner upon coactivator binding.

Amino Acid Sequence↗

PubMed1998

A regulatory role for RIP140 in nuclear receptor activation.

Transcriptional regulation of gene expression by nuclear receptors requires negatively and positively acting cofactors. Recent models for receptor activation propose that certain receptors in the absence of ligands can recruit corepressors while ligand binding results in conformational changes leading to the recruitment of coactivators. Previous work has established a coactivator role for the SRC-1 family members as well as an involvement of the coactivators CBP/p300 in nuclear receptor signaling. However, in addition to coactivators, ligand-activated nuclear receptors bind a number of different proteins that possibly serve other functions. Using peroxisome proliferator-activated receptor-alpha (PPAR alpha) as bait in a yeast two-hybrid screening, we have isolated nuclear factor RIP140 whose function in receptor activation is unclear. We now report a detailed characterization of RIP140 action with a focus on the retinoid X receptor (RXR) heterodimeric receptors PPAR and thyroid hormone receptor (TR). We show that putative PPAR ligands enhance the interaction of RIP140 with the rat PPAR subtypes alpha and gamma in solution but not with PPAR/RXR heterodimers on DNA. However, RIP140 forms ternary complexes in the presence of RXR ligands. Similar experiments with TR support the high affinity of RIP140 to the RXR subunit and also suggest that either partner in the TR/RXR heterodimer can independently respond to ligand. Coactivation experiments in yeast and mammalian cells confirm the coactivator role for SRC-1, but not for RIP140. We provide important evidence that the in vitro binding of RIP140 and SRC-1 to nuclear receptors is competitive. Since RIP140 generally down-regulates receptor activity in mammalian cells and specifically down-regulates coactivation mediated by SRC-1, we propose a model in which RIP140 indirectly regulates nuclear receptor AF-2 activity by competition for coactivators such as SRC-1.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Enhancement of nuclear receptor transcriptional signalling.

Glucocorticoids and thyroid hormones induce complex responses in about every mammalian tissue. These effects are mediated by the transcription factor function of the corresponding nuclear receptors, which in most cases achieve the observed regulatory strength in synergy with other factors. Here we describe the functional interaction of the glucocorticoid receptor (GR) with liver-specific transcription factors, the functional synergy of GR with the thyroid hormone receptor (TR), the synergizing sub-domains of the TR, and finally the direct interaction of the GR with other proteins.

Animals↗

PubMed1994

A thyroid hormone receptor-dependent glucocorticoid induction.

Glucocorticoid and thyroid hormones exert their effects in many body tissues by binding to their respective receptors. The search for possible cross-talking mechanisms in overlapping target cells led to the discovery of synergism between a thyroid hormone receptor-binding site and a cryptic glucocorticoid-responsive element. Glucocorticoid responsiveness could only be detected in the presence of thyroid hormone and its receptor. This synergism requires the glucocorticoid receptor (GR) DNA-binding domain and is mediated by the transactivation domains. We found that synergism also occurs when the thyroid hormone receptor is replaced by the retinoic acid receptor or the GR is replaced by the progesterone receptor. Synergism is qualitatively independent of the type of thyroid hormone receptor-binding site and promoter. In several combinations of promoter and response elements, including a retinoic acid response element, T3 induction was only seen in the presence of the cryptic glucocorticoid-responsive element, GR, and glucocorticoids.

Animals↗