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Andreas Jung

Publications and source records attributed to Andreas Jung.

At least 19 recordsLinked to original sources
PubMed2007

Wnt/FZD signaling and colorectal cancer morphogenesis.

Malignant progression of colorectal carcinomas is characterized by an epithelial-mesenchymal transition (EMT)-like de-differentiation of the invading tumor cells. However a re-differentiation towards an epithelial phenotype, resembling a mesenchymal-epithelial transition (MET), is detectable in metastases. This indicates that malignant progression is based on dynamic processes, which can not be explained solely by irreversible genetic alterations, but must be additionally regulated by the tumor environment. The main oncoprotein in colorectal cancer is the Wnt-pathway effector beta-catenin, which in most cases is overexpressed due to mutations in the adenomatous polyposis coli (APC) tumor suppressor. EMT of tumor cells is associated with a nuclear accumulation of the transcriptional activator beta-catenin, which is reversed in metastases. Nuclear beta-catenin is involved in two fundamental processes in embryonic development: EMT and stem cell formation. Accumulating data demonstrate that aberrant nuclear expression of beta-catenin can also confer these two abilities to tumor cells, indicating the crucial role of aberrant Wnt-signaling for malignant tumor progression.

Carcinoma↗
PubMed2007

Beta-catenin expression in relation to genetic instability and prognosis in colorectal cancer.

In the carcinogenesis of colorectal cancer (CRC) genetic instability and dysfunction of the Wnt-signalling pathway play important roles. Most Wnt-signalling dysfunctions lead to the nuclear accumulation of beta-catenin. The aim of the present study was to investigate whether nuclear accumulation of beta-catenin is associated with prognosis and genetic instability. We used immunohistochemistry to study nuclear beta-catenin expression in 67 CRCs. The expression was evaluated in the entire tumour section as mean values and in tumour budding at the invasive margin. We compared the results with chromosomal and microsatellite instability (CIN vs. MSI), p53 accumulation, and clinicopathological variables including survival. The nuclear accumulation of beta-catenin was significantly associated with abnormal p53 expression and aneuploidy, typically for CIN, whereas no tumour with nuclear beta-catenin expression at the invasive margin displayed MSI. The beta-catenin expression pattern did not correlate significantly with CRC patient prognosis when including all stages. However, in the clinically most interesting prognostic group, Dukes' stage B patients, high nuclear accumulation of beta-catenin was associated with a poor prognosis (p=0.01). Our results suggest that nuclear accumulation of beta-catenin in CRC is related to CIN and may be of prognostic importance. However, larger studies are needed to verify these findings.

Aged↗
PubMed2006

5'-Triphosphate RNA is the ligand for RIG-I.

The structural basis for the distinction of viral RNA from abundant self RNA in the cytoplasm of virally infected cells is largely unknown. We demonstrated that the 5'-triphosphate end of RNA generated by viral polymerases is responsible for retinoic acid-inducible protein I (RIG-I)-mediated detection of RNA molecules. Detection of 5'-triphosphate RNA is abrogated by capping of the 5'-triphosphate end or by nucleoside modification of RNA, both occurring during posttranscriptional RNA processing in eukaryotes. Genomic RNA prepared from a negative-strand RNA virus and RNA prepared from virus-infected cells (but not from noninfected cells) triggered a potent interferon-alpha response in a phosphatase-sensitive manner. 5'-triphosphate RNA directly binds to RIG-I. Thus, uncapped 5'-triphosphate RNA (now termed 3pRNA) present in viruses known to be recognized by RIG-I, but absent in viruses known to be detected by MDA-5 such as the picornaviruses, serves as the molecular signature for the detection of viral infection by RIG-I.

Animals↗
PubMed2006

Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.

The innate immune system senses viral infection by recognizing a variety of viral components (including double-stranded (ds)RNA) and triggers antiviral responses. The cytoplasmic helicase proteins RIG-I (retinoic-acid-inducible protein I, also known as Ddx58) and MDA5 (melanoma-differentiation-associated gene 5, also known as Ifih1 or Helicard) have been implicated in viral dsRNA recognition. In vitro studies suggest that both RIG-I and MDA5 detect RNA viruses and polyinosine-polycytidylic acid (poly(I:C)), a synthetic dsRNA analogue. Although a critical role for RIG-I in the recognition of several RNA viruses has been clarified, the functional role of MDA5 and the relationship between these dsRNA detectors in vivo are yet to be determined. Here we use mice deficient in MDA5 (MDA5-/-) to show that MDA5 and RIG-I recognize different types of dsRNAs: MDA5 recognizes poly(I:C), and RIG-I detects in vitro transcribed dsRNAs. RNA viruses are also differentially recognized by RIG-I and MDA5. We find that RIG-I is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, RIG-I-/- and MDA5-/- mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Together, our data show that RIG-I and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.

Animals↗
PubMed2006

Somatostatin or octreotide as treatment options for chylothorax in young children: a systematic review.

OBJECTIVE: Chylothorax is a rare but life-threatening condition in children. To date, there is no commonly accepted treatment protocol. Somatostatin and octreotide have recently been used for treating chylothorax in children. We set out to summarise the evidence on the efficacy and safety of somatostatin and octreotide in treating young children with chylothorax. DESIGN: Systematic review: literature search (Cochrane Library, EMBASE and PubMed databases) and literature hand search of peer reviewed articles on the use of somatostatin and octreotide in childhood chylothorax. PATIENTS: Thirty-five children treated for primary or secondary chylothorax (10/somatostatin, 25/octreotide) were found. RESULTS: Ten of the 35 children had been given somatostatin, as i.v. infusion at a median dose of 204 microg/kg/day, for a median duration of 9.5 days. The remaining 25 children had received octreotide, either as an i.v. infusion at a median dose of 68 microg/kg/day over a median 7 days, or s.c. at a median dose of 40 microg/kg/day and a median duration of 17 days. Side effects such as cutaneous flush, nausea, loose stools, transient hypothyroidism, elevated liver function tests and strangulation-ileus (in a child with asplenia syndrome) were reported for somatostatin; transient abdominal distension, temporary hyperglycaemia and necrotising enterocolitis (in a child with aortic coarctation) for octreotide. CONCLUSIONS: A positive treatment effect was evident for both somatostatin and octreotide in the majority of reports. Minor side effects have been reported, however caution should be exercised in patients with an increased risk of vascular compromise as to avoid serious side effects. Systematic clinical research is needed to establish treatment efficacy and to develop a safe treatment protocol.

Child, Preschool↗
PubMed2006

A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer.

BACKGROUND & AIMS: Loss of the basement membrane (BM) is considered an important step toward tumor malignancy. However, the BM is still expressed in most typical colorectal adenocarcinomas; nevertheless, these tumors can invade and develop metastases. The aim of this study was to investigate the role, mechanisms, and clinical relevance of BM turnover in malignant colorectal cancer (CRC) progression. METHODS: Expression of BM components and their transcriptional regulation and clinical relevance were investigated in human CRCs and cell lines. RESULTS: Our data show new aspects in BM turnover in CRCs with impact on malignant tumor progression: (1) The BM is still expressed in the main tumor mass of most colorectal adenocarcinomas, but selectively lost at invasive regions of the tumor in many cases. (2) Selective loss of the BM at the invasive front has high clinical and tumor biologic relevance for distant metastasis and survival. (3) The BM is reexpressed in metastases, indicating that its loss is transient and regulated by environmental factors. (4) This transient loss is not only due to proteolytic breakdown but to a down-regulated synthesis and linked to an epithelial-mesenchymal transition (EMT) in tumor cells, and, thereby, zinc-finger-enhancer protein 1 (ZEB1) is the crucial transcriptional repressor of BM components in CRCs. CONCLUSIONS: A transient BM loss at the invasive front is correlated with increased distant metastasis and poor patient survival, indicating its tumor biologic relevance and usefulness as a prognostic marker. Targeting ZEB1 might be a promising therapeutic option to prevent metastasis.

Adenocarcinoma↗
PubMed2005

beta-Catenin regulates the expression of tenascin-C in human colorectal tumors.

Tenascin-C (TN-C) is a component of the extracellular matrix (ECM). It is expressed during development and re-expressed in many types of cancers, where it is involved in the modulation of adhesion and proliferation. TN-C expression is especially high at sites of epithelial mesenchymal transition (EMT), which are found frequently at the invasion front of well-differentiated human colorectal adenocarcinomas. Tumor cells in this compartment are characterized by a strong nuclear expression of the oncogenic transcription factor beta-catenin. Here, we demonstrate that TN-C is a beta-catenin target gene in human colorectal tumors. Thus, by far the most common mutations in colorectal tumors, found in the Wnt-signaling pathway and leading to the stabilizing of beta-catenin, might influence invasion by altering adhesive properties and EMT of tumor cells.

Adenocarcinoma↗
PubMed2005

A mathematical model of cerebral circulation and oxygen supply.

A compartment model of cerebral circulation and oxygen supply including an autoregulation mechanism is presented. The model is focused on the analysis of slow dynamical variations of long term neurophysiological parameters like the partial oxygen pressure of brain tissue or the cerebral blood flow. The circulatory part of the model is built up of seven compartments including arteries, capillaries, veins, brain tissue, cerebrospinal fluid, the sagittal sinus and an artificial compartment for the simulation of brain swelling. The description of oxygen supply is based on a Krogh model. Numerical calculations reproduce the experimentally well established connection between arterial blood pressure and the production of cerebrospinal fluid. Furthermore we found an approximately linear correlation of the partial oxygen pressure of brain tissue to the mean arterial blood pressure in the case of an impaired autoregulation mechanism. In a first test such a linear dependence could also be detected in clinical data from the neurosurgical intensive care monitoring.

Blood Pressure↗
PubMed2005

Overexpression of MMP9 and tissue factor in unstable carotid plaques associated with Chlamydia pneumoniae, inflammation, and apoptosis.

Tissue remodeling by matrix metalloproteinases (MMPs) and plasminogen activators such as tissue factor (TF) is postulated to be involved in the pathogenesis of atherosclerosis. The in situ expression of MMP9 and TF in unstable atherosclerotic plaques has not been examined in detail. Moreover, interference of tissue remodeling by vascular inflammation, apoptosis, and Chlamydia pneumoniae inside plaque subregions is unclear. A total of 40 autopsy carotid arteries (controls) and 20 atherosclerotic carotid endarterectomy specimens (with type VI lesions, according to the American Heart Association classification) from stroke patients were analyzed for expression of MMP9 and TF using in situ techniques. The data on tissue remodeling were correlated with the presence of inflammatory cells (T cells, B-cells, macrophages), apoptosis, and the presence of C. pneumoniae using immunohistochemistry and Western blot analyses. We found a significant overexpression of MMP9 and TF in progressive atherosclerotic carotid arteries, especially in the shoulder and cap subregions (both p < 0.05). Expression of MMP9 and TF correlated significantly with T-cell and macrophage infiltrates as well as with apoptosis (p < 0.05). C. pneumoniae infection was significantly associated with elevated TF expression (p < 0.01) but not with MMP9. MMP9 and TF are thus significantly overexpressed in progressive atherosclerotic plaques, and their relevant subregions (shoulder and cap) are involved in plaque instability. This process is associated with local inflammatory cell infiltrates and apoptosis, which might be influenced by infectious agents such as C. pneumoniae.

Aged↗
PubMed2005

Molecular aspects of declining sperm motility in older men.

OBJECTIVE: To investigate the molecular mechanism for declining sperm motility in older men. DESIGN: Retrospective and prospective study. SETTING: University-based andrology unit. PATIENT(S): Semen was collected from 2,111 patients and sperm donors. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Age, sperm concentration, ejaculate volume, sperm motility (including velocity average path, velocity straight line, velocity curvilinear, linearity, and lateral head displacement), normal sperm morphology, percentage of abnormally blue-stained flagella, and total and free T, FSH, and LH concentrations were analyzed. In addition, the zinc concentration in the seminal fluid, flagella, and the whole spermatozoa was measured by means of atomic absorption spectrometry. RESULT(S): Patient age correlated negatively with T concentration and sperm motility, including velocity, but positively with the percentage of abnormally stained flagella and the flagellar zinc. Whereas the percentage of abnormally stained flagella correlated negatively with motility and sperm velocity, there was a positive relationship with the flagellar zinc content. Flagellar zinc content was negatively correlated with motility. Testosterone showed a positive relationship with motility and sperm concentration. CONCLUSION(S): Because the epididymis is functionally T-dependent, our data suggest that the removal of zinc from the outer dense fibers during epididymal sperm maturation is affected in aging men, which in turn will result in decreased sperm motility.

Adolescent↗
PubMed2005

Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression.

The dissemination of tumour cells is the prerequisite of metastases and is correlated with a loss of epithelial differentiation and the acquisition of a migratory phenotype, a hallmark of malignant tumour progression. A stepwise, irreversible accumulation of genetic alterations is considered to be the responsible driving force. But strikingly, metastases of most carcinomas recapitulate the organization of their primary tumours. Although current models explain distinct and important aspects of carcinogenesis, each alone can not explain the sum of the cellular changes apparent in human cancer progression. We suggest an extended, integrated model that is consistent with all aspects of human tumour progression - the 'migrating cancer stem (MCS)-cell' concept.

Animals↗
PubMed2005

Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin.

Invasion by colorectal carcinomas is characterized by an epithelial-mesenchymal transition (EMT)-like dedifferentiation of the tumor cells. However, a redifferentiation towards an epithelial phenotype, resembling a mesenchymal-epithelial transition, is detectable in metastases. This indicates that malignant progression is based on dynamic processes, which cannot be explained solely by irreversible genetic alterations, but must be additionally regulated by the tumor environment. The main oncoprotein in colorectal cancer is the Wnt pathway effector beta-catenin, which is overexpressed due to mutations in the APC tumor suppressor in most cases. EMT of the tumor cells is associated with a nuclear accumulation of the transcriptional activator beta-catenin, which is reversed in metastases. Nuclear beta-catenin is involved in two fundamental processes in embryonic development: EMT and stem cell formation. Accumulating data demonstrate that aberrant nuclear expression of beta-catenin can also confer these two abilities to tumor cells, thereby driving malignant tumor progression.

Cell Nucleus↗
PubMed2005

Post-transplantation lymphoproliferative disorder of recipient origin in a boy with acute T-cell leukemia with detection of B-cell clonality 3 months before stem cell transplantation.

Post-transplantation lymphoproliferative disorder is an infrequent complication after hematopoietic stem cell transplantation. It is hypothesized that lack of T-cell surveillance following transplantation permits reactivation of latent EBV leading to polyclonal B-cell expansion and finally outgrowth of a predominant clone. Most cases are of donor origin. Here, we describe an 8-year old boy with early onset post-transplantation lymphoproliferative disorder following matched-unrelated stem cell transplantation for high-risk T-cell leukemia whose disease was unusual for two reasons. First, his B-cell clone was of host origin and, in contrast to the few PTLD of host origin described so far, not associated with autologous reconstitution. Secondly, using clonal analysis, we could retrospectively show that the B-cell clone emerged during consolidation chemotherapy for T-cell leukemia, 3 months before stem cell transplantation.

Antibodies, Monoclonal↗
PubMed2004

Alterations in the tissue inhibitor of metalloproteinase-3 (TIMP-3) are found frequently in human colorectal tumours displaying either microsatellite stability (MSS) or instability (MSI).

Methylation of promoter regions and frameshift mutations in microsatellites of the coding sequence (CDS) of genes are frequently associated with loss of expression in microsatellite instable (MSI) colorectal carcinoma. In a panel of 40 MSI and 24 microsatellite stable (MSS) colorectal tumours as well as six cultured colorectal carcinoma cell lines hypermethylation of the TIMP3-promoter was found in 28% of MSI and 25% of MSS tumours, respectively. Additionally, three MSI tumours and one cell line displayed instability of a C7-repeat located in the CDS of the TIMP-3 gene. TIMP-3 fulfils all important criteria for being a target gene in the mutator pathway. Thus, TIMP-3 might be a factor of general importance for colorectal carcinogenesis.

Animals↗
PubMed2004

Down-regulation of the homeodomain factor Cdx2 in colorectal cancer by collagen type I: an active role for the tumor environment in malignant tumor progression.

The homeobox transcription factor Cdx2 specifies intestinal development and homeostasis and is considered a tumor suppressor in colorectal carcinogenesis. However, Cdx2 mutations are rarely found. Invasion of colorectal cancer is characterized by a transient loss of differentiation and nuclear accumulation of the oncoprotein beta-catenin in budding tumor cells. Strikingly, this is reversed in growing metastases, indicating that tumor progression is a dynamic process that is not only driven by genetic alterations but also regulated by the tumor environment. Here we describe a transient loss of Cdx2 in budding tumor cells at the tumor host interface, and reexpression of Cdx2 in metastases. Cell culture experiments show that collagen type I, through beta(1) integrin signaling, triggers a transient transcriptional down-regulation of Cdx2 and its intestine-specific target gene sucrase isomaltase, associated with a loss of differentiation. These data indicate an active role for the tumor environment in malignant tumor progression.

Adenocarcinoma↗
PubMed2004

Male sexuality with advancing age.

People aged 60 years or older are commonly given the image of grandparents who are sexually rather inactive. However, a high percentage of men over 60 years have sexual desires and are sexually active. Aging men need more time and more direct stimulation of the penis to achieve full erection. The risk of developing erectile dysfunction increases with age. Almost one man in 22 aged 60-69 years without previous erection problems develops erectile dysfunction within 1 year. Hormone replacement therapy is only indicated if testosterone deficiency is combined with the syndrome of the "aging male" and lack of other disorders that are possibly causative and could be treated. For hormone replacement therapy testosterone gel preparations are preferable because they have a short half-time and can be immediately discontinued in the event that a pre-existing occult prostate carcinoma is stimulated.

Aged↗