The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Reduces but Does Not Prevent Tumorigenesis in Chemical and Hormonal Induced Hepatocarcinogenesis Rat Models.

Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions to HCC. In short- and long-term experiments, administration of N-Nitrosomorpholine (NNM) or intrahepatic transplantation of pancreatic islets in diabetic (PTx), thyroid follicles in thyroidectomized (TTx) and ovarian fragments in ovariectomized (OTx) rats was conducted for the induction of foci of altered hepatocytes (FAH). Gefitinib was administered for two weeks (20 mg/kg) or three and nine months (10 mg/kg). In NNM-treated rats, Gefitinib administration decreased the amount of FAH when compared to controls. The amount of HCA and HCC was decreased, but development was not prevented. Upon all transplantation models, proliferative activity of FAH was lower after administration of Gefitinib in short-term experiments. Nevertheless, the burden of HCA and HCC was not changed in later stages. Thus, EGFR inhibition by Gefitinib diminishes chemical and hormonal also induced hepatocarcinogenesis in the initiation stage in the non-cirrhotic liver. However, progression to malignant hepatocellular tumors was not prevented, indicating only a limited relevance of the EGFR signaling cascade in later stages of hepatocarcinogenesis.

Rare case of a large mediastinal cyst involved in Hodgkin's lymphoma.

We report a case of a mediastinal cystic retrosternal process, discovered by magnetic resonance imaging (MRI) in a 19-year-old male patient, with unusual inhomogenous signals in both T1- and T2-weighted images and contrast-enhancing septation. Macroscopically, the tumor weighed 1330 g, and was constituted by one dominating cyst measuring 14 cm in diameter. Additional small cysts were seen microscopically. The cystic wall was continuously infiltrated by nodular sclerosing Hodgkin's lymphoma, also affecting adjacent lymph-nodes. Age and sex of the patient and the diagnosed subtype of Hodgkin's lymphoma are in line with previously reported rare cases of mediastinal cysts with Hodgkin's lymphoma. The cyst reported here, most likely a secondary thymic cyst, is larger than those reported before. The main reason for the development of these cysts might be the accompanying inflammation of the lymphoma. Little is known about the imaging features of mediastinal cysts caused by lymphoma. Plain thymic cysts are normally homogenous on T1- and T2-weighted images. Hodgkin's lymphoma might be homogenous on T1-weighted images and is mostly inhomogenous on T2-weighted images. In case of inhomogenous cysts with contrast-enhancing septation, one should consider the diagnosis of an associated neoplasm.

Heparin inhibits interferon-γ signaling in human endometrial stromal cells by interference with the cellular binding of interferon-γ.

OBJECTIVE: To examine the impact of heparins on interferon-γ (IFN-γ) signaling in human endometrial stromal cells (ESCs) in vitro. DESIGN: In vitro experiment. SETTING: Research laboratory at a medical university center. PATIENT(S): Premenopausal women undergoing hysterectomy for benign reasons. INTERVENTION(S): The ESCs were isolated from hysterectomy specimens, decidualized in vitro using P and 17ß-E(2), and incubated with recombinant IFN-γ, unfractionated heparin, and low molecular weight heparins (LMWHs). MAIN OUTCOME MEASURE(S): Interferon response factor 1 (IRF-1) and N-myc interactor (Nmi) messenger RNA (mRNA) were measured using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Phosphorylation of signal transducer and activator of transcription 1 (STAT-1) was detected by an in-cell Western assay, expression of the IFN-γ receptor by flow cytometry. Cell-bound IFN-γ was determined in lysates by an ELISA. RESULT(S): Heparin and LMWHs inhibit the IFN-γ-mediated induction of IRF-1, but not Nmi in undifferentiated and decidualized ESCs. The phosphorylation of signal transducer and activator of transcription 1 STAT-1 upon IFN-γ stimulation is inhibited as well. Heparin has no effect on the IFN-γ receptor in ESCs, but inhibits the binding of IFN-γ to the cells. CONCLUSION(S): Unfractionated heparin, as well as LMWHs, are able to inhibit IFN-γ signaling in human ESCs and therefore might be clinically interesting agents to modulate the actions of this proinflammatory cytokine at the implantation site.

Immunolocalization of glycodelin in human adenocarcinoma of the lung, squamous cell carcinoma of the lung and lung metastases of colonic adenocarcinoma.

Glycodelin (Gd), which is localized in cells of bronchial epithelium, type II pneumocytes and alveolar macrophages in rats and humans, plays an important role in the pulmonary immune response in asthmatic inflammation. In this study, sections of paraffin-embedded tumor adjacent lung tissue and sections of adenocarcinoma of the lung, squamous cell carcinoma of the lung and metastases of colonic adenocarcinoma were investigated for the distribution and expression of Gd using a polyclonal anti-Gd antibody. Glycodelin protein is located in the cytoplasm of bronchial epithelial cells, pneumocytes and alveolar macrophages. Furthermore, Gd is expressed in adenocarcinoma and squamous cell carcinoma of the lung as well as in lung metastases of colonic adenocarcinoma. Densitometric analyses showed a significantly increased expression of glycodelin protein in cancer tissue compared to tumor adjacent lung tissue. The Gd protein level was 1.7-2.6-fold increased in lung carcinoma compared to tumor adjacent lung tissue. The Gd protein level did not differ from each other between the investigated types of cancer tissue. Because these data validate the recent findings of Gd mRNA expression, it may be concluded that glycodelin plays an important role in the pathogenesis of lung cancer and lung metastases.

Heparin and low-molecular-weight heparins modulate the decidualization of human endometrial stromal cells.

OBJECTIVE: To examine the impact of unfractionated heparin and low-molecular-weight heparins (LMWHs) on the decidualization of human endometrial stromal cells (ESCs) in vitro. DESIGN: In vitro experiment. SETTING: Research laboratory at a medical university center. PATIENT(S): Premenopausal women undergoing hysterectomy for benign reasons. INTERVENTION(S): The ESCs were isolated from hysterectomy specimens, decidualized in vitro using progesterone and 17beta-estradiol, and incubated with unfractionated heparin and three different LMWHs. MAIN OUTCOME MEASURE(S): Insulin-like growth factor-binding protein (IGFBP) 1, PRL, and insulin-like growth factor (IGF) I were measured using ELISA and real-time reverse-transcription polymerase chain reaction. Cell viability was determined by a fluorometric assay. Intracellular cyclic adenosine 3',5'-monophosphate (cAMP) was measured using a luminescent assay. RESULT(S): Heparin dose- and time-dependently delayed the production of IGFBP-1 and amplified the levels of PRL and IGF-I in ESCs during decidualization in vitro. Similar effects were seen under the influence of the three different LMWHs. Intracellular cAMP was increased in decidualizing ESCs under the influence of heparin and LMWHs. CONCLUSION(S): Unfractionated heparin as well as LMWHs are able to modulate the decidualization of human ESCs in vitro and therefore might be useful to control endometrial differentiation and receptivity in assisted reproduction.

Nonapoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand on interleukin-6, leukemia inhibitory factor, interleukin-8, and monocyte chemoattractant protein 1 vary between undifferentiated and decidualized human endometrial stromal cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is known to exert death-inducing as well as nonapoptotic functions, has been shown to be expressed by the early trophoblast. Here we report that TRAIL has no apoptotic effects on human endometrial stromal cells, but differentially regulates cytokines and chemokines and might therefore play a role in the modulation of the cytokine milieu at the implantation site.