KLF6 depletion promotes NF-κB signaling in glioblastoma.

Dysregulation of the NF-κB transcription factor occurs in many cancer types. Krüppel-like family of transcription factors (KLFs) regulate the expression of genes involved in cell proliferation, differentiation and survival. Here, we report a new mechanism of NF-κB activation in glioblastoma through depletion of the KLF6 tumor suppressor. We show that KLF6 transactivates multiple genes negatively controlling the NF-κB pathway and consequently reduces NF-κB nuclear localization and downregulates NF-κB targets. Reconstitution of KLF6 attenuates their malignant phenotype and induces neural-like differentiation and senescence, consistent with NF-κB pathway inhibition. KLF6 is heterozygously deleted in 74.5% of the analyzed glioblastomas and predicts unfavorable patient prognosis suggesting that haploinsufficiency is a clinically relevant means of evading KLF6-dependent regulation of NF-κB. Together, our study identifies a new mechanism by which KLF6 regulates NF-κB signaling, and how this mechanism is circumvented in glioblastoma through KLF6 loss.

[Novel immunodiagnostics for inflammatory arthritis]. / Neue Immundiagnostik bei Arthritiden.

Immunodiagnostics play an important role in the differential diagnostics of arthritis but the test results must be interpreted with respect to the clinical context. The detection of antibodies against citrullinated proteins has significantly improved the immunodiagnostics of arthritis, whereas the importance of testing for rheumatoid factor has decreased due to the low specificity. Antibodies against carbamylated or oxidized proteins will expand the immunodiagnostics of arthritis (especially rheumatoid arthritis) in the future. In contrast, the determination of cytokine concentrations in plasma or synovial fluid plays a subordinate role in the differential diagnostics of arthritis. Indirect immunofluorescence continues to be the gold standard in the detection of antinuclear antibodies (ANA) and in the case of positive results further testing for antigen specificity should be carried out. The presence of ANA is not necessarily associated with autoimmune diseases. An example of a non-pathogenic ANA is anti-DFS70 antibodies.

The German Mouse Clinic: a platform for systemic phenotype analysis of mouse models.

The German Mouse Clinic (GMC) is a large scale phenotyping center where mouse mutant lines are analyzed in a standardized and comprehensive way. The result is an almost complete picture of the phenotype of a mouse mutant line--a systemic view. At the GMC, expert scientists from various fields of mouse research work in close cooperation with clinicians side by side at one location. The phenotype screens comprise the following areas: allergy, behavior, clinical chemistry, cardiovascular analyses, dysmorphology, bone and cartilage, energy metabolism, eye and vision, host-pathogen interactions, immunology, lung function, molecular phenotyping, neurology, nociception, steroid metabolism, and pathology. The German Mouse Clinic is an open access platform that offers a collaboration-based phenotyping to the scientific community (www.mouseclinic.de). More than 80 mutant lines have been analyzed in a primary screen for 320 parameters, and for 95% of the mutant lines we have found new or additional phenotypes that were not associated with the mouse line before. Our data contributed to the association of mutant mouse lines to the corresponding human disease. In addition, the systemic phenotype analysis accounts for pleiotropic gene functions and refines previous phenotypic characterizations. This is an important basis for the analysis of underlying disease mechanisms. We are currently setting up a platform that will include environmental challenge tests to decipher genome-environmental interactions in the areas nutrition, exercise, air, stress and infection with different standardized experiments. This will help us to identify genetic predispositions as susceptibility factors for environmental influences.

Evaluation of performance of EUS-FNA in preoperative lymph node staging of cancers of esophagus, lung, and pancreas.

We reviewed the cytologic and histologic diagnoses and EUS report of 77 consecutive patients who had undergone EUS-FNA preoperative staging for esophageal, lung, and pancreatic cancers at our institution. A total of 122 EUS-FNA lymph nodes were identified. Thirty of 77 cases had histologic follow-up. Using surgical node staging and/or surgical resection as the reference standard, the sensitivity, specificity, accuracy, and positive and negative predictive values were 75%, 95%, 89%, 86%, and 90%, respectively, for EUS-FNA node staging. We compared cytologically malignant and benign lymph node groups with eight EUS parameters including the total number of lymph nodes found by EUS, the shape, margin, long axis, short axis, echogenicity, location of the lymph node, and EUS tumor staging. We found that the short axis is the best EUS feature to predict malignancy. Lymph nodes found in an abdominal location in esophageal and lung cancer are likely malignant.

Serum thrombomodulin. A novel marker of disease activity in systemic lupus erythematosus.

OBJECTIVE: Soluble thrombomodulin (sTM), a proposed serum marker of endothelial cell injury, was investigated as a parameter of disease activity in patients with systemic lupus erythematosus (SLE). METHODS: Levels of sTM were determined by enzyme-linked immunosorbent assay. Disease activity was assessed using 3 established scoring systems: the American College of Rheumatology (ACR), the New York Hospital for Special Surgery (NYHSS), and the Systemic Lupus Activity Measure (SLAM) systems. RESULTS: A close correlation was found between sTM levels and disease activity as assessed with all 3 scoring systems: r = 0.52 by the ACR, 0.75 by the NYHSS, and 0.82 by the SLAM. CONCLUSION: We found that sTM is a sensitive serologic marker of organ involvement in patients with SLE. Furthermore, sTM may prove to be an important marker for vasculitis in general.

Circulating intercellular adhesion molecule 1 as a new activity marker in patients with systemic lupus erythematosus.

To determine the value of soluble intercellular adhesion molecule 1 (sICAM-1) as a measure of disease activity in patients with systemic lupus erythematosus (SLE), 25 patients with SLE were studied in an active and in a less active state. Disease activity was assessed according to the New York Hospital for Special Surgery System (NYHSS) score. The levels of sICAM-1 were significantly higher in an active than in a less active state of the disease (P < 0.001). The correlation between ICAM and the NYHSS score was r = 0.3412 (P < 0.001) and that between NYHSS index and soluble interleukin-2 receptors (sIL-2R) was r = 0.6620 (P < 0.001). There was a good correlation between levels of sICAM-1 and sIL-2R (r = 0.6792, P < 0.001). Both sICAM-1 and sIL-2R were positively and significantly correlated with an increase in the erythrocyte sedimentation rate, but only sIL-2R levels were significantly correlated with increased dsDNA antibodies and with a decrease in serum complement factor C3. Our data suggest that sICAM-1 reflects disease activity in patients with SLE, but this parameter per se should not be used to guide the therapeutic decision in SLE patients suspected of suffering from exacerbation of disease.

Platelet-induced thrombin generation time: a new sensitive global assay for platelet function and coagulation. Method and first results.

A new sensitive test--platelet-induced thrombin generation time (PITT)--is described, in which the formation of thrombin in partially anticoagulated platelet-rich plasma (PRP) leads to aggregation immediately followed by coagulation of PRP. 0.6 ml PRP are rotated in a disk-shaped cuvette within the light beam of a photometer. In PITT, platelets stick to the cuvette wall and, mediated by a large PRP/surface/air interface at the cuvette wall, are activated and participate in thrombin formation which leads to aggregation and clotting. The times from onset of rotation until aggregation (Ta) and until coagulation (Tc) of the PRP samples are recorded. PITT was very sensitive and detected low concentrations of unfractionated heparin (0.01 IU/ml) in vitro. PITT parameters were significantly prolonged ex vivo 2 h after oral administration of acetylsalicylic acid (0.5 g) and after single subcutaneous injections of heparin (5,000 IU). Patients receiving phenprocoumon prophylaxis had markedly prolonged Ta and Tc values (longer than 20 min, n = 23). Patients with recent thrombotic episodes had markedly shorter values than healthy volunteers. PITT may become a very sensitive global test to detect mild hemorrhagic disorders, to monitor the effects of antithrombotic drugs and to detect patients with a risk of vascular occlusions.

Intermittent catheterisation versus percutaneous suprapubic cystostomy in the early management of traumatic spinal cord lesions.

Spinal injury patients initially treated by intermittent catheterisation (IUC) and those who received a fine-bore suprapubic catheter (SPC) have been reviewed. The results show that fine-bore suprapubic catheterisation seems to be superior to intermittent catheterisation because the rate of urinary tract infections is significantly lower in the SPC-group (50%) than in the IUC-patients (71.9%), and the first infecting organisms in the SPC-group differ from those in the IUC-group and are much more easily treated by antibiotic therapy.

Effect of 250 and 1000 ppm fluoride dentifrice on caries. A three-year clinical study.

In a 3-year clinical trial, the caries prophylactic effect of two dentifrices containing 1000 ppm F and one containing 250 ppm F was compared. 541 twelve and thirteen-year-old children took part in the study. The children were randomly divided into three groups. Each group of children and their families used one of the dentifrices daily at home. The children were examined for caries at the start of the study and again after an interval of one year. The caries increment was equal in the three groups during the experimental period. This indicates that a 250 ppm F dentifrice has the same caries preventive effect as a 1000 ppm F dentifrice.

Sequential activation of human peripheral lymphocytes displaying two distinct euchrysine binding patterns in PHA-stimulated cultures.

The patterns of supravital staining with euchrysine, a fluorescent dye thought to bind preferentially to membranes of lysosomes and other structures involved in endocytosis, were evaluated sequentially in PHA-stimulated cultures of human unseparated, T and non-T lymphocytes under conditions of a reversible, amethopterine-imposed DNA synthesis block. It was found that type I cells (with a single conglomerate of fluorescent granules, constituting approx. 50% of resting T cells) were almost completely replaced by type III cells (with large conglomerates of coarse granules, typical of lymphocytes undergoing blast transformation) up to the end of second day of culture. Type II cells (with very fine fluorescent granules scattered over the cytoplasms, present in about 50% of T and all non-T lymphocytes) did not initially change their number but later were replaced by type III cells, usually starting from the third day of culture. A hypothesis is discussed according to which only type I cells are primarily responsive to PHA, whereas type II cells require "help" from the former, prior to transition into the proliferative stage.