Two-Step Nanoscale Approach for Well-Defined Complex Alkanethiol Films on Au Surfaces.

Controlling the molecular organization of organic self-assembled monolayers (SAM) is of utmost importance in nanotechnology, molecular electronics, and surface science. Here we propose two well-differentiated approaches, double printing based on microcontact printing (µ-cp) and molecular backfilling adsorption, to produce complex alkanethiol films. The resulting films on model Au surfaces were characterized by atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and contact angle measurements. Double printing alkanethiols results in clear coexisting regions where no molecular displacement is observed, highlighting the slow diffusion rates of long alkanethiols and large attractive interaction between long alkyl chains. Exposing a single-print µ-cp Au substrate to an additional alkanethiol solution yields the formation of differently ordered domain boundaries with different thickness and micrometer lateral size. The high order is a result of enhanced molecular mobility and restructuring during solution backfilling. The formed molecular assemblies constitute an excellent testing ground for nanoscale phenomena that strongly depend on the nanoscale geometrical and chemical features of the surface such as designed functionality or corrosion initiation and inhibition.

The effect of psychotherapy for depression on improvements in social functioning: a meta-analysis.

BACKGROUND: Patients with depression often report impairments in social functioning. From a patient perspective, improvements in social functioning might be an important outcome in psychotherapy for depression. Therefore, it is important to examine the effects of psychotherapy on social functioning in patients with depression. METHOD: We conducted a meta-analysis on studies of psychotherapy for depression that reported results for social functioning at post-treatment. Only studies that compared psychotherapy to a control condition were included (31 studies with 2956 patients). RESULTS: The effect size of psychotherapy on social functioning was small to moderate, before [Hedges' g = 0.46, 95% confidence interval (CI) 0.32-0.60] and after adjusting for publication bias (g = 0.40, 95% CI 0.25-0.55). Univariate moderator analyses revealed that studies using care as usual as a control group versus other control groups yielded lower effect sizes, whereas studies conducted in the USA versus other countries and studies that used clinician-rated instruments versus self-report yielded higher effect sizes. Higher quality studies yielded lower effect sizes whereas the number of treatment sessions and the effect size of depressive symptoms were positively related to the effect size of social functioning. When controlling for these and additional characteristics simultaneously in multivariate meta-regression, the effect size of depressive symptoms, treatment format and number of sessions were significant predictors. The effect size of social functioning remained marginally significant, indicating that improvements in social functioning are not fully explained by improvements in depressive symptoms. CONCLUSIONS: Psychotherapy for depression results in small to moderate improvements in social functioning. These improvements are strongly associated with, but not fully explained by, improvements in depressive symptoms.

Prevalence of flat lesions in a large screening population and their role in colonoscopy quality improvement.

BACKGROUND AND STUDY AIMS: Flat lesions pose new challenges for endoscopists, but the importance of detecting them is still controversial. Most screening studies do not survey macroscopic polyp morphology. The aims were to evaluate the percentage of flat polyp findings in a large asymptomatic adult screening population (n = 52 521), to assess the impact of shape and size on malignant transformation, and to assess the role of flat lesions regarding quality assurance in colorectal cancer prevention. MATERIAL AND METHODS: Retrospective analysis of screening colonoscopies performed between 2007 and 2011 according to the Austrian "Quality management for colon cancer prevention" program. RESULTS: 17 771 patients with polyps were included in the study. Patients with flat polyps represented 24.2 % (n = 4293), 62.4 % (n = 11 097) were classified as having sessile and 13.4 % (n = 2381) as pedunculated polyps. Among those with flat polyps 51.4 % had adenomas (n = 2207). High grade dysplasia (HGD) was found in 2.1 % (n = 47) of flat adenomas, in 1.5 % (n = 89) of sessile adenomas and 4.7 % (n = 92) of pedunculated adenomas (P < 0.0001. The risk for containing HGD was 1.0 % for flat lesions ≤ 10 mm in size compared with 10.3 % for lesions > 10 mm, and 1.0 % for polypoid lesions ≤ 10 mm compared with 9.3 % for lesions > 10 mm (P < 0.0001). Multivariable logistic regression showed that polyp size (P < 0.0001) but not polyp shape (P = 0.438) is an independent predictor for HGD. Adenoma detection rate (ADR) correlated weakly with the flat polyp detection rate (Pearson r = 0.24). CONCLUSION: Malignant potential of polyps is mostly affected by size but not by shape. Since flat polyp detection rate only correlates poorly with ADR we do not recommend its incorporation in quality assured screening colonoscopy.

Initial corrosion observed on the atomic scale.

Corrosion destroys more than three per cent of the world's GDP. Recently, the electrochemical decomposition of metal alloys has been more productively harnessed to produce porous materials with diverse technological potential. High-resolution insight into structure formation during electrocorrosion is a prerequisite for an atomistic understanding and control of such electrochemical surface processes. Here we report atomic-scale observations of the initial stages of corrosion of a Cu3Au111 single crystal alloy within a sulphuric acid solution. We monitor, by in situ X-ray diffraction with picometre-scale resolution, the structure and chemical composition of the electrolyte/alloy interface as the material decomposes. We reveal the microscopic structural changes associated with a general passivation phenomenon of which the origin has been hitherto unclear. We observe the formation of a gold-enriched single-crystal layer that is two to three monolayers thick, and has an unexpected inverted (CBA-) stacking sequence. At higher potentials, we find that this protective passivation layer dewets and pure gold islands are formed; such structures form the templates for the growth of nanoporous metals. Our experiments are carried out on a model single-crystal system. However, the insights should equally apply within a crystalline grain of an associated polycrystalline electrode fabricated from many other alloys exhibiting a large difference in the standard potential of their constituents, such as stainless steel (see ref. 5 for example) or alloys used for marine applications, such as CuZn or CuAl.

[Antibiotic prophylaxis in gastrointestinal endoscopy--recommendations of the Austrian Society of Gastroenterology and Hepatology]. / Antibiotikaprophylaxe in der gastrointestinalen Endoskopie--Empfehlungen der Österreichischen Gesellschaft für Gastroenterologie und Hepatologie.

The recommendations of the Austrian Society of Gastroenterology and Hepatology (ÖGGH) for antibiotic prophylaxis in gastrointestinal endoscopy of the year 2002 have been updated in accord with the recently published guidelines of the American Society of Gastrointestinal Endoscopy (ASGE) and the American Heart Association (AHA). Antibiotic prophylaxis for any endoscopic intervention to prevent infectious endocarditis is no longer necessary. Moreover, the prophylactic use of antibiotics for ERCP without biliary obstruction and ERCP with obstruction and a likelihood of complete drainage is no longer recommended. For ERCP with obstruction and anticipated incomplete drainage, a full course of antibiotics should be administered to prevent cholangitis. For the prevention of local infections antibiotics are useful prior to endoscopic puncturing, contrasting or drainage of cystic lesions as well as just before application of a PEG tube. In cirrhotic patients with GI bleeding antibiotic prophylaxis should be started as early as possible and be administered for several days.

Tacrolimus intoxication resolved by gastrointestinal bleeding: case report.

Tacrolimus is a potent immunosuppressive agent widely used in renal and liver transplantations. Its potential side effects due to overdosing are variable. Most commonly toxic tacrolimus blood levels affect the central and peripheral nervous systems. Once absorbed, tacrolimus binds to plasma proteins and accumulates within erythrocytes. Current treatment strategies to overcome acute intoxications focus on the induction of hepatic cytochrome P450 enzymes to accelerate tacrolimus degradation. We report the case of a 69-year-old renal transplant recipient presenting with acute liver failure, septic shock, and tacrolimus intoxication. The intoxication was resolved by massive gastrointestinal bleeding and subsequent transfusion of packed erythrocytes. We concluded that exchange blood transfusions offer an alternative therapeutic approach for patients with severe liver function impairment and tacrolimus intoxication.

Immunoglobulin induction therapy in renal transplant recipients: Effects on immunoglobulin and regulatory antibody levels.

We have previously shown that high pretransplant regulatory autoantibodies are associated with better kidney graft outcome. To analyze the effect of intravenous immunoglobulin (IVIG) induction therapy on these regulatory antibodies, we performed a prospective randomized study in 50 renal transplant recipients who were randomly assigned to receive 7 x 10 g IVIG or 7 x 10 g IV albumin infusions. Basic immunosuppressive therapy consisted of tacrolimus/azathioprine (n = 24) and tacrolimus/mycophenolate mofetil (n = 26), respectively. ELISA was used to assess IgG-/IgA-anti-Fab, -anti-F(ab)2 and -anti-hinge regulatory antibodies. IVIG induction therapy resulted in upregulation of serum IgG and IgA levels within the first 20 days posttransplant (P = .001, IgG; P = .04, IgA), so that a significant IgG deficiency was found only in non-IVIG patients (day 10: IgG <6 g/L: 7/25 (28%) non-IVIG versus 0/25 IVIG patients; P = .005). As the IVIG charges contained all of the regulatory antibodies tested, intravenous administration of these antibodies explain the elevated IgG- and IgA-anti-F(ab)2 antibody levels found in IVIG compared to non-IVIG patients on day 10 (P = .005 and P = .04, respectively). Our data indicated that IVIG induction prevented severe IgG deficiency in the early posttransplant period but had no impact on severe infectious complications. IVIG induction enhanced immunoregulatory antibody levels early posttransplant, which might provide graft protective effects.

Applications of time-series analysis to mood fluctuations in bipolar disorder to promote treatment innovation: a case series.

Treatment innovation for bipolar disorder has been hampered by a lack of techniques to capture a hallmark symptom: ongoing mood instability. Mood swings persist during remission from acute mood episodes and impair daily functioning. The last significant treatment advance remains Lithium (in the 1970s), which aids only the minority of patients. There is no accepted way to establish proof of concept for a new mood-stabilizing treatment. We suggest that combining insights from mood measurement with applied mathematics may provide a step change: repeated daily mood measurement (depression) over a short time frame (1 month) can create individual bipolar mood instability profiles. A time-series approach allows comparison of mood instability pre- and post-treatment. We test a new imagery-focused cognitive therapy treatment approach (MAPP; Mood Action Psychology Programme) targeting a driver of mood instability, and apply these measurement methods in a non-concurrent multiple baseline design case series of 14 patients with bipolar disorder. Weekly mood monitoring and treatment target data improved for the whole sample combined. Time-series analyses of daily mood data, sampled remotely (mobile phone/Internet) for 28 days pre- and post-treatment, demonstrated improvements in individuals' mood stability for 11 of 14 patients. Thus the findings offer preliminary support for a new imagery-focused treatment approach. They also indicate a step in treatment innovation without the requirement for trials in illness episodes or relapse prevention. Importantly, daily measurement offers a description of mood instability at the individual patient level in a clinically meaningful time frame. This costly, chronic and disabling mental illness demands innovation in both treatment approaches (whether pharmacological or psychological) and measurement tool: this work indicates that daily measurements can be used to detect improvement in individual mood stability for treatment innovation (MAPP).

sCD30 and neopterin as risk factors of chronic renal transplant rejection: impact of cyclosporine A, tacrolimus, and mycophenolate mofetil.

High pretransplantation sCD30 levels have been shown to be associated with lower 5-year kidney graft survival in mainly Cyclosporine A (CsA)-treated recipients (Collaborative Transplant Study database). To analyze the effect of different immunosupressive regimens (CsA/Azathioprine [Aza], CsA/Mycophenolate Mofetil [MMF], Tacrolimus [Tacr]/Aza) on sCD30, we assessed serum sCD30 and neopterin together with in vitro cytokine responses in a prospective randomized study of 84 renal transplant recipients before, 4 months, and 1 year after transplantation. Panel-reactive antibody (PRA) formation, HLA matching, ATG induction therapy, and acute rejections had no impact on sCD30 levels, whereas cytomegalovirus (CMV) infections induced an up-regulation of sCD30 4 months posttransplantation (P = .003). Whereas MMF showed no effect on sCD30 compared with Aza therapy, we found a significant impact of Tacr versus CsA treatment (1-year sCD30 > or = 60 U/mL: 14/42 (33%), CsA; 1/38 (3%), Tacr; P < .0005). Chronic rejection 2 years posttransplantation was associated with elevated 1-year sCD30 (P = .001) and neopterin levels (P = .006). Our data indicate that the Th2 activation marker sCD30 provides a risk factor for chronic rejection independent of classical immunological risk factors and may be down-regulated using Tacr treatment.

Uncertainties in Monte Carlo-based absorbed dose calculations for an experimental benchmark.

There is a need to verify the accuracy of general purpose Monte Carlo codes like EGSnrc, which are commonly employed for investigations of dosimetric problems in radiation therapy. A number of experimental benchmarks have been published to compare calculated values of absorbed dose to experimentally determined values. However, there is a lack of absolute benchmarks, i.e. benchmarks without involved normalization which may cause some quantities to be cancelled. Therefore, at the Physikalisch-Technische Bundesanstalt a benchmark experiment was performed, which aimed at the absolute verification of radiation transport calculations for dosimetry in radiation therapy. A thimble-type ionization chamber in a solid phantom was irradiated by high-energy bremsstrahlung and the mean absorbed dose in the sensitive volume was measured per incident electron of the target. The characteristics of the accelerator and experimental setup were precisely determined and the results of a corresponding Monte Carlo simulation with EGSnrc are presented within this study. For a meaningful comparison, an analysis of the uncertainty of the Monte Carlo simulation is necessary. In this study uncertainties with regard to the simulation geometry, the radiation source, transport options of the Monte Carlo code and specific interaction cross sections are investigated, applying the general methodology of the Guide to the expression of uncertainty in measurement. Besides studying the general influence of changes in transport options of the EGSnrc code, uncertainties are analyzed by estimating the sensitivity coefficients of various input quantities in a first step. Secondly, standard uncertainties are assigned to each quantity which are known from the experiment, e.g. uncertainties for geometric dimensions. Data for more fundamental quantities such as photon cross sections and the I-value of electron stopping powers are taken from literature. The significant uncertainty contributions are identified as the energy of the radiation source and the underlying photon cross sections as well as the I-value of media involved in the simulation. The combined standard uncertainty of the Monte Carlo calculation yields 0.78% as a conservative estimation. The result of the calculation is close to the experimental result and with each combined standard uncertainty <1%, the accuracy of EGSnrc is confirmed. The setup and methodology of this study can be employed to benchmark other Monte Carlo codes for the calculation of absorbed dose in radiotherapy.

Localized dealloying corrosion mediated by self-assembled monolayers used as an inhibitor system.

The structure and chemistry of thiol or selenol self-assembled organic monolayers have been frequently addressed due to the unique opportunities in functionalization of materials. Such organic films can also act as effective inhibition layers to mitigate oxidation or corrosion. Cu-Au alloy substrates covered by self-assembled monolayers show a different dealloying mechanism compared to bare surfaces. The organic surface layer inhibits dealloying of noble metal alloys by a suppression of surface diffusion at lower potentials but at higher applied potentials dealloying proceeds in localized regions due to passivity breakdown. We present an in situ atomic force microscopy study of a patterned thiol layer applied on Cu-Au alloy surfaces and further explore approaches to change the local composition of the surface layers by exchange of molecules. The pattern for the in situ experiment has been applied by micro-contact printing. This allows the study of corrosion protection with its dependence on different molecule densities at different sites. Low-density thiol areas surrounding the high-density patterns are completely protected and initiation of dealloying proceeds only along the areas with the lowest inhibitor concentration. Dealloying patterns are highly influenced and controlled by molecular thiol to selenol exchange and are also affected by introducing structural defects such as scratches or polishing defects.

Vibrio cholerae non-O1 septicaemia in a patient with liver cirrhosis and Billroth-II-gastrectomy.

This report deals with the first diagnosed case of Vibrio cholerae non-O1 septicaemia in Austria. After a vacation in Tunisia, a 51-year-old male patient with liver cirrhosis and Billroth-II-gastrectomy was admitted to hospital because of abdominal pain, growing ascites, and jaundice. Four days later, the patient developed a single peak of high fever (39.6 degrees C). A blood culture was drawn and treatment with amoxycillin/clavulanic acid commenced. The blood culture yielded Gram-negative comma-like rods which were identified as V. cholerae non-O1.

[Diagnosis of varices in liver cirrhosis: duplex ultrasound versus gastroscopy]. / Varizendiagnostik bei Leberzirrhose: Duplexultraschall versus Gastroskopie.

This study assesses the usefulness of duplex sonography in the diagnosis of oesophageal varices. 32 patients with liver cirrhosis were studied by endoscopy and duplex sonography. There was an excellent correlation in the case of the medium-sized and large-sized varices. Only small varices could not be detected by duplex sonography. On the other hand, 3 large-sized paraoesophageal varices, which were not identified by endoscopy, were easily seen by duplex sonography. The sensitivity of duplex sonography was between 0.8 and 0.9, the accuracy between 0.93 and 0.96.

Intestinal metabolism of plasma free fatty acids in streptozotocin diabetic rats.

Moderate insulin deficiency was reported to be accompanied by an increased production of intestinal very low density lipoprotein (VLDL) triglyceride in the rat. Because plasma free fatty acids (FFA) are incorporated into triglyceride by intestinal mucosa of rats and humans and plasma FFA are increased in insulin-deficient diabetes mellitus, we investigated several aspects of the intestinal metabolism of plasma FFA in diabetic rats. All experiments were performed on the third day following the i.v. injection of streptozotocin (45 mg/kg body weight) or buffer alone. A (14 C)palmitic acid-rat serum complex was rapidly injected intravenously and its initial uptake by small bowel mucosa, the intracellular incorporation into lipids and water soluble metabolites and the specific radioactivity of triglycerides of mucosal homogenates was determined. No significant differences could be found between diabetic and control rats at 2 and 5 min after 14C-palmitate i.v., suggesting that neither the influx of plasma free fatty acids into intestinal mucosal cells nor their initial intracellular metabolic pathways are significantly altered in moderately diabetic rats. A pronounced decrease in intestinal mucosal triglyceride at 10 min after 14C-palmitate i.v. might be interpreted as indirect evidence for an enhanced triglyceride efflux from intestinal mucosa into mesenteric lymph in diabetic rats.

Hepatitis A and B in non-institutionalized mentally retarded patients.

The high incidence of hepatitis A and B in institutionalized patients with Down's syndrome is not fully understood. Under poor hygienic conditions immunological alterations might predispose to these infections. To minimize environmental influences, 125 patients with Down's syndrome (mean age 11.9 years) living at home with their families were studied for the occurrence of serological markers of Hepatitis A and B. 106 outpatients with mental retardation of other genesis (mean age 12.4 years), and 114 consecutive voluntary blood donors (mean age 18.0 years) from the same area served as controls. Evidence of previous hepatitis A virus infection was found in 5.6% of Down's patients, in 9.4% of other mentally retarded patients, and in 16.7% of healthy controls. Evidence of previous or ongoing hepatitis B virus infection was a common finding in both groups of mental retardation (Down's syndrome 20.0%, other mentally retarded patients 11.3%) in sharp contrast to healthy blood donors (0.9%, p less than 0.05). Patients with Down's syndrome, however, revealed a much higher incidence of HBs-antigenemia as compared with other mentally retarded patients (12.8% vs. 2.8%, p less than 0.01). All HBs antigen-positive cases had normal transaminase levels and no overt clinical signs of liver disease, suggesting an asymptomatic carrier state. These data indicate that hepatitis A is not a special risk for mentally retarded outpatients, while hepatitis B virus infection is hyperendemic even in not-institutionalized patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Early diagnosis of diabetic gastroparesis]. / Untersuchungen zur Frühdiagnostik der diabetischen Magenentleerungsstörung.

Recognition of early phases of diabetic gastroparesis is hampered by the absence of characteristic symptoms and practicable detection systems in clinical practice. Hence, a new procedure estimating phase III activity of the interdigestive migrating motor complex by monitoring gastric emptying of an undigestible marker particle by means of a metal detector was evaluated in 40 diabetic patients (13 type I, 27 type II diabetes) and 14 non-diabetic controls. Simultaneously, orocecal transit of fluids was measured by the hydrogen breath test. Gastric emptying of a solid marker was significantly delayed in diabetics as compared with controls (112.5 +/- 8.6 vs 51.2 +/- 6.8 minutes, M +/- SEM, p < 0.05). Of the diabetics investigated 77.5% had delayed gastric emptying but only 22.5% of those were clinically symptomatic as assessed by a standardized questionnaire. Gastric emptying velocity did not correlate significantly with age, length of diabetes, neuropathy, blood glucose and orocecal transit of fluids. We conclude that determination of gastric emptying time of undigestible marker particles by means of a sensitive metal detector appears to be a clinically promising and easy to perform method to detect early phases of diabetic gastroparesis.

[The diagnostic value and risks of small bowel biopsy: an assessment in 80 patients (author's transl)]. / Möglichkeiten und Risiko der Dünndarmbiopsie: Erfahrung an 80 Patienten.

Small bowel biopsy is a routine procedure used mainly in the evaluation of malabsorption. The Crosby-Kugler capsule, which permits the performance of just one biopsy per session and hydraulic biopsy tubes, permitting multiple biopsies from any level of the small bowel, have been in use now with several modifications for about 20 years. The diagnostic range and risks of these tools are described briefly in this paper and discussed in the light of our own experience in 80 patients. In accordance with the experience of others, we found that small bowel biopsy was accompanied by only a few minor complications and we consider it a valuable procedure in clinical diagnosis and experimental research.

[Addison's disease with enlarged adrenal glands in sonography and computer tomography. Differential diagnostic considerations based on 2 cases of tuberculous adrenalitis]. / Morbus Addison mit sonographisch und computertomographisch vergrösserten Nebennieren. Differentialdiagnostische Uberlegungen an Hand zweier Fälle von tuberkulöser Adrenalitis.

One of the major causes of chronic adrenal insufficiency (Addison's disease) is tuberculous adrenalopathy. Since sonography and computed tomography have become generally available in recent years and are of potential help in the diagnosis of this disease the merits of these methods are discussed in the light of 2 cases of adrenal tuberculosis, followed by a review of the literature. Adrenal calcification is the most significant, although not specific sign of adrenal insufficiency due to tuberculosis. Computed tomography has proven to be the method of choice in the non-invasive diagnosis of tuberculous adrenalopathy and in the monitoring of tuberculostatic treatment in this disease. Sonography is helpful as a preliminary investigation.

The risk of polyomavirus-associated graft nephropathy is increased by a combined suppression of CD8 and CD4 cell-dependent immune effects.

Polyomavirus-associated graft nephropathy (PAN) has emerged as a significant risk factor for kidney graft loss. We analyzed intracellular cytokine responses for possible protective versus permissive immunologic effects on BK-virus replication. One hundred five renal transplant patients included in a prospective single-center study were randomized to receive cyclosporine mycophenolate mofetil (MMF) (CM: n = 31), tacrolimus (Tac)/MMF (TM: n = 32) or Tac/MMF with conversion to everolimus (TErl; n = 32). Ten patients were not randomized (NR) due to contraindications to MMF. The immunosuppressive therapy was monitored pre- and posttransplantation at 4, 12, and 24 months using triple fluorescence flow cytometry for intracellular interleukin (Il)-2 Il-4 and interferon (IFN)-γ production in phorbol myristate acetate- and lipopolysaccharide- stimulated lymphocyte cultures. BK viremia screening was performed by reverse-transcriptase polymerase chain reaction testing on days 0, 14, 30, 60, 90, 120, 180, 270, 360, and 720. Seven of 105 (6.7%) patients developed biopsy-proven PAN (CM: n = 1, TM: n = 3, TErl: n = 2, NR: n = 1), among whom 4 lost their grafts (TM: n = 1, TErl: n = 2, NR: n = 1). Twenty-one of 105 (20.0%) patients had documented BK viremia. BK viremia which preceded PAN in all cases, was significantly associated with TM immunosuppression: 4/31 (12.9%) CM: 11/32 (34.4%) TM; 5/32 (15.6%) TErl, and 1/10 (10.0%) NR patients (P = .034). BK-viremic patients showed significantly diminished CD8(+) T-cell Il-2 production at 120 days (P = .011) and 1 year posttransplantation (P = .014) compared with non-BK-viremic patients. Patients with PAN displayed significantly lower CD4(+) T-cell Il-4 responses at 1 and 2 years after transplantation (1 year: P = .007; 2 years: P = .001) with diminished IFN-γ responses at 1 year after transplantation (P = .011). Our analysis showed the incidence of BK viremia to be increased among patients with defective cytotoxic CD8(+) T-cell -dependent immune reactivity. Recipients who progressed from BK viremia to overt PAN showed an additional immunologic defect in CD4(+) T-cell function. Patients on a Tac- plus MMF-based immunosuppression were at higher risk to develop BK viremia.

Deregulated expression of TANK in glioblastomas triggers pro-tumorigenic ERK1/2 and AKT signaling pathways.

Signal transmission by the noncanonical IkappaB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IKKɛ, requires interaction with adapter proteins such as TRAF associated NF-κB activator (TANK). Although increased expression or dysregulation of both kinases has been described for a variety of human cancers, this study shows that deregulated expression of the TANK protein is frequently occurring in glioblastomas (GBMs). The functional relevance of TANK was analyzed in a panel of GBM-derived cell lines and revealed that knockdown of TANK arrests cells in the S-phase and prohibits tumor cell migration. Deregulated TANK expression affects several signaling pathways controlling cell proliferation and the inflammatory response. Interference with stoichiometrically assembled signaling complexes by overexpression or silencing of TANK prevented constitutive interferon-regulatory factor 3 (IRF3) phosphorylation. Knockdown of TANK frequently prevents constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). TANK-mediated ERK1/2 activation is independent from the canonical MAP kinase or ERK kinase (MEK) 1/2-mediated pathway and utilizes an alternative pathway that uses a TBK1/IKKɛ/Akt signaling axis, thus identifying a novel pathway suitable to block constitutive ERK1/2 activity.