Receptor tyrosine kinase and p16/CDKN2 expression in a case of tripe palms associated with non-small-cell lung cancer

Background: Tripe palms is a descriptive term for a cutaneous paraneoplastic keratoderma. Tripe palms are frequently associated with gastric and pulmonary carcinoma. The pathogenetic mechanism remains unknown. Objective: To determine the influence of receptor tyrosine kinases, which are both expressed in pulmonary carcinomas and in human skin, we performed expression studies on epidermal growth factor receptor (EGFR), HER2, HERS in a skin sample of tripe palms obtained from a patient with non-small-cell lung cancer with lymph node involvement. Two months after diagnosis, the patient had developed palmoplantar `tripe palms'. Additionally, the expression of SRC, c-myc and p16/CDKN2 were studied. Method: Conventional reverse-transcription polymerase chain reaction was performed on a tissue sample of tripe palms. Results: Weak expression of HER2 and of p16/CDKN2 was found. EGFR, HERS, c-myc and SRC were not expressed. Conclusion: Receptor tyrosine kinases of subclass I, the tyrosine kinase SRC and the oncogene c-myc play no major role in the pathogenesis of this case of tripe palms. Copyright (C) 2000 S. Karger AG. Basel

Stimulation beta-adrenerger Rezeptoren auf neutrophilen Granulozyten - Effekte auf Adhäsionsmoleküle, Zytokine und intrazelluläre Botenstoffe

In der vorliegenden Arbeit wurden unstimulierte und vorstimulierte neutrophile Granulozyten aus dem Blut gesunder Spender mit Adrenalin und Noradrenalin inkubiert. Auf der Ebene der Signaltransduktion adrenerger Rezeptoren wurden die intrazelluläre cAMP-Konzentration und der Kalzium-Influx nach Inkubation mit Adrenalin gemessen. Außerdem wurde die Expression der drei Adhäsionsmoleküle CD15, CD44 und CD54 (ICAM-1) sowie die Produktion der drei Zytokine IL-6, IL-8 und TNF-alpha untersucht. Auf der intrazellulären Ebene induzierte Adrenalin ein Erhöhung der Konzentration des second messenger cAMP und keine signifikante Veränderung der Konzentration freier Ca2+-Ionen. Dies könnte als Hinweis gedeutet werden, dass beta-Adrenozeptoren auf neutrophilen Granulozyten vorhanden und funktionell aktiv sind, nachgewiesene alpha-Adrenozeptoren jedoch eher von untergeordneter Bedeutung sind. Da in Neutrophilen Ca2+ als proinflammatorisch und cAMP als antiinflammatorisch gilt, sind diese beiden Ergebnisse untereinander stringent. Sie fügen sich gut in den wissenschaftlichen Kontext, in dem Adrenalin auf neutrophile Granulozyten eher einen inhibierenden als einen stimulierenden Einfluss ausübt. Nach LPS-Stimulation konnte eine Hochregulation aller untersuchten Oberflächenproteine sowie eine Neosynthese des CXC-Chemokins IL-8 festgestellt werden, letzteres mit Hilfe einer fluoreszenzimmunologischen Doppelfärbung. Die erhöhte Expression der drei untersuchten Adhäsionsmoleküle kann als proinflammatorisches Ereignis im Rahmen der Immunantwort gesehen werden, denn sie erleichtert das Übertreten von neutrophilen Granulozyten in infizierte Gewebe. Auch die Produktion von IL-8 durch Neutrophile lässt sich als proinflammatorisches Geschehen interpretieren, da IL-8 als CXC-Chemokin in der Lage ist, weitere polymorphkernige Leukozyten zu rekrutieren. In der Anfangsphase einer Immunantwort ist ein solcher positiver Feedback-Mechanismus physiologisch durchaus „sinnvoll“. Adrenalin in sehr hoher Dosis bewirkte eine leichte Stimulation der Expression von CD44. Da CD44 für den Vorgang der Phagozytose unerlässlich ist, kann dies als ein die Phagozytose stimulierender Effekt gesehen werden. Auch die Expression von CD54 ließ sich durch Adrenalin in hoher Konzentration nach 12-stündiger Inkubation stimulieren. Man könnte vermuten, dass die erhöhte Expression von CD54 durch Adrenalin den Übertritt neutrophiler Granulozyten aus der Blutbahn in das Interstitium erleichtert, und dass dies nur an Orten inflammatorischer Vorgänge relevant ist, da dort hohe Konzentrationen von Adrenalin herrschen können. Die Inkubation LPS-stimulierter neutrophiler Granulozyten führte zu einer leichten Inhibition der Expression von CD54. Dies könnte im Rahmen einer systemisch-inflammatorischen Reaktion LPS-stimulierte neutrophile Granulozyten davor bewahren zu verklumpen. Hier kann auch allgemein ein hemmender Effekt von Adrenalin auf bereits vorstimulierte Neutrophile postuliert werden, der eine überschießende Entzündungsreaktion verhindern würde. Zusammenfassend deuten die Ergebnisse darauf hin, dass beta-Adrenozeptoren auf neutrophilen Granulozyten vorhanden und funktionell aktiv sind. Es kann vermutet werden, dass das Muster der Adhäsionsmoleküle auf neutrophilen Granulozyten und damit deren Migrationsverhalten durch Adrenalin reguliert wird, und zwar abhängig vom Grad der Aktivität der Zelle. Vorstimulierte Zellen würden eher gehemmt und unstimulierte Zellen eher aktiviert. Mit diesen Ergebnissen leistet die vorliegende Arbeit einen Beitrag zum Thema der Regulation von neutrophilen Granulozyten durch LPS und Katecholamine

Quantum-limited measurements of optical signals from a geostationary satellite

The measurement of quantum signals that traveled through long distances is of fundamental and technological interest. We present quantum-limited coherent measurements of optical signals, sent from a satellite in geostationary Earth orbit to an optical ground station. We bound the excess noise that the quantum states could have acquired after having propagated 38600 km through Earth's gravitational potential as well as its turbulent atmosphere. Our results indicate that quantum communication is feasible in principle in such a scenario, highlighting the possibility of a global quantum key distribution network for secure communication.Comment: 8 pages (4 pages main article, 4 pages supplementary material), 9 figures (4 figures main article, 5 figures supplementary material), Kevin G\"unthner and Imran Khan contributed equally to this wor

Cardiovascular magnetic resonance risk stratification in patients with clinically suspected myocarditis

BACKGROUND: The diagnosis of myocarditis is challenging due to its varying clinical presentation. Since myocarditis can be associated with significant 5-year mortality, and postmortem data show myocarditis in almost 10% of all adults suffering sudden cardiac death, individual risk stratification for patients with suspected myocarditis is of great clinical interest. We sought to demonstrate that patients with clinically suspected myocarditis and a normal cardiovascular magnetic resonance (CMR) according to our definition have a good prognosis, independent of their clinical symptoms and other findings. METHODS: Prospective clinical long-term follow-up of consecutive patients undergoing CMR for work-up of clinically suspected myocarditis at our institution in 2007-2008. RESULTS: Follow-up was available for n = 405 patients (all-comers, 54.8% inpatients, 38% outpatient referrals from cardiologists). Median follow-up time was 1591 days. CMR diagnosis was “myocarditis” in 28.8%, “normal” in 55.6% and “other pathology” in 15.6%. Normal CMR was defined as normal left ventricular (LV) volumes and normal left ventricular ejection fraction (LV-EF) in the absence of late Gadolinium Enhancement (LGE). The overall mortality was 3.2%. There were seven cardiac deaths during follow-up, in addition one aborted SCD and two patients had appropriate internal cardioverter defibrillator (ICD) shocks – all of these occurred in patients with abnormal CMR. Kaplan-Meier analysis with log-rank test showed significant difference for major adverse cardiac events (cardiac death, sudden cardiac death (SCD), ICD discharge, aborted SCD) between patients with normal and abnormal CMR (p = 0.0003). CONCLUSION: In our unselected population of consecutive patients referred for CMR work-up of clinically suspected myocarditis, patients with normal CMR have a good prognosis independent of their clinical symptoms and other findings

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Medulloblastoma Exome Sequencing Uncovers Subtype-Specific Somatic Mutations

Medulloblastomas are the most common malignant brain tumors in children1. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles2–5. Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma

Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases

Amplification and overexpression of the c-myc gene have been associated with neoplastic transformation in a plethora of malignant tumours. We applied interphase fluorescence in situ hybridization (FISH) with a locus-specific probe for the c-myc gene (8q24) in combination with a corresponding chromosome 8 α-satellite probe to evaluate genetic alterations in 8 primary melanomas and 33 advanced melanomas and compared it to 12 melanocytic nevi, 7 safety margins and 2 cases of normal skin. Additionally, in metaphase spreads of 7 melanoma cell lines a whole chromosome 8 paint probe was used. We investigated the functionality of the c-myc gene by detecting c-myc RNA expression with RT-PCR and c-myc protein by immunohistochemistry. 4/8 primary melanomas and 11/33 melanoma metastases showed additional c-myc signals relative to the centromere of chromosome 8 copy number. None of the nevi, safety margins or normal skin samples demonstrated this gain. In 2/7 melanoma cell lines (C32 and WM 266–4) isochromosome 8q formation with a relative gain of c-myc copies and a loss of 8p was observed. The highest c-myc gene expression compared to GAPDH was found in melanoma metastases (17.5%). Nevi (6.6%) and primary melanomas (5.0%) expressed the c-myc gene on a lower level. 72.7% of the patients with c-myc extra copies had visceral melanoma metastases (UICC IV), patients without c-myc gain in 35.0% only. The collective with additional c-myc copies also expressed the gene on a significantly higher level. These results indicate that a c-myc gain in relation to the centromere 8 copy number might be associated with advanced cutaneous melanoma. © 2001 Cancer Research Campaign http://www.bjcancer.co