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Supplementary Figure 1, Tables 1-7 from ADAM17 Regulates Epidermal Growth Factor Receptor Expression through the Activation of Notch1 in Non–Small Cell Lung Cancer

Density functional theory calculations using well-established semilocal and hybrid functionals are typically accurate for structural properties of semiconductors, but they often fail to quantitatively describe electronic-structure and optical properties of these materials. An improvement to conventional hybrid functionals is the class of screened range-separated hybrid (SRSH) functionals. In the SRSH approach, the range-separation parameter is used to empirically fit the band gap of the semiconductor, which was shown to lead to highly accurate predictions of electronic-structure and optical properties. Here we assess the accuracy of the SRSH approach for computing other important bulk properties of seven prototypical semiconductors, including lattice constants and phonon dispersion relations. Our SRSH results are compared to data from semilocal (PBE) and hybrid (HSE) functional calculations as well as to experimental data from the literature. We find that SRSH can compete with the high accuracy provided by the two well-established functionals PBE and HSE for computing bulk properties of semiconductors. Furthermore, similarly to the case of the HSE functional, the SRSH method yields phonon dispersion relations of semiconductors that tend to be more accurate than those calculated with PBE. The SRSH approach thus provides a consistently accurate framework for calculations of semiconductor bulk properties.

Melanotic schwannoma (MS) is a rare nerve sheath tumor with fewer than 200 cases reported. MS has uncertain malignant potential and comprises 1% of all nerve sheath tumors with a predilection for the spinal nerve roots. An even rarer location for this tumor is the vagina. Up to 55% of MSs that contain psammoma bodies are associated with the Carney complex, an autosomal dominant syndrome. Criteria for malignancy in MS are still not well established and long term follow-up of patients is recommended. A 26-year-old woman presented with a bleeding vaginal tumor which was diagnosed as MS following excision. The clinical, histopathological, and immunohistochemical features of this tumor are discussed.

Ionizers are often used to limit the charging of insulators in an EPA. Unfortunately, a simple table top characterization with a charged plate monitor is not sufficient to guarantee safe performance when mounted inside a production machine. In this contribution we present a novel alternative by directly measuring the discharge current of an ionizer.

For objects with different sizes, distances and orientations to an electric field, potentials, charging, and discharge currents of the objects are measured in order to assess the ESD risk due to the E-field. The current rules in ANSI/ESD S20.20 and IEC 61340-5-1 might need an update to cover worst-case scenarios.

Aims: Currently pulmonary carcinoids are separated into typical and atypical based on mitotic count and presence of necrosis, according to the World Health Organization. At variance with gastroenteropancreatic neuroendocrine tumours, which are graded based on mitotic count and Ki-67 proliferative index, the use of Ki-67 for grading pulmonary carcinoids is still under debate. Methods and results: In this study we evaluated the prognostic impact of Ki-67 assessment in a multicentre cohort of 201 carcinoids [147 typical carcinoids (TCs) and 54 atypical carcinoids (ACs)] using manual analysis (2000 cells counted) and digital image analysis (in-house Leica Qwin program; ≥4500 cells counted). The Ki-67 proliferative index was correlated with overall survival by means of univariate analysis and in comparison to clinical data by means of multivariable analysis. The Ki-67 index was significantly higher in ACs than in TCs for both counting methods (P ≤ 2.7e−5). In addition, using cut-offs of 2.5% and 4% (manual counting) or 1% and 5% (digital analysis), the highest differences in overall survival were observed (P ≤ 0.0067). Nevertheless, histopathological classification into TCs and ACs showed an equally strong association with disease outcome, although Ki-67 had some additive value within TCs. Ki-67 index was not an independent predictor of survival in multivariable analysis. Conclusions: Our study demonstrates that, although Ki-67 is a strong prognostic factor for pulmonary carcinoids, its usefulness in addition to histopathology in prediction of prognosis is limited. None the less, it may have additional value, especially in cases that are difficult to classify, in combination with histopathology and other molecular markers.

The introduction of the CDM Joint Standard has an impact on the electrical properties of the tester hardware due to updated waveform requirements. Models of different CDM discharge heads are generated using measurement data in frequency domain. Discharge currents of a device are simulated according to the different standards in time domain. In comparison to the popular but replaced JEDEC standard peak current levels have increased.

An investigation was carried out on the charging voltage of deionized (DI) water during wafer cleaning at wafer sawing process, since it was supposed to be the root cause for EOS damages during semiconductor production. The charging voltage was measured using a non-contact electrostatic field meter. It was found that the positioning of the water filter influenced the amount of charging voltage of DI water.

The ductus arteriosus (DA) is a fetal shunt vessel between the pulmonary artery and the aorta that closes promptly after birth. Failure of postnatal DA closure is a major cause of morbidity and mortality particularly in preterm neonates. The events leading to DA closure are incompletely understood. Here we show that platelets have an essential role in DA closure. Using intravital microscopy of neonatal mice, we observed that platelets are recruited to the luminal aspect of the DA during closure. DA closure is impaired in neonates with malfunctioning platelet adhesion or aggregation or with defective platelet biogenesis. Defective DA closure resulted in a left-to-right shunt with increased pulmonary perfusion, pulmonary vascular remodeling and right ventricular hypertrophy. Our findings indicate that platelets are crucial for DA closure by promoting thrombotic sealing of the constricted DA and by supporting luminal remodeling. A retrospective clinical study revealed that thrombocytopenia is an independent predictor for failure of DA closure in preterm human newborns, indicating that platelets are likely to contribute to DA closure in humans.

Arterial aneurysms are very rare in children, and aneurysms with an idiopathic etiology have been reported in only a few cases. In most cases, aneurysms are caused by infection, arteritides, collagen vascular disease, vascular malformations, or trauma. We report the case of an 11-year-old girl with an idiopathic and symptomatic left common iliac artery aneurysm. The aneurysm was resected and replaced by a reversed femoral vein. Because the external iliac artery was atrophied, an additional bypass with a reversed great saphenous vein was made. In the postoperative work-up, no etiologic cause could be found for the development of the aneurysm. The symptoms immediately subsided after the operation.

Self-assembled semiconductor quan-tum dots (QDs) exhibit the remarkable spectral feature of optical resonance linewidths (1 3µeV)- far below the thermal energy (362µeV at 42K). [1]. The small linewidth corresponds to the long coherence time of the exciton in the quantum dot of up to a1ns [2]. The strong confinement of the excitons in the QD and the resulting large intraband level spacing of several meVs [3–5] suppress the interac-tion of the electronic states in the QD with the solid crystal lattice of the host material. This remarkable feature shows a close resemblance between atom and QD optics. Many of the proposed applications of QDs in the fields of quantum communication and quantum information processing are based on these atom like optical properties. However, de-spite the importance of dephasing mechanisms for the ap-plication of solid state quantum systems in novel quantum-electronic devices, there is still no consistent microscopic picture of their temperature dependence. The optical spectra of strongly confined electronic sys-tems (QDs or molecules) are expected to show two spectral features. The so called zero-phonon line (ZPL) is tempera-ture broadened due to acoustic phonon scattering, with a certain threshold or activation energy which corresponds to a phonon mediated excitation of the electron or hole into an excited state. These mechanisms correspond to pure dephasing and hence to a lorentzian lineshape of the reso-nance. Apart from the ZPL, there are phonon sidebands which correspond to a mixing of the excitonic states with phonon modes: the absorption or emission of a photon in the QD leading to creation or recombination of an exciton involves the emission or absorption of acoustic phonons. In molecular spectroscopy, this is known as the Frank–Condon principle. In QD spectroscopy the ZPL and phonon sidebands have been observed in non-linear spectroscopy (four-wave-mixing) on an ensemble of InGaAs dots [2]. However, only at temperatures above 50 K the phonon sidebands contributed significantly to the spectra [2]. In PL experi-ments, the observation of phonon sidebands was reported on single CdTe QDs [6] which exhibit a stronger coupling to phonons than III–V semiconductors. In PL spectroscopy on single InGaAs QDs however, only a linear increase of the linewidth of the ZPL was reported without any signifi-cant phonon sidebands [7–10]. This can most probably be

Rho GTPases are a family of major regulators of E-cadherin-mediated cell adhesion that are implicated in the carcinogenic process by deregulated expression of the family members itself or of upstream modulators or downstream effectors. Combined investigation of the Rho GTPase Rac1, the effector protein IQGAP1 and the activator Tiam1 in relation to expression or mutation of E-cadherin in gastric adenocarcinomas has not been reported. The aim of the study was to determine the expression and prognostic significance of Rac1, IQGAP1, Tiam1 and E-cadherin in gastric adenocarcinomas. Gastric carcinomas of 76 patients were investigated immunohistochemically in a tissue microarray study for expression of Rac1, IQGAP1, Tiam1 and E-cadherin. Correlations with clinical and follow-up data were examined. Moderate or strong reactivity for Rac1 was observed in 46% and for Tiam1 in 56% of tumors. Expression of IQGAP1 was present in 59% and of E-cadherin in 87% of tumors. While Rac1 and E-cadherin expression were not related to prognosis, a trend was observed between a lack of IQGAP1 expression (log-rank 0.088) as well as presence of Tiam1 (log-rank 0.097) and favorable prognosis in Kaplan-Meier survival analysis. Expression of Rac1 was positively linked to IQGAP1 expression (P=0.007, r=0.343) and tended to be inversely associated with expression of E-cadherin (P=0.055, r=-0.245). In conclusion, we observed deregulated expression of Rac1, IQGAP1, Tiam1 and E-cadherin in gastric cancer. We present evidence that either upregulation (for Rac1 and IQGAP1) or downregulation (for Tiam1 and E-cadherin) occurs. Rac1 and E-cadherin expression were not related to prognosis, while trends pointing to favorable prognosis of patients with Tiam1 expression and a lack of IQGAP1 expression were observed. These results indicate that the investigated regulators of E-cadherin-mediated cell adhesion play a role in gastric carcinogenesis.

Platelet adhesion to the atherosclerotic vascular wall induces thrombosis and boosters vascular inflammation and atheroprogression. In the present study we studied the binding of the platelet collagen receptor glycoprotein (GP) VI to human atherosclerotic plaques (AP) and the role of GPVI-mediated platelet adhesion for atheroprogression. Soluble GPVI-Fc fusion protein bound to immobilized collagen type I, collagen type III, and predominantly to the core region of human carotid atheromatous plaques. The pattern of GPVI-Fc binding was similar to the immunostaining pattern of collagen type III and differed from the immunostaining of collagen type I, which was more intense in the cap than in the core. Plaque-induced platelet aggregation in stirred blood and platelet adhesion/aggregate formation under flow were inhibited by the anti-GPVI monoclonal antibody 5C4 or by pretreatment of plaques with anti-collagen type I and anti-collagen type III antibody, or GPVI-Fc. However, there was no correlation between GPVI-Fc binding and platelet aggregating activity of individual plaques. GPVI bound also to atherosclerotic arteries of ApoE-deficient mice in vivo as assessed by small animal positron emission tomography (PET). Prolonged administration of soluble GPVI attenuated atheroprogression in ApoE-deficient mice. In humans, GPVI binding to collagenous type I and type III structures of the plaque core region mediates plaque-induced platelet adhesion and aggregation, but GPVI binding is not the sole platelet-activating determinant of plaques. In mice, GPVI-mediated platelet adhesion to the atherosclerotic vascular wall is involved in atheroprogression in vivo. Taken together, our data suggests that GPVI is a relevant target to prevent atherothrombotic events and atheroprogression.

The hypoxia-inducible factor-1 alpha (HIF-1 alpha) activates angiogenesis in response to cellular hypoxia, suggesting a spatial correlation between angiogenesis and tissue hypoxia. Methods: Using digital autoradiography of coinjected F-18-labeled azomycin arabinoside (F-8-FAZA) (assessing regional hypoxia) and a glycosylated RGD-containing peptide (I-125-3-iodo-DTyr(4)-cyclo(-Arg-Gly-Asp-DTyr-Lys(SAA)-), or I-125-Gluco-RGD) (assessing angiogenesis via binding to alpha v beta 3 integrin receptors on endothelial cells) performed on 22 EMT6 tumor xenografts, we investigated the intratumoral spatial distribution of these tracers. We applied a Bayesian bivariate image analysis using the mean tumor-to-muscle ratio as a discriminator, resulting in 4 groups: FAZA high/RGD high (Q1), FAZA low/RGD high (Q2), FAZA low/RGD low (Q3), and FAZA high/RGD low (Q4). In an additional 18 xenografts, the immunohistochemically derived HIF-1 alpha protein distribution was compared with F-18-FAZA autoradiography. Animals were divided into groups breathing either room air or carbogen (95% oxygen, 5% CO2) for 4 In until sacrifice. Results: Under room air conditions, roughly 60% of the tumor surface displayed a spatial coupling of F-18-FAZA and I-125-Gluco-RGD uptake: either high (Q1) or low (Q3) uptake for both tracers, with Q1 indicating spatial association of hypoxia and angiogenesis and Q3 indicating adequate oxygenation without active angiogenesis. However, the remaining approximately 40% of the tumor surface showed discordant F-18-FAZA and I-125-Gluco-RGD uptake, indicating that hypoxia and angiogenesis are not necessarily spatially linked to each other and highlighting substantial intratumoral heterogeneity of the F-18-FAZA and I-125-Gluco-RGD uptake. Although carbogen breathing conditions significantly decreased the mean F-18-FAZA tumor-to-muscle ratio, no significant changes were observed for I-125 -Gluco-RGD, indicating that an acute increase in tumor oxygenation did not influence alpha v beta 3 integrin receptor expression. The HIF-1 alpha-positive (HIFpos tumor cell fraction was not significantly influenced by breathing conditions and covered between 0% and 35% of the total tumor section surface. However, the HIFpos tumor section surface was much smaller than the tumor section surface of increased F-18-FAZA uptake, suggesting that both markers are identifying distinctly different biologic processes associated with hypoxia. Conclusion: The study revealed a substantial spatial discordance of the F-18-FAZA and I-125-Gluco-RGD tumor distribution suggesting that hypoxia and angiogenesis are not necessarily spatially linked in malignancies. These results may prove essential in developing advanced targeted systemic chemotherapeutic approaches (such as combinations of hypoxia-activated cytotoxins and antiangiogenic drugs) for hypoxic tumors.

Aims Neointima formation after vascular injury is strongly associated with inflammation. Rapamycin inhibits human neointima formation and reduces expression of the proinflammatory cytokine endothelial-monocyte activating peptide II (EMAP-II) in vitro . Here we investigated the interplay between EMAP-II and rapamycin after vascular injury in vivo . Methods and results In a mouse model of vascular injury, mice were either not treated, given everolimus, a rapamycin derivate, or subjected to simultaneous challenge with everolimus and EMAP-II. EMAP-II expression was measured in coronary artery smooth muscle cells (CASMC) and monocytic cells in vitro and in patients after percutaneous coronary intervention (PCI). After vascular injury, rapamycin reduced neointima formation and adventitial thickening. Immunohistochemistry revealed reduced EMAP-II protein expression and suppressed recruitment of inflammatory cells. Simultaneous challenge with EMAP-II counteracted these effects of rapamycin. Expression of EMAP-II and its inhibition by rapamycin was confirmed in CASMC and monocytic cells. In patients, EMAP-II upregulation was confined to PCI of distal coronary artery segments and profoundly suppressed by oral rapamycin treatment. Conclusion These data suggest important yet unrecognized roles of EMAP-II and adventitial inflammation in neointima formation: Through inhibition of EMAP-II, rapamycin reduces the recruitment of inflammatory cells to the adventitia and supports an early and bland healing.

Recently, a technique has been developed for performing laser spectroscopy on single self-assembled quantum dots. A summary is presented here of spectroscopy results concerning the charge- and magnetic-field dependent energies and selection rules of the fundamental exciton. In addition, it is also shown how the resonant interaction of a laser with a singly-charged dot can be exploited to pump the electron into one of the spin states. This involves applying a small magnetic field and an appropriate bias in order to suppress spin relaxation through the hyperfine interaction and through co-tunneling processes, respectively.

Objective— The serine protease MT-SP1/matriptase plays an important role in cell migration and matrix degradation. Hepatocyte growth factor (HGF), urokinase-type plasminogen activator (uPA), and protease-activated receptor 2 (PAR-2) have been identified as in vitro substrates of MT-SP1/matriptase. Because PAR-2 is expressed in endothelial cells and contributes to inflammatory processes, we sought to investigate the effects of MT-SP1/matriptase on endothelial cytokine expression and analyzed MT-SP1/matriptase expression in vascular cells and atherosclerotic lesions. Methods and Results— In endothelial cells, recombinant MT-SP1/matriptase dose-dependently induced interleukin (IL)-8 and IL-6 mRNA and protein expression dependent on its proteolytic activity. MT-SP1/matriptase time-dependently induced phosphorylation of p38 MAPK and p42/44 MAPK. Inhibitor experiments revealed that p38 MAPK and PKCα were necessary for IL-8 induction. PAR-2 downregulation abolished and PAR-2 overexpression augmented MT-SP1/matriptase-induced IL-8 expression as evidence for PAR-2 signaling. In human atherectomies, MT-SP1/matriptase was expressed in blood cells adherent to the endothelium. Concordantly, basal MT-SP1/matriptase expression was detected in isolated monocytes. Coincubation of monocytes and endothelial cells resulted in an increased IL-8 release, which was reduced after downregulation of endothelial PAR-2 and monocytic MT-SP1/matriptase. Conclusion— MT-SP1/matriptase induces release of proinflammatory cytokines in endothelial cells through activation of PAR-2. MT-SP1/matriptase is expressed in monocytes, thus, interaction of monocytic MT-SP1/matriptase with endothelial PAR-2 may contribute to atherosclerosis.

Objective— The chemokine fractalkine activates platelets and induces leukocyte adhesion to the endothelium. Expression of fractalkine and its receptor, CX 3 CR1, is elevated in coronary artery disease. We assessed the effects of fractalkine on vascular function in isolated rat aorta. Methods and Results— CX 3 CR1 expression was demonstrated in rat aortic endothelial and smooth muscle cells by immunohistochemistry, Western blot, and polymerase chain reaction (PCR). Fractalkine (up to 1 μg/mL) did not directly induce contractile or relaxant responses when applied to rat aortic rings in organ baths. Short-term incubation with fractalkine (1 μg/mL) for 5 minutes did not affect vascular reactivity. Pretreatment of isolated rat aortic rings with fractalkine for 2 hours impaired acetylcholine-induced nitric oxide (NO)-mediated relaxation after preconstriction with phenylephrine in a concentration-dependent manner. The concentration response to the NO donor DEA-NONOate was significantly shifted to the right. The radical scavenger tiron normalized the attenuated acetylcholine-induced relaxation after fractalkine incubation. Aortic superoxide formation was enhanced by fractalkine, which was inhibited by diphenyleneiodonium but not by inhibitors of xanthine oxidase or NO synthase. Conclusion— In addition to its role as a chemokine and adhesion molecule, fractalkine induces vascular dysfunction by stimulating vascular reactive oxygen species resulting in reduced NO bioavailability.

Charged Device Model (CDM) like stress represents the highest ESD risk during handling of single devices. Today air discharge compromises repeatability of CDM tests of products in a package. The paper demonstrates that the repeatable Capacitive Coupled TLP (CC-TLP) reproduces CDM failure signatures at both package and wafer level. Data will be shown to compare the stress failing level and the failure locations on the chip.

To prospectively compare high-spatial-resolution T1-weighted, T2-weighted, and intermediate-weighted spectral fat-saturated magnetic resonance (MR) imaging for the differentiation of tumor from fibrosis and for delineation of rectal wall layers in rectal cancer specimens.The local ethics committee approved the protocol, and written informed consent was obtained from each patient. Thin-section high-spatial-resolution MR imaging was performed in specimens obtained from 23 patients (16 men, seven women; median age, 64 years; age range, 39-84 years) immediately after resection. Seven patients underwent neoadjuvant treatment. T1-weighted spin-echo, T2-weighted fast spin-echo, and intermediate-weighted spectral fat-saturated MR images were obtained in the transverse plane. Differences in signal intensity between tumor and fibrosis and between tumor and rectal wall layers were evaluated by using visual scoring and measurements of T2 relaxation time. Statistical differences were evaluated by using the Wilcoxon signed rank test and a mixed-model regression analysis. All images were compared with whole-mount histopathologic slices (n = 86).T2-weighted MR images provided the best differentiation between tumor and fibrosis (P.001). Mean visual signal intensity scores were -1.8 for T2-weighted MR images, -1.4 for intermediate-weighted spectral fat-saturated MR images, and -0.2 for T1-weighted MR images. T2 relaxation times were 97 msec +/- 4.6 for tumor and 70 msec +/- 3.8 for fibrosis (P.001). Substantial overlap was noted between the tumor and the circular layer of the muscularis propria (97 msec +/- 2.1), and less overlap was noted between the tumor and the longitudinal layer of the muscularis propria (88 msec +/- 1.6).T2-weighted MR imaging provides superior delineation of rectal wall layers and better differentiation of tumor from fibrosis in rectal cancer specimens compared with T1-weighted MR imaging and intermediate-weighted spectral fat-saturated MR imaging by using thin-section high-spatial-resolution sequences.

We report electron and hole tunnelling phenomena in a single self-assembled quantum dot as a function of the applied electric field. We use absorption spectroscopy which allows us to measure excitonic transitions under conditions where optical recombination cannot be observed due to the high, ionizing, electric field.

Background—Enteroviridae such as coxsackievirus B3 (CVB3) are important infectious agents involved in viral heart disease, hepatitis, and pancreatitis, but no specific antiviral therapy is available.Methods and Results—The aim of the present study was to evaluate the impact of RNA interference on viral replication, cytopathogenicity, and survival. Small interfering RNA (siRNA) molecules were designed against the viral 2A region (siRNA-2A), which is considered to be highly conserved and essential for both virus maturation and host cytopathogenicity. siRNA-2A exhibited a significant protective effect on cell viability mediated by marked inhibition of CVB3 gene expression and viral replication. In highly susceptible type I interferon receptor–knockout mice, siRNA-2A led to significant reduction of viral tissue titers, attenuated tissue damage, and prolonged survival. Repeated siRNA-2A transfection was associated with a further improvement of survival. Various control siRNA molecules had no protective effect in vitro or in vivo.Conclusions—RNA interference directed against the 2A protease encoding genomic region effectively confers intracellular immunity toward CVB3-mediated cell injury and improves survival, suggesting a potential role for RNA interference for future treatment options targeting enteroviral diseases.

The ground state of neutral and negatively charged excitons confined to a single self-assembled InGaAs quantum dot is probed in a direct absorption experiment by high resolution laser spectroscopy. We show how the anisotropic electron-hole exchange interaction depends on the exciton charge and demonstrate how the interaction can be switched on and off with a small dc voltage. Furthermore, we report polarization sensitive analysis of the excitonic interband transition in a single quantum dot as a function of charge with and without magnetic field., Comment: Conference Proceedings, Physics and Applications of Spin-Related Phenomena in Semiconductors, Santa Barbara (CA), 2004. 4 pages, 4 figures; content as published

Emery-Dreifuss muscular dystrophy (EDMD) is a common form of muscular dystrophy frequently involving cardiac muscle, thus leading to dilated cardiomyopathy. Clinical outcome and prognosis is frequently determined by the involvement of the cardiac conduction system causing symptomatic bradyarrhythmias, as well as tachyarrhythmias and, if untreated, frequent sudden cardiac death. Typical features of the cardiac involvement of EDMD are presented, caused by a novel missense mutation in the splice receptor sequence of intron 6 of the LMNA gene on chromosome 1, encoding for the lamin A/C gene, consistent with the autosomal dominant form of EDMD.

ObjectivesThe goal of this study was to evaluate the feasibility of [18F]Galacto-RGD positron emission tomography (PET)/computed tomography (CT) imaging of αvβ3 expression in human carotid plaques.BackgroundThe integrin αvβ3 is expressed by macrophages and angiogenic endothelial cells in atherosclerotic lesions and thus is a marker of plaque inflammation and, potentially, of plaque vulnerability. [18F]Galacto-RGD is a PET tracer binding specifically to αvβ3. Therefore, [18F]Galacto-RGD PET/CT imaging of αvβ3 expression in human carotid plaques might provide a novel noninvasive biomarker of plaque vulnerability.Methods[18F]Galacto-RGD PET/CT imaging was performed in 10 patients with high-grade carotid artery stenosis scheduled for carotid endarterectomy. Tracer uptake was measured in the stenotic areas of the carotid arteries, as well as on the contralateral side, and was corrected for blood pool activity, measured in the distal common carotid artery (target-to-background [TB] ratio). TB ratio was correlated with immunohistochemistry of αvβ3 expression (LM609), macrophage density (CD68), and microvessel density (CD31) of the surgical specimen. In addition, ex vivo autoradiography of the surgical specimen with [18F]Galacto-RGD and competition experiments with an unlabeled αvβ3-specific RGD peptide were performed.Results[18F]Galacto-RGD PET/CT showed significantly higher TB ratios in stenotic areas compared with nonstenotic areas (p = 0.01). TB ratios correlated significantly with αvβ3 expression (R = 0.787, p = 0.026) and intensity of ex vivo autoradiography (R = 0.733, p = 0.038). Binding to atherosclerotic plaques was efficiently blocked in ex vivo competition experiments. A weak-to-moderate correlation was found with macrophage density (R = 0.367, p = 0.299) and microvessel density (R = 0.479, p = 0.176), which did not reach statistical significance.Conclusions[18F]Galacto-RGD PET/CT shows specific tracer accumulation in human atherosclerotic carotid plaques, which correlates with αvβ3 expression. Based on these initial data, larger prospective studies are now warranted to evaluate the potential of molecular imaging of αvβ3 expression for assessment of plaque inflammation in patients.

Background: Due to rising cure rates in cancer, the question of preserving fertility in young female patients becomes more important. Especially in lymphomas, incidence and long-time survival have increased. Hematologists and gynecologists have to treat more and more female patients who wish to become pregnant despite their disease and/or after finishing treatment. Case Report: We report on a 28-year-old patient with highly malignant non-Hodgkins lymphoma (peripheral T cell lymphoma, Ann Arbor stage IV) and main manifestation at the gastric antrum, with a distinct wish for becoming pregnant. Chemotherapy was strongly recommended to her, but she refused. After she had conceived, the disease recurred, followed by stillbirth in week 19 of gestation and death due to gastric perforation and septic shock. Conclusions: Facing the risk of sterility after chemotherapy should not induce patients to refuse chemotherapy and risk their lives. Treatment of young female cancer patients should therefore always include a thorough discussion about other ways of preserving fertility for the time after treatment. Such strategies exist, although their success is still limited and not every patient is eligible for them.

The fine structure splitting of neutral excitons in InGaAs quantum dots is investigated using polarization sensitive photoluminescence. The QDs were grown with an in situ annealing step to shift the emission wavelength to ∼ 950 nm . Statistics of the fine structure reveal a large spread in magnitude and little preferential orientation of the polarization axis. We speculate that these findings are due to the redistribution of QD material during the annealing step.

We performed high resolution resonant laser spectroscopy on a single self-assembled quantum dot (QD) at liquid He temperatures. We explore the two-level nature of the QD excitonic transition through the investigation of its behavior as a function of the laser power. The quantum ground state exciton absorption peak size diminishes with increasing power while its width increases. Fitting these dependencies to the predictions of a two-level atom model we extract unambiguously a radiative lifetime of 660 ps, a residual collisional broadening about 0.18 μ eV as well as the spectral fluctuation 1.3 μ eV . We find that at high power the line width of the exciton absorption is essentially given by the Rabi frequency.

We show that a piezoelectric actuator can be used to apply uniaxial stress to a layer of self-assembled quantum dots. The applied stress leads to a change of the quantum dot's ground state exciton energy by up to a few hundred μeV. This approach allows the possibility of an in situ and continuous tuning of the stress at temperatures down to 4 K and offers an alternative to tuning by temperature and Stark effect. We measure the relative change in the charging energy to the n-doped back contact by capacitance and the change in the exciton energy by photoluminescence. By tuning the uniaxial stress we are able to perform reflection spectroscopy on a single dot.

Epidermal growth factor receptor (EGFR) overexpression and activation are hallmarks of non–small cell lung carcinoma (NSCLC). Although EGFR-targeted therapies are used, the prognosis of NSCLC remains poor. ADAM17 induces activation of the EGFR through ligand cleavage. However, we show that inhibition or knockdown of ADAM17 markedly reduces tumorigenesis and survival to a large part independently from EGFR ligand shedding in NSCLC cells. These findings strongly indicate additional oncogenic mechanisms regulated by ADAM17. We identified Notch1 signaling as an ADAM17-controlled pathway and a critical regulator of anchorage-independent growth by using both Notch1 shRNA and ectopic expression of the active intracellular Notch1 fragment. Strikingly, Notch1 knockdown led to a strong reduction of EGFR expression in all analyzed cell lines. Proliferation, survival, and colony formation of Notch1-deficient cells were insensitive to EGF stimulation. Moreover, targeting Notch1 or ADAM17 resulted in substantial cell death, whereas EGFR inhibition predominantly induced cell cycle arrest. Immunohistochemical analysis of primary human tissue revealed a significant correlation between ADAM17, Notch1 signaling, and high EGFR expression levels. In conclusion, this article describes a novel molecular circuitry in NSCLC, incorporating ADAM17 as a regulator of EGFR expression through the activation of Notch1. Due to their central role in tumorigenesis and survival of NSCLC cells, both ADAM17 and Notch1 constitute promising targets for the treatment of NSCLC. Cancer Res; 70(13); 5368–78. ©2010 AACR.

Introduction Sex reassignment surgery (SRS) can be considered a reasonable and secure treatment for transsexualism, today. Because the population of patients who have received SRS is growing steadily, it can be expected that the number of patients who present with diseases specific to their original gender will increase as well. Aim In female-to-male transsexuals, vaginal cancer has not been reported so far. This article reports, to our knowledge, the first case of a female-to-male transsexual who developed vaginal cancer. Methods Eighteen years after receiving female-to-male SRS, the patient presented with vaginal cancer, which infiltrated rectum and bladder and also showed involvement of inguinal lymph nodes. Surgery consisted of an anterior and posterior pelvic demolition and extended lymphadenectomy with preservation of the penoid and reconstruction of the pelvic defect with multiple flaps. Results The tumor was removed completely (R0), and 2 years after surgery, the patient has no signs or symptoms of tumor recurrence and enjoys good quality of life. Conclusions In SRS patients, diseases of their original gender should always be considered and patients should be encouraged to participate in screening programs. When choosing the surgical approach for SRS, the risks for developing cancer from remaining structures of the genetic gender should be considered. Of course, removal of e.g., ovaries, cervix and vagina, will prevent cancer of these structures. When it comes to surgery in SRS patients with malignancies, an interdisciplinary approach should be chosen. Schenck TL, Holzbach T, Zantl N, Schuhmacher C, Vogel M, Seidl S, Machens H-G, and Giunta RE. Vaginal carcinoma in a female to male transsexual.

There is a need for in vivo monitoring of cell engraftment and survival after cardiac cell transplantation therapy. This study assessed the feasibility and usefulness of combined PET and MRI for monitoring cell engraftment and survival after cell transplantation. Methods: Human endothelial progenitor cells (HEPCs), derived from CD34+ mononuclear cells of umbilical cord blood, were retrovirally transduced with the sodium iodide symporter (NIS) gene for reporter gene imaging by 124I-PET and labeled with iron oxides for visualization by MRI. Imaging and histologic analysis were performed on 3 groups of nude rats on days 1, 3, and 7 after intramyocardial injection of 4 million HEPCs. Results: In vitro studies demonstrated stable expression of functional NIS protein and normal viability of HEPCs after transduction. On day 1, after intramyocardial transplantation, iron- and NIS-labeled HEPCs were visualized successfully on MRI as a regional signal void in the healthy myocardium and on PET as 124I accumulation. The 124I uptake decreased on day 3 and was undetectable on day 7, and the MRI signal remained unchanged throughout the follow-up period. Histologic analysis with CD31 and CD68 antibodies confirmed the presence of either labeled or nonlabeled control transplanted HEPCs at the site of injection on day 1 but not on day 7, when only iron-loaded macrophages were seen. Furthermore, deoxyuride-5′-triphosphate biotin nick end labeling showed extensive apoptosis at the site of transplantation. Conclusion: The combination of MRI and PET allows imaging of localization and survival of transplanted HEPCs together with morphologic information about the heart. Although iron labeling rapidly loses specificity for cell viability because of phagocytosis of iron particles released from dead cells, reporter gene expression provided specific information on the number of surviving cells. This multimodality approach allows complementary analysis of cell localization and viability.

There is growing evidence that STW 5 (Iberogast), fixed combination of hydroethanolic herbal extracts), besides being effective in functional dyspepsia, also improves symptoms in irritable bowel syndrome (IBS). Clinical data indicate that modulation of mucosal secretion is a promising approach to treat intestinal disorders associated with IBS. We therefore explored the effect of STW 5 on secretion in the human intestine and the mechanisms by which it acts. The Ussing chamber technique was used to measure mucosal secretion in human intestinal mucosa/submucosa preparations and in human epithelial cell line T84. In addition, we recorded STW 5 effects on human enteric neurons with voltage sensitive dye imaging. In human tissue and T84 cells STW 5 induced a dose-dependent increase in ion secretion that was significantly reduced by the Na-K-Cl cotransporter blocker bumetanide, the adenylate cyclase inhibitor MDL-12 330, the non-specific and selective cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors glibenclamide and CFTR(inh)-172, respectively, and the blocker of calcium dependent Cl(-) channels (ClCa) SITS (4-acetamido-4-isothiocyanatostilbene-2,2-disulphonic acid). It was unaffected by amiloride, a blocker of epithelial Na(+) channels. In human tissue, the nerve blocker tetrodotoxin significantly suppressed the STW 5 response. STW 5 evoked an increased spike discharge in 51% of human submucous neurons. Results suggest that STW 5 is a secretogogue in the human intestine by direct epithelial actions and through activation of enteric neurons. The prosecretory effect is due to increased epithelial Cl(-) fluxes via CFTR and Ca-dependent ClCa channels. STW 5 may be a novel option to treat secretory disorders associated with IBS and constipation.

In clinical routine somatostatin analogue positron emission tomography/computed tomography (PET/CT) such as (68)Ga-DOTA-Tyr-octreotide (DOTATOC)-PET/CT could substitute conventional (111)In-Octreotide scintigraphy. Immunohistochemistry (IHC) for somatostatin receptor 2 (SSTR2) might be a tool to predict positivity of (68)Ga-DOTATOC in patients where initial staging was not performed, e.g., in incidental findings. We therefore compared a score of SSTR2-IHC with the in vivo standard uptake value (SUV) of preoperative or prebiopsy (68)Ga-DOTATOC PET/CT.In 18 patients, (68)Ga-DOTATOC PET/CT scans were quantified with SUV calculations and correlated to a cell membrane-based SSTR2-IHC score (ranging from 0 to 3).Negative IHC scores were consistent with SUV values below 10. Furthermore, all score 2 and 3 specimens corresponded with high SUV values (above 15).SSTR2-IHC scores correlated well with SUV values and we propose to use SSTR2 immunohistochemistry in patients missing a preoperative PET scan to indicate (68)Ga-DOTATOC-PET/CT as method for restaging and follow-up in individual patients.

Atherosclerosis, restenosis, and posttransplant graft atherosclerosis are characterized by endothelial damage, infiltration of inflammatory cells, and proliferation of smooth muscle cells. The CXCR3-activating chemokines interferon-γ inducible protein 10 (IP10) and MIG (monokine induced by interferon-γ) have been implicated in vascular repair and remodeling. The underlying molecular mechanisms, however, remain elusive. Here, we show that wire-mediated arterial injury induced local and systemic expression of IP10 and MIG, resulting in enhanced recruitment of CXCR3 + leukocytes and hematopoietic progenitor cells. This was accompanied by profound activation of mammalian target of rapamycin complex (mTORC)1, increased reactive oxygen species production, apoptosis, and intimal hyperplasia. Genetic and pharmacological inactivation of CXCR3 signaling not only suppressed recruitment of inflammatory cells but also abolished mTORC1 activation, reduced reactive oxygen species generation, and blocked apoptosis of vascular cells, resulting in significant reduction of intimal hyperplasia in vivo. In vitro, stimulation of T cells with IP10 directly activated mTORC1 and induced generation of reactive oxygen species and apoptosis in an mTORC1-dependent manner. These results strongly indicate that CXCR3-dependent activation of mTORC1 directly links stimulation of the Th1 immune system with the proliferative response of intimal cells in vascular remodeling.

Objectives: Abdominal aortic aneurysm (AAA) wall is characterized by degradation of extracellular matrix through matrix metalloproteinases (MMPs), chronic inflammatory cell infiltration and extensive neovascularization. So far, MMP expression within AAA wall in association with infiltrates and neovascularization has not yet been studied. Methods: Vessel walls of 15 AAA patients and 8 organ donors were analyzed by immunohistochemistry for expression of various MMPs (MMP-1, -2, -3, -7, -8, -9, -12 and -13) in all cells located within the AAAs and correlated with infiltrates and neovascularization. Results: Luminal endothelial cells (ECs) were positive for MMP-1, -3 and -9, ECs of mature neovessels were furthermore positive for MMP-2. Immature neovessels expressed all MMPs tested except for MMP-13. Aortic medial smooth muscle cells (SMCs) expressed MMP-1, -2, -3 and -9, SMCs of mature neovessels, only MMP-1, -3 and -9. Inflammatory infiltrates expressed all MMPs tested except for MMP-2, macrophages expressed all MMPs. Infiltrates were composed mainly of B cells (58.5 ± 10.9%) and T lymphocytes (26.3 ± 9.5%). Furthermore, significant inverse correlations were found between the amounts of inflammatory cells, neovessels and collagen/elastin content of the aortic vessel wall (r = +0.806/p < 0.001, r = –0.650/p = 0.012, r = –0.63/p < 0.015; respectively). Conclusion: Inflammatory infiltrates and invading neovessels are relevant sources of MMPs in the AAA wall and may substantially contribute to aneurysm wall instability.

Background: Recent studies suggest that endothelial progenitor cells (EPC) from bone marrow or peripheral blood improve myocardial function in experimental myocardial infarction (MI). Since applications for cell therapy are limited by the number of available cells, expansion of EPC may facilitate its therapeutic use in ischemic disease. The aim of this study was to expand late outgrowth EPC from peripheral blood from patients with acute myocardial infarction, characterize them and investigate their therapeutic effect in experimental MI. Methods and Results: Venous blood samples were obtained from patients with acute MI (n=51), stable angina (sAP, n=57) and healthy controls (H,n=47). CD34+ cells were isolated using immunomagnetic beads (Miltenyi Biotec). CD34+ cells cultured on fibronectin in endothelial cell medium formed colonies after 1–2 weeks and were further expanded for up to 3 months to generate late outgrowth EPC (eEPC). Expansion was observed up to 2.9x10′9 (MI), 11x10′9 (sAP) and 7x10′9 cells (H) with a mean culture duration of 61 days. Expanded cells showed an endothelial morphology and expressed endothelial surface markers (CD31, VEGF-R2, CD105). Intramyocardial transplantion of 1x10′6 eEPC in experimental myocardial infarction in athymic nude rats revealed improvement in echocardiographic ejection fraction after 2 weeks. This was associated with enhanced vessel density after 1 week and increased mRNA expression of HGF. No differences in infarct size were observed. Similarly in a chronic model of myocardial infarction (eEPC transplantation 1 week after MI) myocardial function significantly improved after 5 weeks in comparison to the control group. Conclusion: Expansion of eEPC from circulating CD34+ cells in patients with coronary artery disease is feasible and improves myocardial function after local transplantation in acute and chronic myocardial infarction. The large number of generated eEPC may prove benefical for therapeutic use and this advantage may prevail time-consuming expansion procedures.

We report high-resolution resonant two-color laser spectroscopy on single self-assembled InGaAs quantum dots. The negatively charged exciton in a quantum dot can decay radiatively into both electron-spin ground states, the states with an electron in the quantum dot with its spin parallel or antiparallel to an applied magnetic field. The two decay paths can be used for optical spin alignment via optical pumping. We apply two laser fields at two different colors resonant with the two Zeeman split optical transitions to study the properties of the spin of the resident electron in the quantum dot in both the Faraday and Voigt geometries. The resonant two-color signal is monitored as a function of the laser power as well as the applied magnetic and electric field allowing us to determine spin decay and dephasing rates. We find the rate at which the optical spin alignment can be performed depending on the direction and the magnitude of the applied magnetic field. Finally we demonstrate the feasibility of performing coherent all-optical spin manipulation of an electron spin in a quantum dot.

Background/Aim: True adenomas of the cardia appear to be extremely rare lesions. There are no data on the natural history and histopathological background of these lesions. We report 3 patients with true adenomas of the cardia. Methods and Results: Three patients with polypoid masses at the cardia below the Z-line were submitted to a tertiary referral center for further diagnosis and therapy. In 2 of the 3 cases Barrett’s esophagus with low-grade intraepithelial neoplasia was assumed on the basis of histopathological examination of biopsy specimens taken from the surface of the lesions. Polypectomy was performed in all 3 cases. In 2 of the 3 cases the final histopathological diagnosis of low-grade adenoma of the cardia could only be established after complete removal of the polypoid masses. Conclusions: Adenomas of the cardia can be mistaken for dysplasia arising from Barrett’s esophagus, if the diagnosis is based on endoscopic biopsies only. It is, therefore, reasonable to completely remove any suspicious lesions by endoscopy not only for therapeutic but also for diagnostic reasons.