SDHB loss predicts malignancy in pheochromocytomas/sympathethic paragangliomas, but not through hypoxia signalling

Prediction of malignant behaviour of pheochromocytomas/sympathetic paragangliomas (PCCs/PGLs) is very difficult if not impossible on a histopathological basis. In a familial setting, it is well known that succinate dehydrogenase subunit B (SDHB)-associated PCC/PGL very often metastasise. Recently, absence of SDHB expression as measured through immunohistochemistry was shown to be an excellent indicator of the presence of an SDH germline mutation in PCC/PGL. SDHB loss is believed to lead to tumour formation by activation of hypoxia signals. To clarify the potential use of SDHB immunohistochemistry as a marker of malignancy in PCC/PGL and its association with classic hypoxia signalling we examined SDHB, hypoxia inducible factor-1 (Hif-1 ) and its targets CA-9 and GLUT-1 expression on protein level using immunohistochemistry on a tissue micro array on a series of familial and sporadic tumours of 115 patients. Survival data was available for 66 patients. SDHB protein expression was lost in the tumour tissue of 12 of 99 patients. Of those 12 patients, 5 had an SDHB germline mutation, in 4 patients no germline mutation was detected and mutational status remained unknown in parts in 3 patients. Loss of SDHB expression was not associated with increased classic hypoxia signalling as detected by Hif-1 , CA-9 or GLUT-1 staining. Loss of SDHB expression was associated with an adverse outcome. The lack of correlation of SDHB loss with classic hypoxia signals argues against the current hypoxia hypothesis in malignant PCC/PGL. We suggest SDHB protein loss as a marker of adverse outcome both in sporadic and in familial PCC/PGL.

Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases

Intravenously administered radiolabeled peptides targeting somatostatin receptors are used for the treatment of unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Recently, we demonstrated a high first-pass effect during intra-arterial (i.a.) administration of positron emission tomography (PET) labeled (68)Ga-DOTA(0)-d-Phe(1)-Tyr(3)-octreotide (DOTATOC). In this pilot study, we investigated the therapeutic effectiveness of arterial administered DOTATOC, labeled with the therapeutic β emitters (90)Y and (177)Lu. (90)Y- and/or (177)Lu-DOTATOC were infused into the hepatic artery of 15 patients with liver metastases arising from GEP-NETs. Response was assessed using DOTATOC-PET, multiphase contrast enhanced computed tomography, magnetic resonance imaging, and the serum tumor marker chromogranin A. Pharmacokinetic data of the arterial approach were assessed using (111)In-DOTATOC scans. With the treatment regime of this pilot study, complete remission was achieved in one (7%) patient and partial remission was observed in eight (53%) patients, six patients were classified as stable (40%; response evaluation criteria in solid tumors criteria). The concomitant decrease of elevated serum tumor marker confirmed the radiologic response. Median time to progression was not reached within a mean follow-up period of 20 months. Receptor saturation and redistribution effects were identified as limiting factors for i.a. DOTATOC therapy. The high rate of objective radiologic response in NET patients treated with arterial infusion of (90)Y-/(177)Lu-DOTATOC compares favorably with systemic chemotherapy and intravenous radiopeptide therapy. While i.a. DOTATOC therapy is only applicable to patients with tumors of limited anatomic distribution, the results of this pilot study are a promising development in the treatment of GEP-NET and warrants further investigation of this novel approach.

Effective compression ratio-A new measurement of the quality of thorax compression during CPR

PURPOSE: Computer-based feedback systems for assessing the quality of cardiopulmonary resuscitation (CPR) are widely used these days. Recordings usually involve compression and ventilation dependent variables. Thorax compression depth, sufficient decompression and correct hand position are displayed but interpreted independently of one another. We aimed to generate a parameter, which represents all the combined relevant parameters of compression to provide a rapid assessment of the quality of chest compression-the effective compression ratio (ECR). METHODS: The following parameters were used to determine the ECR: compression depth, correct hand position, correct decompression and the proportion of time used for chest compressions compared to the total time spent on CPR. Based on the ERC guidelines, we calculated that guideline compliant CPR (30:2) has a minimum ECR of 0.79. To calculate the ECR, we expanded the previously described software solution. In order to demonstrate the usefulness of the new ECR-parameter, we first performed a PubMed search for studies that included correct compression and no-flow time, after which we calculated the new parameter, the ECR. RESULTS: The PubMed search revealed 9 trials. Calculated ECR values ranged between 0.03 (for basic life support [BLS] study, two helpers, no feedback) and 0.67 (BLS with feedback from the 6th minute). CONCLUSION: ECR enables rapid, meaningful assessment of CPR and simplifies the comparability of studies as well as the individual performance of trainees. The structure of the software solution allows it to be easily adapted to any manikin, CPR feedback devices and different resuscitation guidelines (e.g. ILCOR, ERC).

Prolactin upregulates sphingosine kinase-1 expression and activity in the human breast cancer cell line MCF7 and triggers enhanced proliferation and migration

Sphingosine kinases (SK) catalyze the formation of sphingosine-1-phosphate (S1P) which plays a crucial role in cell growth and survival. Here, we show that prolactin (PRL) biphasically activates the SK-1, but not the SK-2 subtype, in the breast adenocarcinoma cell-line MCF7. A first peak occurs after minutes of stimulation and is followed by a second delayed activation after hours of stimulation. A similar biphasic effect on SK-1 activity is seen for 17beta-estradiol (E(2)). The delayed activation of SK-1 derives from an upregulated mRNA and protein expression and is due to increased SK-1 promoter activity and mechanistically involves STAT5 activation as well as protein kinase C and the classical mitogen-activated protein kinases. Furthermore, glucocorticoids also block both hormone-induced SK-1 expression and activity. Functionally, long-term stimulation of MCF7 cells with PRL or E(2) is well known to trigger increased cell proliferation and migration. Both hormone-induced cell responses critically involve SK-1 activation since the depletion of SK-1, but not SK-2, by siRNA transfection abolishes the hormone-induced cell proliferation and migration. In summary, our data show that PRL and E(2) cause a pronounced delayed SK-1 activation which is due to increased gene transcription, and critically determines the capability of cells to grow and move. Thus, the SK-1 may represent a novel attractive target for anti-tumor therapy.

High expression of gastrin-releasing peptide receptors in the vascular bed of urinary tract cancers: promising candidates for vascular targeting applications

Tumoral gastrin-releasing peptide (GRP) receptors are potential targets for diagnosis and therapy using radiolabeled or cytotoxic GRP analogs. GRP-receptor overexpression has been detected in endocrine-related cancer cells and, more recently, also in the vascular bed of selected tumors. More information on vascular GRP-receptors in cancer is required to asses their potential for vascular targeting applications. Therefore, frequent human cancers (n = 368) were analyzed using in vitro GRP-receptor autoradiography on tissue sections with the (125)I-[Tyr(4)]-bombesin radioligand and/or the universal radioligand (125)I-[d-Tyr(6), beta-Ala(11), Phe(13), Nle(14)]-bombesin(6-14). GRP-receptor expressing vessels were evaluated in each tumor group for prevalence, quantity (vascular score), and GRP-receptor density. Prevalence of vascular GRP-receptors was variable, ranging from 12% (prostate cancer) to 92% (urinary tract cancer). Different tumor types within a given site had divergent prevalence of vascular GRP-receptors (e.g. lung: small cell cancer: 0%; adenocarcinoma: 59%; squamous carcinoma: 83%). Also the vascular score varied widely, with the highest score in urinary tract cancer (1.69), moderate scores in lung (0.91), colon (0.88), kidney (0.84), and biliary tract (0.69) cancers and low scores in breast (0.39) and prostate (0.14) cancers. Vascular GRP-receptors were expressed in the muscular vessel wall in moderate to high densities. Normal non-neoplastic control tissues from these organs lacked vascular GRP-receptors. In conclusion, tumoral vessels in all evaluated sites express GRP-receptors, suggesting a major biological function of GRP-receptors in neovasculature. Vascular GRP-receptor expression varies between the tumor types indicating tumor-specific mechanisms in their regulation. Urinary tract cancers express vascular GRP-receptors so abundantly, that they are promising candidates for vascular targeting applications.

VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors

A small subset of familial pancreatic endocrine tumors (PET) arises in patients with von Hippel-Lindau syndrome and these tumors may have an adverse outcome compared to other familial PET. Sporadic PET rarely harbors somatic VHL mutations, but the chromosomal location of the VHL gene is frequently deleted in sporadic PET. A subset of sporadic PET shows active hypoxia signals on mRNA and protein level. To identify the frequency of functionally relevant VHL inactivation in sporadic PET and to examine a possible prognostic significance we correlated epigenetic and genetic VHL alterations with hypoxia signals. VHL mutations were absent in all 37 PETs examined. In 2 out of 35 informative PET (6%) methylation of the VHL promoter region was detected and VHL deletion by fluorescence in situ hybridization was found in 14 out of 79 PET (18%). Hypoxia inducible factor 1alpha (HIF1-alpha), carbonic anhydrase 9 (CA-9), and glucose transporter 1 (GLUT-1) protein was expressed in 19, 27, and 30% of the 152 PETs examined. Protein expression of the HIF1-alpha downstream target CA-9 correlated significantly with the expression of CA-9 RNA (P<0.001), VHL RNA (P<0.05), and VHL deletion (P<0.001) as well as with HIF1-alpha (P<0.005) and GLUT-1 immunohistochemistry (P<0.001). These PET with VHL alterations and signs of hypoxia signalling were characterized by a significantly shortened disease-free survival. We conclude that VHL gene impairment by promoter methylation and VHL deletion in nearly 25% of PET leads to the activation of the HIF-pathway. Our data suggest that VHL inactivation and consecutive hypoxia signals may be a mechanism for the development of sporadic PET with an adverse outcome.

P450 oxidoreductase deficiency: a new disorder of steroidogenesis affecting all microsomal P450 enzymes

Combined partial deficiency of 17alpha-hydroxylase and 21-hydroxylase activities was first described in 1985; however the genes for P450c17 and P450c21 in these patients lack mutations. In 1986 we postulated that this disorder might be due to mutations in P450 oxidoreductase (POR), the flavoprotein that donates electron to these and all other microsomal P450 enzymes, but this hypothesis was not tested until the POR gene sequence became available through the genome database. We found five POR missense mutations in our first four patients. In vitro assays of the activities of these mutations showed that the standard assay of POR activity, reduction of cytochrome c, correlated poorly with the patients' phenotypes, but that assays of POR-supported 17alpha-hydroxylase and 17,20 lyase activities correlated well. POR deficiency is a new disorder of adrenal and gonadal steroidogenesis that affects all microsomal cytochrome P450 enzymes, hence may have important implications for genetic differences in drug metabolism.

Estrogen receptor β expression and androgen receptor phosphorylation correlate with a poor clinical outcome in hormone-naive prostate cancer and are elevated in castration-resistant disease

Patients with advanced prostate cancer (PC) are usually treated with androgen withdrawal. While this therapy is initially effective, nearly all PCs become refractory to it. As hormone receptors play a crucial role in this process, we constructed a tissue microarray consisting of PC samples from 107 hormone-naïve (HN) and 101 castration-resistant (CR) PC patients and analyzed the androgen receptor (AR) gene copy number and the protein expression profiles of AR, Serin210-phosphorylated AR (pAR(210)), estrogen receptor (ER)β, ERα and the proliferation marker Ki67. The amplification of the AR gene was virtually restricted to CR PC and was significantly associated with increased AR protein expression (P<0.0001) and higher tumor cell proliferation (P=0.001). Strong AR expression was observed in a subgroup of HN PC patients with an adverse prognosis. In contrast, the absence of AR expression in CR PC was significantly associated with a poor overall survival. While pAR(210) was predominantly found in CR PC patients (P<0.0001), pAR(210) positivity was observed in a subgroup of HN PC patients with a poor survival (P<0.05). Epithelial ERα expression was restricted to CR PC cells (9%). ERβ protein expression was found in 38% of both HN and CR PCs, but was elevated in matched CR PC specimens. Similar to pAR(210), the presence of ERβ in HN patients was significantly associated with an adverse prognosis (P<0.005). Our results strongly suggest a major role for pAR(210) and ERβ in HN PC. The expression of these markers might be directly involved in CR tumor growth.

Tall cell papillary thyroid carcinoma: new diagnostic criteria and mutations in BRAF and TERT

The tall cell (TC) variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diagnostic criteria remain inconsistent, and the role of a minor TC component is unclear. Molecular diagnostic markers are not available; however, there are two potential candidates: BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutations. Using a novel approach, we enriched a collective with PTCs that harbored an adverse outcome, which overcame the limited statistical power of most studies. This enabled us to review 125 PTC patients, 57 of which had an adverse outcome. The proportion of TCs that constituted a poor prognosis was assessed. All of the tumors underwent sequencing for TERT promoter and BRAF V600E mutational status and were stained with an antibody to detect the BRAF V600E mutation. A 10% cutoff for TCs was significantly associated with advanced tumor stage and lymph node metastasis. Multivariate analysis showed that TCs above 10% were the only significant factor for overall, tumor-specific, and relapse-free survival. Seven percent of the cases had a TERT promoter mutation, whereas 61% demonstrated a BRAF mutation. The presence of TC was significantly associated with TERT promoter and BRAF mutations. TERT predicted highly significant tumor relapse (P<0.001). PTCs comprised of at least 10% TCs are associated with an adverse clinical outcome and should be reported accordingly. BRAF did not influence patient outcome. Nevertheless, a positive status should encourage the search for TCs. TERT promoter mutations are a strong predictor of tumor relapse, but their role as a surrogate marker for TCs is limited.

La economía del conocimiento : perspectivas urbano - regionales

El conocimiento y su aplicación en la economía, ha sido siempre un factor importante del desarrollo socio-económico. El conocimiento toma relevancia en la economía contemporánea al invertirse la jerarquización de los factores del desarrollo, cobrando mayor importancia los factores intangibles, como el conocimiento, el cual se convierte en el recurso fundamental para los procesos productivos. En este contexto, surgieron los estudios relacionados con la Economía Regional del Conocimiento (ERC) así como los estudios relativos al Desarrollo basado en el Conocimiento (DBC). Ambas perspectivas teóricas han establecido indicadores para explicar el fenómeno de la economía del conocimiento desde su base territorial, sea a nivel regional (ERC) o desde la ciudad (DBC). A manera exploratoria consideramos que los indicadores de los sistemas regionales de innovación pueden complementarse con los indicadores del desarrollo basado en el conocimiento, sobre todo por la dimensión meta-cultural a la que hacen referencia estos estudios.

Pollen analysis of modern mangrove systems

Three sediment cores from the Bragança Peninsula located in the coastal region in the north-eastern portion of Pará State have been studied by pollen analysis to reconstruct Holocene environmental changes and dynamics of the mangrove ecosystem. The cores were taken from an Avicennia forest (Bosque de Avicennia (BDA)), a salt marsh area (Campo Salgado (CS)) and a Rhizophora dominated area (Furo do Chato). Pollen traps were installed in five different areas of the peninsula to study modern pollen deposition. Nine accelerator mass spectrometry radiocarbon dates provide time control and show that sediment deposits accumulated relatively undisturbed. Mangrove vegetation started to develop at different times at the three sites: at 5120 14C yr BP at the CS site, at 2170 14C yr BP at the BDA site and at 1440 14C yr BP at the FDC site. Since mid Holocene times, the mangroves covered even the most elevated area on the peninsula, which is today a salt marsh, suggesting somewhat higher relative sea-levels. The pollen concentration in relatively undisturbed deposits seems to be an indicator for the frequency of inundation. The tidal inundation frequency decreased, probably related to lower sea-levels, during the late Holocene around 1770 14C yr BP at BDA, around 910 14C yr BP at FDC and around 750 14C yr BP at CS. The change from a mangrove ecosystem to a salt marsh on the higher elevation, around 420 14C yr BP is probably natural and not due to an anthropogenic impact. Modern pollen rain from different mangrove types show different ratios between Rhizophora and Avicennia pollen, which can be used to reconstruct past composition of the mangrove. In spite of bioturbation and especially tidal inundation, which change the local pollen deposition within the mangrove zone, past mangrove dynamics can be reconstructed. The pollen record for BDA indicates a mixed Rhizophora/Avicennia mangrove vegetation between 2170 and 1770 14C yr BP. Later Rhizophora trees became more frequent and since ca. 200 14C yr BP Avicennia dominated in the forest.

Database of Ice-Rich Yedoma Permafrost (IRYP)

Vast portions of Arctic and sub-Arctic Siberia, Alaska and the Yukon Territory are covered by ice-rich silty to sandy deposits that are containing large ice wedges, resulting from syngenetic sedimentation and freezing. Accompanied by wedge-ice growth in polygonal landscapes, the sedimentation process was driven by cold continental climatic and environmental conditions in unglaciated regions during the late Pleistocene, inducing the accumulation of the unique Yedoma deposits up to >50 meters thick. Because of fast incorporation of organic material into syngenetic permafrost during its formation, Yedoma deposits include well-preserved organic matter. Ice-rich deposits like Yedoma are especially prone to degradation triggered by climate changes or human activity. When Yedoma deposits degrade, large amounts of sequestered organic carbon as well as other nutrients are released and become part of active biogeochemical cycling. This could be of global significance for future climate warming as increased permafrost thaw is likely to lead to a positive feedback through enhanced greenhouse gas fluxes. Therefore, a detailed assessment of the current Yedoma deposit coverage and its volume is of importance to estimate its potential response to future climate changes. We synthesized the map of the coverage and thickness estimation, which will provide critical data needed for further research. In particular, this preliminary Yedoma map is a great step forward to understand the spatial heterogeneity of Yedoma deposits and its regional coverage. There will be further applications in the context of reconstructing paleo-environmental dynamics and past ecosystems like the mammoth-steppe-tundra, or ground ice distribution including future thermokarst vulnerability. Moreover, the map will be a crucial improvement of the data basis needed to refine the present-day Yedoma permafrost organic carbon inventory, which is assumed to be between 83±12 (Strauss et al., 2013, doi:10.1002/2013GL058088) and 129±30 (Walter Anthony et al., 2014, doi:10.1038/nature13560) gigatonnes (Gt) of organic carbon in perennially-frozen archives. Hence, here we synthesize data on the circum-Arctic and sub-Arctic distribution and thickness of Yedoma for compiling a preliminary circum-polar Yedoma map. For compiling this map, we used (1) maps of the previous Yedoma coverage estimates, (2) included the digitized areas from Grosse et al. (2013) as well as extracted areas of potential Yedoma distribution from additional surface geological and Quaternary geological maps (1.: 1:500,000: Q-51-V,G; P-51-A,B; P-52-A,B; Q-52-V,G; P-52-V,G; Q-51-A,B; R-51-V,G; R-52-V,G; R-52-A,B; 2.: 1:1,000,000: P-50-51; P-52-53; P-58-59; Q-42-43; Q-44-45; Q-50-51; Q-52-53; Q-54-55; Q-56-57; Q-58-59; Q-60-1; R-(40)-42; R-43-(45); R-(45)-47; R-48-(50); R-51; R-53-(55); R-(55)-57; R-58-(60); S-44-46; S-47-49; S-50-52; S-53-55; 3.: 1:2,500,000: Quaternary map of the territory of Russian Federation, 4.: Alaska Permafrost Map). The digitalization was done using GIS techniques (ArcGIS) and vectorization of raster Images (Adobe Photoshop and Illustrator). Data on Yedoma thickness are obtained from boreholes and exposures reported in the scientific literature. The map and database are still preliminary and will have to undergo a technical and scientific vetting and review process. In their current form, we included a range of attributes for Yedoma area polygons based on lithological and stratigraphical information from the original source maps as well as a confidence level for our classification of an area as Yedoma (3 stages: confirmed, likely, or uncertain). In its current version, our database includes more than 365 boreholes and exposures and more than 2000 digitized Yedoma areas. We expect that the database will continue to grow. In this preliminary stage, we estimate the Northern Hemisphere Yedoma deposit area to cover approximately 625,000 km². We estimate that 53% of the total Yedoma area today is located in the tundra zone, 47% in the taiga zone. Separated from west to east, 29% of the Yedoma area is found in North America and 71 % in North Asia. The latter include 9% in West Siberia, 11% in Central Siberia, 44% in East Siberia and 7% in Far East Russia. Adding the recent maximum Yedoma region (including all Yedoma uplands, thermokarst lakes and basins, and river valleys) of 1.4 million km² (Strauss et al., 2013, doi:10.1002/2013GL058088) and postulating that Yedoma occupied up to 80% of the adjacent formerly exposed and now flooded Beringia shelves (1.9 million km², down to 125 m below modern sea level, between 105°E - 128°W and >68°N), we assume that the Last Glacial Maximum Yedoma region likely covered more than 3 million km² of Beringia. Acknowledgements: This project is part of the Action Group "The Yedoma Region: A Synthesis of Circum-Arctic Distribution and Thickness" (funded by the International Permafrost Association (IPA) to J. Strauss) and is embedded into the Permafrost Carbon Network (working group Yedoma Carbon Stocks). We acknowledge the support by the European Research Council (Starting Grant #338335), the German Federal Ministry of Education and Research (Grant 01DM12011 and "CarboPerm" (03G0836A)), the Initiative and Networking Fund of the Helmholtz Association (#ERC-0013) and the German Federal Environment Agency (UBA, project UFOPLAN FKZ 3712 41 106).

Research activities of Spanish antenna groups

When we look at the history of electricity and electromagnetism in Spain we discover that the most important Spanish researchers are generally out of the official institutions or stable research groups until the 20th century [1] [2]. In the 20th century most of the scientific research is done in stable research institutions and universities and the most important electromagnetism research centres in Spain are located in the Faculty of Physics of the most important universities, the National Scientific Research Council (CSIC) and the School for Telecommunication Engineering created in 1923. But the greatest impulse of research in the antenna and radiowave propagation field is done after 1960 reaching the first national URSI conference in 1980. After that year, the relation between groups and the number of research groups is continuously growing and the relation to industry is also increasing. When Spain joins the European research organizations (COST, ERC...) and the European Union in 1985 the research support experience a fast growing and the participation in the European research structures. In the antenna design field, there exist some specializations although most of the groups have dome specific projects in almost all the antenna analysis and design fields. Here, we have selected the most important and characteristic area related to each of the research groups and institutions. The easiest way to classify the research work in antennas is the selection between antenna analysis, design and measurement. After that the selected frequency bands technology, the type of antennas and the related circuits can be a good criterion to describe the variety of research work and specialization between groups.

Characteristics of the turbulent/nonturbulent interface in boundary layers, jets and shear-free turbulence

The characteristics of turbulent/nonturbulent interfaces (TNTI) from boundary layers, jets and shear-free turbulence are compared using direct numerical simulations. The TNTI location is detected by assessing the volume of turbulent flow as function of the vorticity magnitude and is shown to be equivalent to other procedures using a scalar field. Vorticity maps show that the boundary layer contains a larger range of scales at the interface than in jets and shear-free turbulence where the change in vorticity characteristics across the TNTI is much more dramatic. The intermittency parameter shows that the extent of the intermittency region for jets and boundary layers is similar and is much bigger than in shear-free turbulence, and can be used to compute the vorticity threshold defining the TNTI location. The statistics of the vorticity jump across the TNTI exhibit the imprint of a large range of scales, from the Kolmogorov micro-scale to scales much bigger than the Taylor scale. Finally, it is shown that contrary to the classical view, the low-vorticity spots inside the jet are statistically similar to isotropic turbulence, suggesting that engulfing pockets simply do not exist in jets