Phage-Derived Fully Human Monoclonal Antibody Fragments to Human Vascular Endothelial Growth Factor-C Block Its Interaction with VEGF Receptor-2 and 3

Vascular endothelial growth factor C (VEGF-C) is a key mediator of lymphangiogenesis, acting via its receptors VEGF-R2 and VEGF-R3. High expression of VEGF-C in tumors correlates with increased lymphatic vessel density, lymphatic vessel invasion, sentinel lymph node metastasis and poor prognosis. Recently, we found that in a chemically induced skin carcinoma model, increased VEGF-C drainage from the tumor enhanced lymphangiogenesis in the sentinel lymph node and facilitated metastatic spread of cancer cells via the lymphatics. Hence, interference with the VEGF-C/VEGF-R3 axis holds promise to block metastatic spread, as recently shown by use of a neutralizing anti-VEGF-R3 antibody and a soluble VEGF-R3 (VEGF-C/D trap). By antibody phage-display, we have developed a human monoclonal antibody fragment (single-chain Fragment variable, scFv) that binds with high specificity and affinity to the fully processed mature form of human VEGF-C. The scFv binds to an epitope on VEGF-C that is important for receptor binding, since binding of the scFv to VEGF-C dose-dependently inhibits the binding of VEGF-C to VEGF-R2 and VEGF-R3 as shown by BIAcore and ELISA analyses. Interestingly, the variable heavy domain (VH) of the anti-VEGF-C scFv, which contains a mutation typical for camelid heavy chain-only antibodies, is sufficient for binding VEGF-C. This reduced the size of the potentially VEGF-C-blocking antibody fragment to only 14.6 kDa. Anti-VEGF-C VH-based immunoproteins hold promise to block the lymphangiogenic activity of VEGF-C, which would present a significant advance in inhibiting lymphatic-based metastatic spread of certain cancer types

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Search for the standard model Higgs boson produced in association with W and Z bosons in pp collisions at √s=7 TeV

This is the pre-print version of the Article. The official published version can be accessed from the link below - Copyright @ 2012 Springer Verlag.A search for the Higgs boson produced in association with a W or Z boson in proton-proton collisions at a center-of-mass energy of 7 TeV is performed with the CMS detector at the LHC using the full 2011 data sample, from an integrated luminosity of 5 fb−1. Higgs boson decay modes to ττ and WW are explored by selecting events with three or four leptons in the final state. No excess above background expectations is observed, resulting in exclusion limits on the product of Higgs associated production cross section and decay branching fraction for Higgs boson masses between 110 and 200 GeV in these channels. Combining these results with other CMS associated production searches using the same dataset in the H→ γγ and H→ bb− decay modes, the cross section for associated Higgs boson production 3.3 times the standard model expectation or larger is ruled out at the 95% confidence level for a Higgs boson mass of 125 GeV.This study is funded by the BMWF and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS (Colombia); MSES (Croatia); RPF (Cyprus); MoER, SF0690030s09 and ERDF (Estonia); Academy of Finland, MEC, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRT (Greece); OTKA and NKTH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); NRF and WCU (Korea); LAS (Lithuania); CINVESTAV, CONACYT, SEP, and UASLP-FAI (Mexico); MSI (New Zealand); PAEC (Pakistan); MSHE and NSC (Poland); FCT (Portugal); JINR (Armenia, Belarus, Georgia, Ukraine, Uzbekistan); MON, RosAtom, RAS and RFBR (Russia); MSTD (Serbia); SEIDI and CPAN (Spain); Swiss Funding Agencies (Switzerland); NSC (Taipei); ThEP, IPST and NECTEC (Thailand); TUBITAK and TAEK (Turkey); NASU (Ukraine); STFC (United Kingdom); DOE and NSF (USA)

Aging-related tau astrogliopathy (ARTAG):harmonized evaluation strategy

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators

1000 Genomes-based metaanalysis identifies 10 novel loci for kidney function

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-Analysis of kidney function based on the estimated glomerular filtration rate (EGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, wh

Search for the standard model Higgs boson produced in association with W and Z bosons in pp collisions at root s=7 TeV

A search for the Higgs boson produced in association with a W or Z boson in proton-proton collisions at a center-of-mass energy of 7 TeV is performed with the CMS detector at the LHC using the full 2011 data sample, from an integrated luminosity of 5 fb−1. Higgs boson decay modes to ττ and WW are explored by selecting events with three or four leptons in the final state. No excess above background expectations is observed, resulting in exclusion limits on the product of Higgs associated production cross section and decay branching fraction for Higgs boson masses between 110 and 200 GeV in these channels. Combining these results with other CMS associated production searches using the same dataset in the H→ γγ and H→ b b¯ decay modes, the cross section for associated Higgs boson production 3.3 times the standard model expectation or larger is ruled out at the 95% confidence level for a Higgs boson mass of 125 GeV

In your face? Exploring multimodal resonance patterns involving facial responses to verbal and gestural stance-taking expressions

This contribution reports on a corpus-based interdisciplinary study, in which scholars from psychology, linguistics, gesture studies and FACS-analysis jointly investigate multimodal trade-off patterns between verbal, gestural and facial stance-taking expressions in dyadic face-to-face interactions. The general purpose of this study is to explore whether certain stance-taking phenomena may be characterized by an increased, multimodal connectedness of interaction partners while they are engaged in a spontaneous face-to-face conversation (AliLeGra-corpus, 2012). Following the premise that any facial motor response qualifies as a resonance marker relating to what was said by the interaction partner, we studied the effects of verbal and/or gestural stance-taking expressions on a wide array of facial muscle movements. For this we used Facial Action Coding (FACS, Ekman et al., 2002), which allows to code and quantify movements of individual muscles or small groups of muscles independently of any supposed meaning of these. Data are taken from 24 dyads of male participants, who had initially been unknown to each other and were engaged in seven minutes of spontaneous face-to-face conversation, which took place under controlled circumstances. Synchronized close-up and distant shot video recordings allowed a multimodal analysis. On the level of verbal and gestural expressions, stance-taking utterances expressing meanings like subjective obviousness, surprise, disbelief, impatience, but also certain types of humor (comical hypotheticals, stereotypes) were identified. Two certified FACS encoders identified all apexes (maximal expressions of individual facial muscle movements) of 9 upper face, 18 lower face, and 14 miscellaneous action units occurring in the conversations according to standard FACS conventions. Resonance in terms of facial motor responses was quantified as the number of apexes immediately following instances of a certain stance-taking type produced by the interaction partner. The presentation will exemplify and differentiate verbal-gestural stance-taking phenomena that increase or decrease interaction partners' resonance in the motor modality. Similar to direct facial mimicry and emotion-specific facial muscle responses to emotion words (cf. Foroni & Semin, 2009), resonance in terms of unspecific facial motor responses may increase the connectedness and involvement of interaction partners and facilitate understanding and sympathy between them. References: Authors. 2012. AliLeGra Corpus. Alignment Leuven Graz. Dept. of Linguistics, KU Leuven Ekman, P., Friesen, W. V., & Hager, J. C. (2002). Facial action coding system: The manual. Salt Lake City, Utah: A Human Face. Foroni, F., & Semin, G.R. (2009). Language that puts you in touch with your bodily feelings. The multimodal responsiveness of affective expressions. Psychological Science, 20, 974-980.status: publishe

Preliminary study of plasma vascular endothelial growth factor (VEGF) during low- and high-dose radiation therapy of dogs with spontaneous tumors

High plasma vascular endothelial growth factor (VEGF) concentrations are associated with radiation resistance and poor prognosis. After an exposure to ionizing radiation in cell culture an early phase and a late phase of increased VEGF have been documented. The activation was dependent on the radiation dose. Therefore, the purpose of this study was to measure baseline plasma VEGF and changes in VEGF over the course of fractionated radiation therapy in dogs with spontaneous tumors. Dogs with tumors had a significantly higher pretreatment plasma VEGF than did dogs without tumors. Immediately after irradiation no increased plasma VEGF was observed. Over the course of radiation therapy there was an increased plasma VEGF in dogs treated with low doses per fraction/high total dose, whereas plasma VEGF remained stable in dogs irradiated with high doses per fraction/low total dose. The regulatory mechanisms are very complex, and therefore the value of plasma VEGF measurements as an indirect marker of angiogenesis induced by radiotherapy is limited