Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the ...pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9
as an imaging marker for pre-metastatic tissue priming.
A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy.
S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r
=0.788; p<0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID).
We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.
The family of iodido OsII arene phenylazopyridine complexes Os(η6‐p‐cym)(5‐R1‐pyridylazo‐4‐R2‐phenyl))I+ (where p‐cym=para‐cymene) exhibit potent sub‐micromolar antiproliferative activity towards ...human cancer cells and are active in vivo. Their chemical behavior is distinct from that of cisplatin: they do not readily hydrolyze, nor bind to DNA bases. We report here a mechanism by which they are activated in cancer cells, involving release of the I− ligand in the presence of glutathione (GSH). The X‐ray crystal structures of two active complexes are reported, 1‐I (R1=OEt, R2=H) and 2‐I (R1=H, R2=NMe2). They were labelled with the radionuclide 131I (β−/γ emitter, t1/2 8.02 d), and their activity in MCF‐7 human breast cancer cells was studied. 1‐131I and 2‐131I exhibit good stability in both phosphate‐buffered saline and blood serum. In contrast, once taken up by MCF‐7 cells, the iodide ligand is rapidly pumped out. Intriguingly, GSH catalyzes their hydrolysis. The resulting hydroxido complexes can form thiolato and sulfenato adducts with GSH, and react with H2O2 generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo‐osmium complexes.
Os−I bond activation: Iodido OsII arene phenylazopyridine complexes show promising anticancer properties both in vitro and in vivo. Surprisingly they can be activated in cells by hydrolysis of their Os−I bond in the presence of glutathione (GSH). The newly formed hydroxido complexes are more reactive and can form chlorido, thiolato and sulfenato adducts with GSH, and react with H2O2 to generate hydroxyl radicals.
Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P) (1) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6) (2). Here, we use multispecies ...sequence comparisons to identify a common SNP (rs642961, G > A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 x 10.sup.-11) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2α and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2α in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
LGBT Identity and Online New Media examines constructions of LGBT identity within new media. The contributors consider the effects, issues, influences, benefits and disadvantages of these new media ...phenomena with respect to the construction of LGBT identities. A wide range of mainstream and independent new media are analyzed, including MySpace, Facebook, YouTube, gay men’s health websites, message boards, and Craigslist ads, among others. This is a pioneering interdisciplinary collection that is essential reading for anyone interested in the intersections of gender, sexuality, and technology.
Preface
Introduction, Christopher Pullen
Part I: Active Youth
1.The Murder of Lawrence King and LGBT Online Stimulations of Narrative Copresence, Christopher Pullen
2."A YouTube of One’s Own?": "Coming Out" Videos as Rhetorical Action Jonathan Alexander & Elizabeth Losh
3.YouTube Courtship: The Private Ins and Public Outs of Chris and Nickas, Damon Lindler Lazzara
4.Virtually Supportive: Self-Disclosure Of Minority Sexualities Through Online Social Networking Sites, Bruce E. Drushel
Part II: Commodity Networks
5.Lesbians Who Are Married to Men: Identity, Collective Stories and the Internet Online Community, Margaret Cooper
6. A Very Personal World: Advertisement and Identity of Trans-persons on Craigslist, Daniel Farr
7.The Facebook Revolution: LGBT Identity and Activism, Margaret Cooper & Kristina Dzara
8. PlanetOut and the Dichotomies of Queer Media Conglomeration, Ben Aslinger
9.Commercial Closet Association: LGBT identities in mainstream advertising, Ian Davies
Part III: Fan Cultures
10: Queering Brad Pitt: The Struggle Between Gay Fans and the Hollywood Machine to Control Star Discourse and Image on the Web, Ronald Gregg
11: Internet Fandom, Queer Discourse and Identities, Rosalind Hanmer
12: Transconversations: New Media, Community and Identity, Monica Edwards
13: Out and About: Slash Fic, Re-imagined Texts and Queer Commentaries, Richard Berger
14: Identity Unmoored: Yaoi in the West, Mark McHarry
Part IV: Body Discourses
15:Look at me! Images, Validation and Cultural Currency on Gaydar, Sharif Mowlabocus
16: Gay Men’s Use of Online Pictures in Fat-Affirming Groups, Jason Whitesel
17: "Compartmentalize Your Life" Advising Army Men on RealJock.com, Noah Tsika
18: "Stephanie is Wired: who shall turn him on?", Trudy Barber
19: Health Information, STDs, and the Internet: Implications for Gay Men, Joseph Clift
Part V: COMMUNITY SPACES
20:The Demise of the Gay Enclave, Communication Infrastructure Theory, and the Reconstitution of Gay Public Space, Nikki Usher & Eleanor Morrison
21: From Websites to Wal-Mart: Youth, Identity Work, and the Queering of Boundary Publics in Small Town, USA, Mary L. Gray
Christopher Pullen is Senior Lecturer in Media Studies at Bournemouth University, UK. He has widely published in the area sexuality and contemporary media, and is the author of Documenting Gay Men: Identity and Performance in Reality Television and Documentary Film (2007), and Gay Identity, New Storytelling and the Media (2009).
Margaret Cooper is a sociologist at Southern Illinois University. Her work on gender identity has been internationally published in journals, textbooks, and various collections. In addition, she is a former recipient of the Humanitarian of the Year Award in Nashville, Tennessee.
Maternal vitamin D deficiency has been associated with numerous adverse health outcomes, but its association with fetal growth restriction remains uncertain. We sought to elucidate the association ...between maternal serum 25-hydroxyvitamin D 25(OH)D concentrations in early pregnancy and the risk of small-for-gestational age birth (SGA) and explore the association between maternal single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene and the risk of SGA. We conducted a nested case-control study of nulliparous pregnant women with singleton pregnancies who delivered SGA infants (n = 77 white and n = 34 black) or non-SGA infants (n = 196 white and n = 105 black). Women were followed from <16 wk gestation to delivery. Women's banked sera at <22 wk were newly measured for 25(OH)D and DNA extracted for VDR genotyping. SGA was defined as live-born infants that were <10th percentile of birth weight according to nomograms based on gender and gestational age. After confounder adjustment, there was a U-shaped relation between serum 25(OH)D and risk of SGA among white mothers, with the lowest risk from 60 to 80 nmol/L. Compared with serum 25(OH)D 37.5-75 nmol/L, SGA odds ratios (95% CI) for levels <37.5 and >75 nmol/L were 7.5 (1.8, 31.9) and 2.1 (1.2, 3.8), respectively. There was no relation between 25(OH)D and SGA risk among black mothers. One SNP in the VDR gene among white women and 3 SNP in black women were significantly associated with SGA. Our results suggest that vitamin D has a complex relation with fetal growth that may vary by race.
Hexahistidine tags (His-tags), incorporated into recombinant proteins to facilitate purification using metal-affinity chromatography, are useful binding sites for radiolabeling with 99mTc(CO)3+ and ...188Re(CO)3+ for molecular imaging and radionuclide therapy. Labeling efficiencies vary unpredictably, and the method is therefore not universally useful. To overcome this, we have made quantitative comparisons of radiolabeling of a bespoke Celluspots array library of 382 His-tag-containing peptide sequences with 99mTc(CO)3+ and 188Re(CO)3+ to identify key features that enhance labeling. A selected sequence with 10-fold enhanced labeling efficiency compared to the most effective literature-reported sequences was incorporated into an exemplar protein and compared biologically with non-optimized analogues, in vitro and in vivo. Optimal labeling with either 99mTc(CO)3+ or 188Re(CO)3+ required six consecutive His residues in the protein sequence, surrounded by several positively charged residues (Arg or Lys), and the presence of phosphate in the buffer. Cys or Met residues in the sequence were beneficial, to a lesser extent. Negatively charged residues were deleterious to labeling. His-tags with adjacent positively charged residues could be labeled as much as 40 times more efficiently than those with adjacent negatively charged residues. 31P NMR of Re(CO)3(H2O)3+ and electrophoresis of solutions of 99mTc(CO)3(H2O)3+ suggest that phosphate bridges form between cationic residues and the cationic metal synthon during labeling. The trial optimized protein, a scFv targeted to the PSMA antigen expressed in prostate cancer, was readily labeled in >95% radiochemical yield, without the need for subsequent purification. Labeling occurred more quickly and to higher specific activity than comparable non-optimized proteins, while retaining specific binding to PSMA and prostate cancer in vivo. Thus, optimized His-tags greatly simplify radiolabeling of recombinant proteins making them potentially more widely and economically available for imaging and treating patients.
GMP-grade
68
Ge/
68
Ga generators provide access to positron-emitting
68
Ga, enabling preparation of Positron Emission Tomography (PET) tracers and PET imaging at sites that do not have access to ...cyclotron-produced radionuclides. Radiotracers based on tris(3-hydroxy-1,6-dimethylpyridin-4-one) (THP) chelators enable simple one-step preparations of
68
Ga PET radiopharmaceuticals from pre-fabricated kits without pre-processing of generator eluate or post-purification. However, trace metal impurities eluted along with
68
Ga could compete for THP and reduce radiochemical yields (RCY). We have quantified trace metal impurities in
68
Ga eluate from an Eckert & Ziegler (E&Z) generator using ICP-MS. The metals Al, Fe,
nat
Ga, Pb, Ti and
nat
Zn were present in generator eluate in significantly higher concentrations than in the starting eluent solution. Concentrations of Fe and
nat
Ga in eluate were in the range of 0.01-0.1 μM, Al, Zn and Pb in the range of 0.1-1 μM, and Ti in the range of 0.9-1.5 μM. To assess the ability of THP to chelate
68
Ga in the presence of such metal ions, radiolabelling reactions were undertaken in which selected metal ions were added to make them equimolar with THP, or higher. Al
3+
, Fe
3+
,
nat
Ga
3+
and Ti
4+
reduced RCY at concentrations equimolar with THP and higher, but at lower concentrations they did not affect RCY. Pb
2+
, Zn
2+
, Ni
2+
and Cr
3+
had no effect on RCY (even under conditions in which each metal ion was present in 100-fold molar excess over THP). The multi-sample ICP-MS analysis reported here is (to date) the most comprehensive and robust quantification of metal impurities in the widely used E&Z
68
Ga generator.
68
Ga from an E&Z generator enables near-quantitative radiolabelling of THP at chelator concentrations as low as 5 μM (lower than other common gallium chelators) without pre-processing. The combination of Al
3+
, Fe
3+
,
nat
Ga
3+
and Ti
4+
in unprocessed
68
Ga eluate is likely to decrease RCY of
68
Ga radiolabelling if a lower amount of THP chelator is used, and future kit design should take this into account. To increase specific activities by using even lower THP concentrations, purification of
68
Ga from trace metal ions will likely be required.
We have quantified trace metal impurities present in
68
Ga generator eluant from the widely used Eckert & Ziegler
68
Ga generator, and measured the effect of these metal impurities on
68
Ga radiolabelling of a THP chelator.
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