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The ADAMTS proteinases are a family of secreted, matrix-associated enzymes that have diverse roles in the regulation of tissue organization and vascular homeostasis. Several of the 19 human family members have been identified as having either tumor promoting or suppressing roles. We previously demonstrated that decreased ADAMTS15 expression correlated with a worse clinical outcome in mammary carcinoma (e.g., Porter et al., Int J Cancer 2006;118:1241-7). We have explored the effects of A Disintegrin and Metalloproteinase with Thrombospondin motifs-15 (ADAMTS-15) on the behavior of MDA-MB-231 and MCF-7 breast cancer cells by stable expression of either a wild-type (wt) or metalloproteinase-inactive (E362A) protein. No effects on mammary cancer cell proliferation or apoptosis were observed for either form of ADAMTS-15. However, both forms reduced cell migration on fibronectin or laminin matrices, though motility on a Type I collagen matrix was unimpaired. Knockdown of syndecan-4 attenuated the inhibitory effects of ADAMTS-15 on cell migration. In contrast to its effects on cell migration, wt ADAMTS-15 but not the E362A inactive mutant inhibited endothelial tubulogenesis in 3D collagen gels and angiogenesis in the aortic ring assay. In experimental metastasis assays in nude mice, MDA-MB-231 cells expressing either form of ADAMTS-15 showed reduced spread to the liver, though lung colonization was enhanced for cells expressing wt ADAMTS-15. These studies indicate that extracellular ADAMTS-15 has multiple actions on tumor pathophysiology. Via modulation of cell-ECM interactions, which likely involve syndecan-4, it attenuates mammary cancer cell migration independent of its metalloproteinase activity; however, its antiangiogenic action requires catalytic functionality, and its effects on metastasis in vivo are tissue niche-dependent.

Background & objectives. The ADAMTS proteinases are a family of secreted, matrix-associated enzymes that have diverse roles in the regulation of tissue organization and vascular homeostasis. Several of the 19 human family members have been identified as having either tumor promoting or suppressing roles. We previously demonstrated that decreased ADAMTS15 expression correlated with a worse clinical outcome in mammary carcinoma. Methods. We have explored the effects of A Disintegrin and Metalloproteinase with Thrombospondin motifs-15 (ADAMTS-15) on the behavior of MDA-MB-231 and MCF 7 breast cancer cells by stable expression of either a wild type (wt) or metalloproteinase-inactive (E362A) protein. Results. No effects on mammary cancer cell proliferation or apoptosis were observed for either form of ADAMTS-15. However, both forms reduced cell migration on fibronectin or laminin matrices, though motility on a Type I collagen matrix was unimpaired. Knockdown of syndecan-4 attenuated the inhibitory effects of ADAMTS-15 on cell migration. In contrast to its effects on cell migration, wt ADAMTS-15 but not the E362A inactive mutant inhibited endothelial tubulogenesis in 3D collagen gels and angiogenesis in the aortic ring assay. In experimental metastasis assays in nude mice, MDA-MB-231 cells expressing either form of ADAMTS-15 showed reduced spread to the liver, though lung colonization was enhanced for cells expressing wt ADAMTS-15. Conclusiona. These studies indicate that extracellular ADAMTS-15 has multiple actions on tumor pathophysiology. Via modulation of cell-ECM interactions, which likely involve syndecan-4, it attenuates mammary cancer cell migration independent of its metalloproteinase activity; however, its antiangiogenic action requires catalytic functionality, and its effects on metastasis in vivo are tissue niche-dependent.

on behalf of Eurocord-Netcord and the Lymphoma Working Party and the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation; International audience; We have reported encouraging results of unrelated cord blood transplantation for patients with lymphoid malignancies. Whether those outcomes are comparable to matched unrelated donor transplants remains to be defined. We studied 645 adult patients with mature lymphoid malignancies who received an allogeneic unrelated donor transplant using umbilical cord blood (n=104) or mobilized peripheral blood stem cells (n=541) after a reduced-intensity conditioning regimen. Unrelated cord blood recipients had more refractory disease. Median follow-up time was 30 months. Neutrophil engraftment (81% vs. 97%, respectively; P

The nickel and platinum complexes [MX2(dppe)] (X=Cl, Br) react with bi- and tri-valent metal diethyldithiocarbamates [M′(S2CNEt2)n] (M′=Pb, Zn, Cd, Hg, Ni, MoO2, VO, n=2; M′=Co, Fe, Mn, n=3) to afford salts [M(S2CNEt2)(dppe)]2[M′X4]; reactions involving [Cu(S2CNEt2)2] and [Ag(S2CNEt2)] gave salts of the form [M(S2CNEt2)(dppe)][M′X2] (M′=Cu, Ag). The complexes cis [RuCl2(dppm)2], [CoCl2(dppe)] and [PdX2(bipy)] likewise react with the same dithiocarbamates to form salts [Ru(S2CNEt2)(dppe)2]2[M′Cl4] [Co(S2CNEt2)2(dppe)]2[M′Cl4] and [Pd(S2CNnBu2)(bipy)]2[M′X4], respectively. Sample reactions involving other S-chelate ligands—S2COEt−, S2PPh2 − and S2P(OEt)2 −—appear to follow the same general pattern. However, the O-ethyldithio carbonates (ethylxanthates) are partly converted to the corresponding dithiocarbonates. An anomalous reaction between [CoCl2(dppe)] and [Zn(S2CNEt2)2] in the presence of (S2CNEt2)2 affords the novel complex [Co(S2CNEt2)2(dppe)]2[Cl3ZnO:(Ph)2PCH2CH2P(Ph)2:OZnCl3]. A selection of these salts have been fully characterised by elemental analysis and spectroscopic techniques, the remainder have been identified by spectroscopic methods alone. X-ray crystal structures are reported for the salts [Ni(S2CNEt2)(dppe)]2 [HgBr4], [Pt(S2CNEt2)(dppe)]2[CdCl4], [Co(S2CNEt2)2(dppe)]2[Cl3ZnO:(Ph)2PCH2CH2P(Ph)2:OZnCl3] and [Pd(S2CNnBu2) (bipy)]2[CdCl4].

N,N′-Diphenylamidines, PhNC(R)NHPh (R=H, Me, Et, Ph), and 1,3-diaryltriazenes, ArNNNHAr (Ar=p-C6H4X, X=H, Cl, Me, OMe) react with ruthenium(II) complexes, [RuCl2(C7H8)]n, [RuCl2(CO)2]n and [RuCl2(Me2SO)4] in the presence of a base (NEt3 or Na2CO3) to afford a selection of bis(chelate) products [Ru{PhNC(R)NPh}2L2] and [Ru(ArNNNAr)2L2] (L=CO, Me2SO; L2=C7H8). In contrast one particular combination — [RuCl2(Me2SO)4]/PhNC(H)NHPh/NEt3 — in refluxing dimethylformamide yields a novel amidine fragmentation product [RuCl(NH2Ph){PhNC(H)NPh}(Me2SO)2] which has been characterised by X-ray diffraction methods.

N,N′-Diphenylthiourea reacts with [RuHCl(CO)(PPh3)3] and [Ru(H)2(CO)(PPh3)3] in refluxing benzene to afford the N,N′-diphenylthioureido complexes [RuCl{PhNC(NHPh)S}(CO)(PPh3)2] and [RuH{PhNC(NHPh)S}(CO)(PPh3)2], respectively. Under more forcing conditions in refluxing toluene the precursors [MHCl(CO)(PPh3)3] (M=Ru or Os) and [Os(H)2(CO)(PPh3)3] afford the thioureido complexes [M{PhNC(NHPh)S}2(CO)(PPh3)] and the known N-phenylthioformamidato complex [OsH{PhNC(H)S}(CO)(PPh3)2], respectively. The reaction of [RuCl2(PPh3)3] with N,N′-diphenylthiourea and triethylamine in boiling toluene yields [Ru{PhNC(NHPh)S}2(PPh3)2]. Finally the reaction of mer-[Ir(H)3(PPh3)3] with N,N′-diphenylthiourea in boiling toluene affords [Ir(H)2{PhNC(NHPh)S}(PPh3)2]. Spectroscopic evidence indicates that the N,N′-diphenylthioureido anions are bound as N,S chelates, and this coordination mode has been confirmed for [Ru{PhNC(NHPh)S}2(CO)(PPh3)] by an X-ray crystal structure determination. Trends in exocyclic CNR2 bond lengths for related guanidinato, thioureido and dithiocarbamato complexes are reported.

Reactions of [RuCl 2 (Me 2 SO) 4 ] with silver carboxylates, [Ag(O 2 CR)] (R=Me, CF 3 ) in cold dichloromethane afford the title compounds, [Ru(O 2 CR) 2 (H 2 O)(Me 2 SO) 3 ] in good yield as pale cream crystals. X-ray crystal structure determinations have been performed on both complexes. In each case the geometry about the ruthenium centre is essentially octahedral with three S-bonded Me 2 SO ligands arranged in a fac configuration, two monodentate carboxylate anions and a coordinated H 2 O molecule. The carboxylate ligands are H-bonded to the H 2 O ligand via their non-coordinated oxygen atoms. The structures are compared with those previously reported for the alcohol dehydrogenation catalyst [Ru(O 2 CCF 3 ) 2 (MeOH)(CO)(PPh 3 ) 2 ] and a closely related ruthenium carboxylate complex [Ru(O 2 CCF 3 ) 2 (H 2 O)(PMe 3 ) 3 ].

The palladium complexes [PdCl2{Ph2P(CH2)nPPh2}] (n=1, 3, 4) react with the bi- and tri-valent metal diethyldithiocarbamates [M(S2CNEt2)2] (M=Zn, Cd, Hg, Pb) and [Mn(S2CNEt2)3] in cold dichloromethane solution to afford salts of the general form [Pd(S2CNEt2){Ph2P(CH2)nPPh2}]2[MCl4] in almost quantitative yield. X-ray crystal structures are reported for the salts [Pd(S2CNEt2){Ph2P(CH2)nPPh2}]2[MCl4] (n=1, 4; M=Cd: n=3, M=Hg). Structural parameters, IR and NMR spectroscopic data for these salts are compared with similar data previously reported for salts of the related cation [Pd(S2CNEt2){Ph2P(CH2)2PPh2}]+.

N,N′,N″-Triphenylguanidine (TpgH) reacts with [Ru(H)2(CO)(PPh3)3] in refluxing toluene and with [Os(H)2(CO)(PPh3)3] in refluxing o-xylene to yield the guanidinate(−1) complexes [RuH(Tpg)(CO)(PPh3)2] (1) and [Os(Tpg)2(CO)(PPh3)] (2), respectively. The reaction of TpgH with [RuCl2(PPh3)3] in refluxing toluene affords a new route to the known complex [Ru(Tpg)2(CO)(PPh3)] (3). Finally the reaction of mer-[Ir(H)3(PPh3)3] with TpgH in refluxing toluene yields the iridium(III) dihydride complex [Ir(H)2(Tpg)(PPh3)2] (4). X-ray crystal structure determinations are reported for (1) and (4).

Apparent recent carbon and peat accumulation rates over the past 1200 years were measured in five peat landforms in the discontinuous permafrost zone near Fort Simpson, Northwest Territories, Canada. The White River volcanic ash layer was used as a chronostratigraphic horizon to ensure a consistent time span of peat deposition among peat cores and to allow a large core sample size (n = 20 cores in each landform) without the expense of radiocarbon dating. Apparent recent carbon accumulation rates were not significantly different (p>0.05) among rich fen (13.58 ± 1.07 g C m−2 yr−1), peat plateau (13.31 ± 2.20 g C m−2 yr−1) and collapse fen (13.54 ± 1.50 g C m−2 yr−1). Poor fen and ombrotrophic bog accumulation rates were 20.34 ± 2.86 and 21.81 ± 3.25 g C m−2 yr−1, respectively, and were not significantly different from each other. Variation within the poor fen and ombrotrophic bog cores is attributed to microtopography, with hollows accumulating carbon at significantly greater rates than hummocks. Vertical peat accumulation rates vary significantly in the poor fen, with hummocks showing a greater annual vertical accumulation rate than hollows. Vertical peat accumulation rates ranged from 0.282 ± 0.052 mm yr−1 in the peat plateau to 0.563 ± 0.070 mm yr−1 in the ombrotrophic bog. Variations in mean core bulk density were also significant and ranged from 0.071 ± 0.011 g cm−3 (collapse fen) to 0.102 ± 0.011 g cm−3 (poor fen). A regional survey incorporating measurements from other parts of the southwestern Northwest Territories and the southeastern Yukon show rates similar to those near Fort Simpson. These rates are significantly lower than published rates from other parts of northern Canada, Finland, and the former Soviet Union. Low and variable summer precipitation in the region may contribute to the low carbon accumulation rates through decreased plant production and/or increased aerobic decomposition.

The assembly of focal adhesions and actin stress fibers by cells plated on fibronectin depends on adhesion-mediated signals involving both integrins and cell-surface heparan sulfate proteoglycans. These two cell-surface receptors interact with different domains of fibronectin. To attempt to identify the heparan sulfate proteoglycans involved, we used fibronectin-null (FN−/−) mouse fibroblasts to eliminate the contribution of endogenous fibronectin during the analysis. FN−/− fibroblasts plated on the cell-binding domain of fibronectin or on antibodies directed against mouse β1 integrin chains attach but fail to spread and do not form focal adhesions or actin stress fibers. When such cells are treated with antibodies directed against the ectodomain of mouse syndecan-4, they spread fully and assemble focal adhesions and actin stress fibers indistinguishable from those seen in cells plated on intact fibronectin. These results identify syndecan-4 as a heparan sulfate proteoglycan involved in the assembly process. The antibody-stimulated assembly of focal adhesions and actin stress fibers in cells plated on the cell-binding domain of fibronectin can be blocked with C3 exotransferase, an inhibitor of the small GTP-binding protein Rho. Treatment of cells with lysophosphatidic acid, which activates Rho, results in full spreading and assembly of focal adhesions and actin stress fibers in fibroblasts plated on the cell-binding domain of fibronectin. We conclude that syndecan-4 and integrins can act cooperatively in generating signals for cell spreading and for the assembly of focal adhesions and actin stress fibers. We conclude further that these joint signals are regulated in a Rho-dependent manner.

N,N′,N″ -Triphenylguanidine (HTpg) reacted with [Ru(O2CCF3)2(CO)(PPh3)2] in boiling toluene to yield [Ru(Tpg)2(CO)(PPh3)], the first example of a mononuclear complex containing two chelate guanidinate(1–) ligands. Palladium(II) acetate reacted with HTpg in warm benzene to form an adduct [Pd(O2CMe)2(HTpg)2] which, under more forcing conditions, converts into the novel binuclear guanidinate(1–) bridged complex [{Pd(µ-Tpg)(Tpg)}2]. Crystal structures have been determined for both guanidinate(1–) complexes.

The palladium complex [PdCl2(PhCN)2] reacts readily with metal bis(dialkyl dithiocarbamates) [M(S2CNR2)2] (M = Pb, Zn, Cd, Hg, Cu, Ni, MoO2, VO; R = Et, Bun), in refluxing dicloromethane, to afford the known complexes [|PdCl(S2CNR2)|2] in virtually quantitative yield. In boiling acetonitrile the diphosphine complexes [PdX2(Ph2PCH2CH2PPh2)] (X = Cl, Br) react readily with bi- and trivalent metal diethyl dithiocarbamates [M(S2CNEt2)n] (M = Pb, Zn, Cd, Hg. Ni, MoO2, VO n = 2; M = Co, Fe, Mn, n = 3) to afford salts of the general form [Pd(S2CNEt2)(Ph2PCH2CH2PPh2)]2+[MX4]2−. Diethyl dithiocarbamates of copper(II) and silver(I) form salts of the [Pd(S2CNEt2)(Ph2PCH2CH2PPh2)]+ cation containing linear [CuX2]− and [AgX2]− anions respectively (X = Cl, Br). The X-ray crystal structures of [Pd(S2CNEt2)(Ph2PCH2CH2PPH2)][CuCl2] and [Pd(S2PCH2CH2PPh2][AgCl2] · 0.5CH2Cl2 are reported.

Glial cell line-derived neurotrophic factor (GDNF)-dependent activation of the tyrosine kinase receptor RET is necessary for kidney and enteric neuron development, and mutations in RET are associated with human diseases. Activation of RET by GDNF has been shown to require an accessory component, GDNFR-α (RETL1). We report the isolation and characterization of rat and human cDNAs for a novel cell-surface associated accessory protein, RETL2, that shares 49% identity with RETL1. Both RETL1 and RETL2 can mediate GDNF dependent phosphorylation of RET, but they exhibit different patterns of expression in fetal and adult tissues. The most striking differences in expression observed were in the adult central and peripheral nervous systems. In addition, the mechanisms by which the two accessory proteins facilitate the activation of RET by GDNF are quite distinct. In vitro binding experiments with soluble forms of RET, RETL1 and RETL2 demonstrate that while RETL1 binds GDNF tightly to form a membrane-associated complex which can then interact with RET, RETL2 only forms a high affinity complex with GDNF in the presence of RET. This strong RET dependence of the binding of RETL2 to GDNF was confirmed by FACS analysis on RETL1 and RETL2 expressing cells. Together with the recent discovery of a GDNF related protein, neurturin, these data raise the possibility that RETL1 and RETL2 have distinctive roles during development and in the nervous system of the adult. RETL1 and RETL2 represent new candidate susceptibility genes and/or modifier loci for RET-associated diseases.

Thiobenzamide reacted with the complexes [MCl 2 (PPh 3 ) 3 ], [MH(X)(CO)(PPh 3 ) 3 ] (M = Ru or Os, X = H or Cl) and mer-[IrH 3 (PPh 3 ) 3 ] in boiling toluene to afford the products [M{S(NH)CPh} 2 (PPh 3 ) 2 ], [MX{S(NH)CPh}(CO)(PPh 3 ) 2 ] and [IrH 2 {S(NH)CPh}(PPh 3 ) 2 ] respectively. The crystal structure of [Os{S(NH)CPh} 2 (PPh 3 ) 2 ] confirms the expected bis(N,S-chelate) formulation and has established the presence of cis-phosphorus, cis-nitrogen and trans-sulfur donor atom pairs within a highly distorted octahedral co-ordination sphere. Thiobenzoic acid reacted with [MCl 2 (PPh 3 ) 3 ] and [MH(X)(CO)(PPh 3 ) 3 ] under similar conditions to yield [M{S(O)CPh} 2 (PPh 3 ) 2 ] and [M{S(O)CPh} 2 (CO)(PPh 3 ) 2 ] respectively. The reactions of thiobenzoic acid with mer-[IrH 3 (PPh 3 ) 3 ] under conditions of increasing severity give [IrH 2 {S(O)CPh}(PPh 3 ) 3 ], [IrH{S(O)CPh} 2 (PPh 3 ) 2 ] and [Ir{S(O)CPh} 3 (PPh 3 ) 2 ] the last two of which on carbonylation afford [IrH{S(O)CPh} 2 (CO)(PPh 3 ) 2 ] and [Ir{S(O)CPh} 3 (CO)(PPh 3 ) 2 ] respectively. The crystal structure of [IrH{S(O)CPh} 2 (PPh 3 ) 2 ] has established the presence of trans phosphorus and trans sulfur donor atom pairs, with the η 1 - and η 2 -thiobenzoate ligands sharing a meridional set of three co-ordination sites. However, the NMR spectra of this complex show two high-field 1 H triplets and two 31 P-{ 1 H} singlets. Possible explanations for this anomalous NMR behaviour, which is also found for the corresponding thioacetate, are advanced.

To investigate the functions of P-cadherin in vivo, we have mutated the gene encoding this cell adhesion receptor in mice. In contrast to E- and N-cadherin– deficient mice, mice homozygous for the P-cadherin mutation are viable. Although P-cadherin is expressed at high levels in the placenta, P-cadherin–null females are fertile. P-cadherin expression is localized to the myoepithelial cells surrounding the lumenal epithelial cells of the mammary gland. The role of the myoepithelium as a contractile tissue necessary for milk secretion is clear, but its function in the nonpregnant animal is unknown. The ability of the P-cadherin mutant female to nurse and maintain her litter indicates that the contractile function of the myoepithelium is not dependent on the cell adhesion molecule P-cadherin. The virgin P-cadherin–null females display precocious differentiation of the mammary gland. The alveolar-like buds in virgins resemble the glands of an early pregnant animal morphologically and biochemically (i.e., milk protein synthesis). The P-cadherin mutant mice develop hyperplasia and dysplasia of the mammary epithelium with age. In addition, abnormal lymphocyte infiltration was observed in the mammary glands of the mutant animals. These results indicate that P-cadherin–mediated adhesion and/or signals derived from cell–cell interactions are important determinants in negative growth control in the mammary gland. Furthermore, the loss of P-cadherin from the myoepithelium has uncovered a novel function for this tissue in maintaining the undifferentiated state of the underlying secretory epithelium.

Some dithiocarbamato-bridged heterobimetallic complexes [M′{M(S 2 CNR 2 ) 3 } 2 ] and [{M′M(S 2 CNR 2 ) 4 } n ], obtained by successive addition of stoichiometric amounts of bivalent metal salts MX 2 (M = Zn, Cd or Hg) and M′Y 2 (M′ = VO, Mn, Fe, Co, Ni, Cu or Zn) to a solution of a sodium dithiocarbamate, are reformulated as mixtures of homonuclear complexes involving, in some instances (M′ = Mn, Fe or Co), trivalent [M′(S 2 CNR 2 ) 3 ] species.

N,N′-Diphenylguanidine reacted with the hydrido complexes [MH 2 (CO)(PPh 3 ) 3 ] (M = Ru or Os) and mer-[IrH 3 (PPh 3 ) 3 ] in boiling toluene to afford the complexes [MH{PhNC(NH 2 )NPh}(CO)(PPh 3 ) 2 ] and [IrH 2 {PhNC(NH 2 )NPh}(PPh 3 ) 2 ] in which the N,N′-diphenylguanidinate anions adopt a symmetrical chelate co-ordination mode. Under similar conditions the trifluoroacetato complexes [M(O 2 CCF 3 ) 2 (CO)(PPh 3 ) 2 ] afforded salts [M{PhNC(NH 2 )NPh}{PhNC(NH 2 )NPh ·H}(CO)(PPh 3 ) 2 ][O 2 CCF 3 ] containing one chelate N,N′-diphenylguanidinate anion and one monodentate N,N′-diphenylguanidine ligand. Spectroscopic evidence indicates that the trifluoroacetate anions are hydrogen bonded to one or more of the N-bound hydrogens.

Genetic ablation of endothelial focal adhesion kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularization. Here we show that reduced stromal FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumour growth in vivo. Our results highlight a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis.

A decision support system (DSS) was developed in consultation with wheat farmers in the mediterranean wheat growing region of Western Australia. This system is targeted at decisions to be made at the start of the season and provides information about changes in the yield distribution of wheat given seasonal conditions to date. The DSS also access to historical weather records, which may be analysed according to simple, user defined rules.

Background Survival of acute myeloid leukaemia (AML) blasts is established to be heavily dependent on the bone marrow microenvironment, where bone marrow mesenchymal stromal cells (BM-MSCs) are an important cell type. Contrary to the Warburg hypothesis, AML blasts rely on oxidative phosphorylation for survival and have increased mitochondrial levels compared to normal CD34+ progenitors. Current research is being directed at the biology behind how the bone marrow microenvironment supports the proliferation of the disease. With the knowledge that AML blasts have an increased mitochondrial mass and that BM-MSCs have the ability to be mitochondrial donors, we examined the BM-MSC AML blast interaction to determine if the increased mitochondrial mass was a result of inter-cellular mitochondrial transfer. Methods Primary AML blasts were obtained from patient bone marrow. Primary AML and normal BM-MSCs were isolated from patients bone marrow, with informed consent and under approval from the UK National Research Ethics Service (LRCEref07/H0310/146), using adherence. BM-MSCs were characterised using flow cytometry for expression of CD90+, CD73+, CD105+ and CD45-. Mitochondrial transfer was assessed in vitro using qPCR and MitoTracker staining based methods. A P0 OCI-AML3 cell line was created using a 40-day incubation with ethidium bromide, pyruvate and uridine. In vivo experiments using an NSG primary AML xenograft model were also carried out (in accordance with University of East Anglia ethics review board). For mechanistic determination, BM-MSCs with a mCherry mitochondrial labelled protein were created using a lentivirus. Levels of mitochondrial transfer were assessed by mCherry mitochondrial protein acquisition in the AML during co-culture with the BM-MSCs. Results We report that BM-MSCs support AML blast survival via the inter-cellular transfer of mitochondria from 'benign' to malignant cells. To examine this transfer we used primary AML blasts and BM-MSCs derived from patient bone marrow, along with AML cell lines. We found in vitro that primary AML blasts increase their mitochondrial mass, respiratory capacity and ATP production after co-culture with primary BM-MSCs. A P0 OCI-AML3 cell line, with mutated mitochondrial DNA (mtDNA), was generated using ethidium bromide treatment allowing mitochondrial transfer to be specifically analysed. mtDNA was restored in this cell line after co-culture with primary BM-MSCs. Further to this mouse mtDNA was detected in the P0 OCI-AML3 cells after co-culture with the mouse BM-MSC cell line (M2-10B4). Moreover, mitochondrial transfer was directly observed between primary BM-MSCs and primary AML blasts, visualised by the acquisition of a mCherry labelled mitochondrial protein. This transfer of mitochondria was one directional. Moreover, a reduction of mitochondrial transfer was observed in AML blasts upon the addition of cytochalasin to the co-culture, highlighting that mitochondrial transfer is at least in part facilitated through tunnelling nanotubes (TNTs). Finally, mitochondrial transfer was confirmed in vivo whereby murine mitochondria were transferred to human AML in a mouse xenografts model. Conclusion Here we show that the bone marrow microenvironment supports the AML blasts by donating mitochondria, which in turn enhances the oxidative phosphorylation and growth capacity of the blasts. Targeting the microenvironment is predicted to provide novel therapeutic approaches for the treatment of cancer. Disclosures Rushworth: Infinity Pharmaceuticals: Research Funding.

Awassi sheep are large framed, fat tailed sheep mostly grown and consumed in Middle East countries. To provide an opportunity for Australian farmers to sell these sheep to Middle East countries, in 1983 an Awassi fat tail sheep importation program was initiated. This program has enabled many Awassi sheep to be raised in quarantine in Western Australia. For the first time Australian farmers now have an opportunity to produce Awassi sheep. To help administrators and farmers determine the likely place and profitability of these Awassi sheep in the farming systems of Western Australia, farming system models were employed. Models of the dryland farming systems in three regions of Western Australia were augmented with Awassi sheep production options. Modelling results suggest that only modest price premiums for Awassi cross sheep are sufficient to ensure the Awassi sheep enterprise is a profitable inclusion in the farming systems of the southern and western wheatbelt regions of Western Australia, providing particular Awassi flock options are adopted.

The maintenance of endothelial cell-cell junctions is vital for the control of blood vessel leakage and is known to be important in the growth and maturation of new blood vessels during angiogenesis. Here we have investigated the role of a tight junction molecule, Claudin 14, in tumour blood vessel leakage, angiogenesis and tumour growth. Using syngeneic tumour models our results showed that genetic ablation of Claudin 14 was not sufficient to affect tumour blood vessel morphology or function. However, and surprisingly, Claudin 14-heterozygous mice displayed several blood vessel-related phenotypes including: disruption of ZO-1-positive cell-cell junctions in tumour blood vessels; abnormal distribution of basement membrane laminin around tumour blood vessels; increased intratumoural leakage and decreased intratumoural hypoxia. Additionally, although total numbers of tumour blood vessels were increased in Claudin 14-heterozygous mice, and in VEGF-stimulated angiogenesis ex vivo, the number of lumenated vessels was not changed between genotypes and this correlated with no difference in syngeneic tumour growth between wild-type, Claudin 14-heterozygous and Claudin 14-null mice. Lastly, Claudin 14-heterozygosity, but not complete deficiency, also enhanced endothelial cell proliferation significantly. These data establish a new role for Claudin 14 in the regulation of tumour blood vessel integrity and angiogenesis that is evident only after the partial loss of this molecule in Claudin 14-heterozyous mice but not in Claudin 14-null mice.

Summary Cellular ribosomal protein L29 (RPL29) is known to be important in protein synthesis, but its function during angiogenesis has never been described before. We have shown previously that mice lacking β3-integrins support enhanced tumour angiogenesis and, therefore, deletion of endothelial αvβ3 can provide a method for discovery of novel regulators of tumour angiogenesis. Here, we describe significant upregulation of RPL29 in β3-null endothelial cells at both the mRNA and protein level. Ex vivo, we show that VEGF-stimulated microvessel sprouting was reduced significantly in Rpl29-heterozygous and Rpl29-null aortic ring assays compared with wild-type controls. Moreover, we provide in vivo evidence that RPL29 can regulate tumour angiogenesis. Tumour blood vessel density in subcutaneously grown Lewis lung carcinomas was reduced significantly in Rpl29-mutant mice. Additionally, depletion of Rpl29 using RNA interference inhibited VEGF-induced aortic ring sprouting, suggesting that anti-RPL29 strategies might have anti-angiogenic potential. Overall, our results identify that loss or depletion of RPL29 can reduce angiogenesis in vivo and ex vivo.

Here we provide a protocol for quantitative three-dimensional ex vivo mouse aortic ring angiogenesis assays, in which developing microvessels undergo many key features of angiogenesis over a timescale similar to that observed in vivo. The aortic ring assay allows analysis of cellular proliferation, migration, tube formation, microvessel branching, perivascular recruitment and remodeling-all without the need for cellular dissociation-thus providing a more complete picture of angiogenic processes compared with traditional cell-based assays. Our protocol can be applied to aortic rings from embryonic stage E18 through to adulthood and can incorporate genetic manipulation, treatment with growth factors, drugs or siRNA. This robust assay allows assessment of the salient steps in angiogenesis and quantification of the developing microvessels, and it can be used to identify new modulators of angiogenesis. The assay takes 6-14 d to complete, depending on the age of the mice, treatments applied and whether immunostaining is performed.

The ruthenium(I) amidinato complex [Ru{PhNC(Me)NPh}(CO)3]2 has been prepared by heating [Ru3(CO)12] with the free amidine, PhNC(Me)NHPh, in boiling benzene under a carbon monoxide atmosphere, and by heating [{Ru(O2CMe)(CO)2}2]n with free amidine and triethylamine in acetonitrile under carbon monoxide. The structure of [Ru{PhNC(Me)NPh}(CO)3]2 has been determined by X-ray diffraction methods. The binuclear complex has two Ru(CO)3 units linked by an RuRu bond [2.714(1) A] and a cis pair of bridging amidinato ligands. Variable temperature 1H and 13C {1H} NMR spectra show evidence of hindered rotation about the Nphenyl bonds of the amidinate ligands. An attempt to prepare the corresponding propionamidinate derivative gave a product which is tentatively formulated as [Ru{PhNC(Et)NPh}(CO)2(HO2CMe)]2 on the basis of analytical and spectroscopic evidence.

N,N′-Diphenylamidines PhNC(R)–NHPh (R = H, Me, Et or Ph) reacted with the precursors [MH2(CO)(PPh3)3], [MH(Cl)(CO)(PPh3)3] and [M(O2CCF3)2(CO)(PPh3)2]·nMeOH (M = Ru, n= 0.75; or Os n= 0.33) in boiling benzene to afford the amidinato complexes [MH{PhNC(R)NPh}(CO)(PPh3)2], [MCl{PhNC(R)NPh}(CO)(PPh3)2] and [M(O2CCF3){PhNC(R)NPh}(CO)(PPh3)2] respectively. The hydrides [MH{PhNC(R)NPh}(CO)(PPh3)2] have also been obtained by oxidative addition of amidines to [Ru(CO)3(PPh3)2] and by treatment of the precursors [MH(Cl)(CO)(PPh3)3] with amidines in the presence of an excess of base (NEt3). The trifluoroacetates [M(O2CCF3)2(CO)(PPh3)2]·nMeOH reacted with amidines in the presence of NEt3 to afford the hydrides [MH{PhNC(R)NPh}(CO)(PPh3)2](M = Ru, R = H; M = Os, R = H, Me, Et or Ph) or the bis(amidinato) complexes [M{PhNC(R)NPh}2(CO)(PPh3)](M = Ru; R = Me, Et or Ph). Reactions of the dichlorides [MCl2(PPh3)3] with amidines and base (NEt3) in boiling toluene containing traces of alcohol were accompanied by a carbonyl-abstraction reaction leading to formation of [MH{PhNC(R)NPh}(CO)(PPh3)2] and/or [MCl{PhNC(R)NPh}(CO)(PPh3)2]. The hydrides [MH{PhNC(R)NPh}(CO)(PPh3)2] are also obtained when [RuH2(PPh3)4] or [OsH4(PPh3)3] reacts with amidines in boiling toluene (containing a trace of alcohol) or in 2-methoxyethanol. The carbonyl abstractions are remarkable in that they have no parallel in the corresponding reactions involving the related triazenide (PhNNNPh–) and carboxylate (RCO2–) ligands even when neat alcohols are used as solvents. Reactions of mer-[IrH3(PPh3)3], [IrHCl2(PPh3)3]–NEt3 and [IrHCl2(PPh3)3] with amidines in boiling benzene or toluene afforded [IrH2{PhNC(R)NPh}(PPh3)2], [IrH(Cl){PhNC(R)NPh}(PPh3)2] and [IrCl2{PhNC(Ph)NPh}(PPh3)2] respectively.

Succinimide reacts with [RuHCl(PPh3)3] in refluxing toluene to afford a maroon air-stable complex 1. A crystal of 1 obatained from CH2Cl2–MeOH solution has been shown by X-ray diffraction methods to possess the succinimido-bridged structure [Ru2(µ-Cl)(µ-H)(µ-C4H4NO2)2(PPh3)4]·2CH2Cl2·0.5H2O. Succinimide also reacts with [RuCl2(PPh3)3] in refluxing toluene in the presence of an excess of NEt3 to form a closely related monocarbonyl derivative [Ru2(µ-Cl)(µ-H)(µ-C4H4NO2)2(CO)(PPh3)3]2 as orange needles. Carbonylation of 2 in refluxing toluene affords the dicarbonyl [Ru2(µ-Cl)(µ-H)(µ-C4H4NO2)2(CO)2(PPh3)2]3 as pale yellow crystals. The products 1–3 have been characterised by infrared and 1H and 31P-{1H} NMR spectroscopies.

Endothelial cell migration is an essential aspect of tumor angiogenesis. Rac1 activity is needed for cell migration in vitro implying a requirement for this molecule in angiogenesis in vivo. However, a precise role for Rac1 in tumor angiogenesis has never been addressed. Here we show that depletion of endothelial Rac1 expression in adult mice, unexpectedly, has no effect on tumor growth or tumor angiogenesis. In addition, repression of Rac1 expression does not inhibit VEGF-mediated angiogenesis in vivo or ex vivo, nor does it affect chemotactic migratory responses to VEGF in 3-dimensions. In contrast, the requirement for Rac1 in tumor growth and angiogenesis becomes important when endothelial beta3-integrin levels are reduced or absent: the enhanced tumor growth, tumor angiogenesis and VEGF-mediated responses in beta3-null mice are all Rac1-dependent. These data indicate that in the presence of alphavbeta3-integrin Rac1 is not required for tumor angiogenesis.

Down's syndrome (DS) is a genetic disorder caused by full or partial trisomy of human chromosome 21 and presents with many clinical phenotypes including a reduced incidence of solid tumours. Recent work with the Ts65Dn model of DS, which has orthologues of about 50% of the genes on chromosome 21 (Hsa21), has indicated that three copies of the ETS2 (ref. 3) or DS candidate region 1 (DSCR1) genes (a previously known suppressor of angiogenesis) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses roughly 81% of Hsa21 genes but not the human DSCR1 region. We transplanted B16F0 and Lewis lung carcinoma tumour cells into Tc1 mice and showed that growth of these tumours was substantially reduced compared with wild-type littermate controls. Furthermore, tumour angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS1and ERG) and novel endothelial cell-specific genes, never previously shown to be involved in angiogenesis (JAM-B and PTTG1IP), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis, explaining the reduced tumour growth in DS. Furthermore, we expect that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will permit the identification of other endothelium-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients.

Ruthenium(II) and osmium(II) complexes [MCl2(PPh3)3] undergo oxidative-substitution reactions with N,N′-diphenylamidines PhNC(R)–NHPh (R = H, Me, Et or Ph) under mild conditions to form the ruthenium(III) and osmium(III) products [MCl2{PhNC(R)NPh}(PPh3)2](M = Ru; R = H or Ph; M = Os, R = H, Me or Ph). However, in contrast to other systems of this type, more prolonged reaction times lead to further substitution and/or oxidation steps which afford the ruthenium(III) complexes [RuCl{PhNC(R)NPh}2(PPh3)] and the osmium(IV) species [OsCl2{PhNC(R)NPh}2](R = Me, Et or Ph). The crystal structure of trans-[OsCl2{PhNC(Et)NPh}2] has been determined.

Laminins are expressed highly in blood vessel basement membranes and have been implicated in angiogenesis. alpha6beta1- and alpha6beta4-integrins are major receptors for laminins in endothelial cells, but the precise role of endothelial alpha6-integrin in tumour angiogenesis is not clear. We show that blood vessels in human invasive ductal carcinoma of the breast have decreased expression of the alpha6-integrin-subunit when compared with normal breast tissue. These data suggest that a decrease in alpha6-integrin-subunit expression in endothelial cells is associated with tumour angiogenesis. To test whether the loss of the endothelial alpha6-integrin subunit affects tumour growth and angiogenesis, we generated alpha6fl/fl-Tie1Cre+ mice and showed that endothelial deletion of alpha6-integrin is sufficient to enhance tumour size and tumour angiogenesis in both murine B16F0 melanoma and Lewis cell lung carcinoma. Mechanistically, endothelial alpha6-integrin deficiency elevated significantly VEGF-mediated angiogenesis both in vivo and ex vivo. In particular, alpha6-integrin-deficient endothelial cells displayed increased levels of VEGF-receptor 2 (VEGFR2) and VEGF-mediated downstream ERK1/2 activation. By developing the first endothelial-specific alpha6-knockout mice, we show that the expression of the alpha6-integrin subunit in endothelial cells acts as a negative regulator of angiogenesis both in vivo and ex vivo.

Sprouting angiogenesis and lymphatic-blood vessel segregation both involve the migration of endothelial cells, but the precise migratory molecules that govern the decision of blood vascular endothelial cells to segregate into lymphatic vasculature are unknown. Here, we deleted endothelial Rac1 in mice (Tie1-Cre+;Rac1fl/fl) and revealed, unexpectedly, that whereas blood vessel morphology appeared normal, lymphatic-blood vessel separation was impaired, with corresponding edema, haemorrhage and embryonic lethality. Importantly, normal levels of Rac1 were essential for directed endothelial cell migratory responses to lymphatic-inductive signals. Our studies identify Rac1 as a crucial part of the migratory machinery required for endothelial cells to separate and form lymphatic vasculature.

Both vascular endothelial growth factor receptors (VEGFR) and integrins are major regulators of VEGF-induced angiogenesis. Previous work has shown that beta3 integrin can regulate negatively VEGFR2 expression. Here we show that beta3 integrin can regulate negatively VEGF-mediated angiogenesis by limiting the interaction of the co-receptor NRP1 (neuropilin-1) with VEGFR2. In the presence of alphav beta3 integrin, NRP1 contributed minimally to VEGF-induced angiogenic processes in vivo, ex vivo, and in vitro. Conversely, when beta3 integrin expression is absent or low or its function is blocked with RGD-mimetic inhibitors, VEGF-mediated responses became NRP1-dependent. Indeed, combined inhibition of beta3 integrin and NRP1 decreased VEGF-mediated angiogenic responses further than individual inhibition of these receptors. We also show that alphav beta3 integrin can associate with NRP1 in a VEGF-dependent fashion. Our data suggest that beta3 integrin may, in part, negatively regulate VEGF signaling by sequestering NRP1 and preventing it from interacting with VEGFR2.

Homoleptic tris(triazenido) derivatives of ruthenium, osmium, rhodium and iridium, M(ArNNNAr) 3 (Ar = p -C 6 H 4 X; X = H, Me or Cl), have been prepared by treatment of the chlorides or chloro complexes—RuCl 3 (aq.), (NH 4 ) 2 OsCl 6 (aq.), RhCl 3 (aq.) and (NH 4 ) 2 IrCl 6 (aq.), respectively—with excess 1,3-diaryltriazene and triethylamine in boiling ethanol (M = Ru, Rh) or aqueous ethanol (M = Os, Ir). The sparingly soluble, air-stable, deep green (M = Ru, Os) or red-orange (M = Rh, Ir) complexes have been characterized by vibrational and NMR spectroscopy, and by magnetic measurements.

The binuclear ruthenium(I, I) triazenido complex [Ru2(RNNNR)2(CO)6](R =p-tolyl) reacts with excess of 2,2′-bipyridyl (bipy) to afford a substitution product [Ru2(RNNNR)2(CO)4(bipy)] which has been shown by X-ray diffraction methods to contain a pair of non-equivalent ruthenium atoms linked by a metal–metal bond (2.706A) and bridged by a 1,3-di-p-tolyltriazenide ligand and a pair of carbonyls. The co-ordination sphere of the first ruthenium atom is completed by a chelate triazenide ligand and a terminal carbonyl, that of the second ruthenium atom by a chelate bipy ligand and a terminal carbonyl.

Salicylaldehyde reacts with [RuH2(CO)(PPh3)3] in refluxing toluene to afford a ruthenium(II) salicylaldehydato(2–) complex which crystallised from CH2Cl2–light petroleum as a dichloromethane-solvated o-hydroxybenzyl alcohol adduct [[graphic omitted])(HOC6H4CH2OH)(CO)-(PPh3)2]·CH2Cl2, and from CH2Cl2–MeOH as the methanol- solvated methanol adduct [[graphic omitted])-(MeOH)(CO)(PPh3)2]·MeOH. Formation of the o-hydroxybenzyl alcohol adduct clearly implies the ruthenium-mediated reduction of the CHO group in salicylaldehyde. Carbon monoxide and pyridine react with [[graphic omitted])(MeOH)(CO)(PPh3)2]·MeOH to form [[graphic omitted])L(CO)(PPh3)2](L = CO or py respectively). The reaction of salicylaldehyde with [OsH2(CO)(PPh3)3] includes a carbonylation step and affords [[graphic omitted])(CO)2(PPh3)2]. Reactions of [RhH(PPh3)4] and mer-[IrH3(PPh3)3] with salicylaldehyde in boiling toluene afford [Rh(OC6H4CHO)(CO)(PPh3)2] and [[graphic omitted])H(CO)(PPh3)2] respectively. X-Ray diffraction studies on [[graphic omitted])(HOC6H4CH2OH)(CO)(PPh3)2]·CH2Cl2and[[graphic omitted])(MeOH)(CO)(PPh3)2]·MeOH establish the presence of O,C-chelated salicylaldehydate(2–) ligands in both cases and a monodentate o-hydroxybenzyl alcohol ligand in the former complex.

Effective reepithelialization after injury is essential for correct wound healing. The upregulation of keratinocyte alpha3beta1 integrin during reepithelialization suggests that this adhesion molecule is involved in wound healing; however, its precise role in this process is unknown. We have shown here that retarded reepithelialization in Itga3(-/-) mouse skin wounds is due predominantly to repressed TGF-beta1-mediated responses. Specifically, expression of the inhibitor of TGF-beta1-signaling Smad7 was elevated in Itga3(-/-) keratinocytes. Indeed, in vivo blockade of Smad7 increased the rate of reepithelialization in Itga3(-/-) and WT wounds to similar levels. Our data therefore indicate that the function of alpha3beta1 integrin as a mediator of keratinocyte migration is not essential for reepithelialization but suggest instead that alpha3beta1 integrin has a major new in vivo role as an inhibitor of Smad7 during wound healing. Moreover, our study may identify a previously undocumented function for Smad7 as a regulator of reepithelialization in vivo and implicates Smad7 as a potential novel target for the treatment of cutaneous wounds.

Constitutive expression of the inflammatory cytokine tumor necrosis factor-α (TNF-α) is characteristic of malignant ovarian surface epithelium. We investigated the hypothesis that this autocrine action of TNF-α generates and sustains a network of other mediators that promote peritoneal cancer growth and spread. When compared with two ovarian cancer cell lines that did not make TNF-α, constitutive production of TNF-α was associated with greater release of the chemokines CCL2 and CXCL12, the cytokines interleukin-6 (IL-6) and macrophage migration-inhibitory factor (MIF), and the angiogenic factor vascular endothelial growth factor (VEGF). TNF-α production was associated also with increased peritoneal dissemination when the ovarian cancer cells were xenografted. We next used RNA interference to generate stable knockdown of TNF-α in ovarian cancer cells. Production of CCL2, CXCL12, VEGF, IL-6, and MIF was decreased significantly in these cells compared with wild-type or mock-transfected cells, but in vitro growth rates were unaltered. Tumor growth and dissemination in vivo were significantly reduced when stable knockdown of TNF-α was achieved. Tumors derived from TNF-α knockdown cells were noninvasive and well circumscribed and showed high levels of apoptosis, even in the smallest deposits. This was reflected in reduced vascularization of TNF-α knockdown tumors. Furthermore, culture supernatants from such cells failed to stimulate endothelial cell growth in vitro. We conclude that autocrine production of TNF-α by ovarian cancer cells stimulates a constitutive network of other cytokines, angiogenic factors, and chemokines that may act in an autocrine/paracrine manner to promote colonization of the peritoneum and neovascularization of developing tumor deposits. [Cancer Res 2007;67(2):585–92]

To determine the optimal serotherapy regimen in idiopathic aplastic anaemia stem cell transplantation, we analysed 1837 patients who underwent either in vivo T cell depletion with either ATG (n=1283) or Alemtuzumab (n=261) or no serotherapy (n=293) as part of their conditioning regimen. All patients had either undergone a matched sibling or matched unrelated donor stem cell transplant (at least 6 out of 6). Data was obtained retrospectively from the EBMT SAA database, between the periods 2000-2013. The major endpoints were graft versus host disease, overall survival and event free survival. Events were classified as graft failure, secondary malignancy, relapse and requirement for second transplant. The median follow up was 34 months in the ATG group, 30.9 months in the Alemtuzumab group and 47.9 months in the no serotherapy group. Rate of grade 2-4 acute GVHD was 19.1% without serotherapy; this was higher than that observed with both ATG (13.3%, p Figure 1. Figure 1. Disclosures Snowden: Celgene: Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; MSD: Consultancy, Other: Educational support, Speakers Bureau; Sanofi: Consultancy. Dufour:Pfizer: Consultancy. Risitano:Pfizer: Consultancy; Novartis: Research Funding; Rapharma: Consultancy, Research Funding; Alnylam: Consultancy, Research Funding; Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: this paper includes discussion of the use of alentuzumab for GVHD prophylaxis, which is currently off-label.

Introduction. The definitive management of R/R FL remains controversial due to various treatment options, including chemoimmunotherapy, pathway inhibitors, and autologous stem cell transplantation (auto-SCT). These options can provide prolonged progression-free survival (PFS). Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the sole curative therapy for FL. Herein, we report the long term outcome of the largest sample of allo-SCT for FL ever studied as well as the identification of patient and disease related factors that were significantly associated with treatment failure. Patients. Eligible were adult patients with R/R FL having received a first allo-SCT between 2001 and 2011 from an HLA identical sibling donor (SIB) or a well-matched unrelated donor (MUD). Patients with transformed lymphoma were excluded from the analysis as well as planned second transplants, allotransplants from cord blood, mismatched donors, and transplants with ex vivo T cell depletion (TCD). Results. 1567 patients met the eligibility criteria (EBMT, n = 1115; CIBMTR, n = 452). Demographics separated by data source demonstrate some differences in transplant practices between the two regions. The CIBMTR cohort had a higher proportion of MUD recipients [167 (37%) vs 252 (23%), p < 0.001], more cases with chemoresistant disease [113 (25%) vs 145 (13%), p < 0.001], less patients having received a prior auto-SCT [53 (12%) vs 403 (36%), p < 0.001], more use of myeloablative conditioning (MAC) (145 (32%) vs 220 (20%), p < 0.001) and less use of alemtuzumab in-vivo TCD [29 (6%) vs 201 (18%), p < 0.001] compared to the EBMT cohort. Median (range) follow up of survivors in months was 58 (3 - 130) and 54 (3 - 160) for CIBMTR and EBMT patients, respectively. Cumulative incidence of acute (grades II-IV) graft versus host disease (GVHD) was 20% (18-22) at 100 days and of chronic GVHD 45% (42-48) and 55% (52-58) at 1 and 3 years, respectively for the whole series; this risk was slightly but significantly reduced in the EBMT cohort. All major outcomes [non-relapse mortality (NRM), relapse/progression (R/P), overall survival (OS) and PFS] were comparable between the CIBMTR and EBMT samples (Table 1). Table 1. Outcomes CIBMTR EBMT p-value NRMN@ 1 y@ 3 y@ 5 y 45021 (17-25)27 (23-32)31 (26-35) 108819 (16-21)24 (21-27)28 (25-31) 0.3630.1720.114 R/PN@ 1 y@ 3 y@ 5 y 45013 (10-16)16 (13-20)17 (13-21) 108813 (11-15)18 (15-20)21 (18-23) 0.8740.4800.114 PFSN@ 1 y@ 3 y@ 5 y 45066 (62-71)56 (52-61)52 (47-57) 108869 (66-72)58 (55-61)52 (48-55) 0.3750.4950.792 OSN@ 1 y@3 y@ 5 y 45274 (70-78)65 (60-69)61 (56-65) 110475 (72-78)67 (64-70)62 (59-65) 0.5890.4550.695 Multivariate analysis indicated that NRM was significantly affected by age (HR 1.04, 1.02-1.05, p < 0.0001), chemoresistant disease (HR 1.61, 1.28-2.03, p < 0.0001), >= 5 lines of prior CT (vs 3-4) (HR 1.62, 1.20-2.19, p=0.0015) and Karnofsky performance score (KPS) < 80 (HR 2.05 (1.32-3.19, p=0.0014); R/P was significantly affected by grade 3 histology (HR 1.63, 1.16-2.26, p=0.0049) and chemoresistant disease (HR 1.46 (1.07-1.97), p=0.0156); PFS by grade 3 histology (HR 1.42, 1.15-1.76, p=0.0012), chemoresistant disease (HR 1.54, 1.28-1.86, p= 5 lines of prior CT (vs 3-4) (HR 1.45, 1.13-1.85, p=0.0031), MAC (HR 1.36, 1.14-1.63, p=0.0008) and KPS < 80 (HR 1.78, 1.23-2.58, p =0.0022) and OS by age (HR 1.03, 1.02-1.04, p= 5 lines of prior CT (vs 3-4) (HR 1.63, 1.25-2.13, p=0.0003), MAC (HR 1.42, 1.16-1.73, p=0.0006) and KPS < 80 (HR 2.23, 1.52-3.25, p Conclusions. This study represents an example of a fruitful cooperation between two important scientific transplant societies, the EBMT and CIBMTR. Despite significant differences in patient characteristics and transplant strategies between these 2 hitherto largest samples on allo-SCT for R/R FL, long-term disease control was similar and remarkably good with an R/P risk of about only 20% at 5 years. Chemoresistant disease, higher age, multiple pretreatment lines, poor KPS, and MAC all were predictors for an adverse outcome, whereas MUD, TCD, and prior auto-SCT had no impact on any survival endpoint. Disclosures Sureda: Takeda: Consultancy, Honoraria, Speakers Bureau. Fenske:Celgene: Honoraria; Millennium/Takeda: Research Funding; Pharmacyclics: Honoraria; Seattle Genetics: Honoraria. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy.