Anti-angiogenic therapy for cancer: Current progress, unresolved questions and future directions

Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies. © 2014 The Author(s)

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13×10– ¹⁵) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65×10– ²⁰) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69×10– ¹²; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR

Using Plant Macrofossils and Other Paleoenvironmental Indicators to Determine Paleoenvironmental Conditions in an Allegan County, Michigan Bog

Detailed plant macrofossil analyses were performed on peat cores from an Allegan County, Michigan bog and used with the paleoenvironmental proxies organic bulk density (OBD) and siliceous microfossil abundances to determine the paleoenvironmental conditions of this bog. The plant macrofossils were divided into four different ecological communities. Community #1, the lowermost assemblage, has sedge species, low OBD values, and abundant sponge spicules and marks the beginning of the accumulation of large amounts of fibrous plant material into a shallow open lake wetland ~8000 cal YBP. Community #2 has deeper water sedge and Nymphaeaceae species, low OBD values, and abundant sponge spicules, suggesting an increase in water depth. Community #3 marks the appearance of ericaceous and Sphagnum species, the disappearance of sponge spicules, and a steady increase in OBD, suggesting the beginning of a near emergent bog surface ~3000 cal YBP. Community #4 begins with charcoal, fine ash and no recognizable vegetative matter, suggesting a fire. The vegetation transitions from ferns and sedges after the fire to ericaceous species and Sphagnum. Sponge spicules are absent and OBD values are high suggesting that the bog surface has become emergent. Over time, the bog has undergone hydroseral succession in conjunction with changes occurring in response to climatic changes

Calc-Silicate Enclaves in High-Grade Gneisses from Halland, Southwest Sweden

The Stensjöstrand association crops out in a 5 kilometer strip along the coast north of Steninge, Halland Province, Southwest Sweden. It consists of amphibolites, sillimanite-bearing quartzofeldspathic gneisses and sillimanite-free quartzofeldspathic gneisses interbanded on scales ranging from 10’s of centimeters to 100’s of meters. On the north and south margins of the coastal strip, the Stensjöstrand association is bordered by granitic to granodioritic orthogneisses. Partial melting has led to the widespread development of metatexites with tonalitic leucosomes in the amphibolites and granitic leucosomes in the sillimanite-bearing and sillimanite-free quartzofeldspathic gneisses. Calc-silicate lenses ranging from 10’s of centimeters to several meters in length occur sporadically in both the amphibolites and sillimanite-free quartzofeldspathic gneisses. These lenses tend to occur in linear arrays suggesting that they may have been continuous layers boudinaged and disrupted during deformation. The core of these lenses contains epidote with variable amounts of plagioclase and garnet. Electron microprobe analyses of samples from 3 lenses give epidote compositions with 9-13 mole % clinozoisite and piemontite concentrations \u3c 2.5 mole %, an average plagioclase concentration of 87% anorthite and calcic garnet compositions that range from 31 to 41 mole % grossular, 33 to 60 mole% andradite, and lesser amounts of almandine (7 to 15 mole %,) and spessartine (1 – 13 mole %). In lenses within amphibolites, the epidote/garnet core is surrounded by a clinopyroxene-plagioclase zone. Microprobe transects across this zone towards the epidote/garnet core show a continuous increase from 50% to 85% in the anorthite content of plagioclase accompanied by an increase from 0.25 to 0.5 in the Fe/(Fe+Mg) ratio of clinopyroxene. The current mineralogy and mineral chemistry of the calc-silicate lenses appear to have developed by diffusion metasomatism during high-grade metamorphism between an iron-rich, calcareous, possibly sedimentary protolith and a mafic, possibly volcanic, rock