Integrating biodiversity: a longitudinal and cross-sectoral analysis of Swiss politics

The effective conservation and promotion of biodiversity requires its integration into a wide range of sectoral policies. For this to happen, the issue must receive attention across policy sectors. Yet, we know little about how attention to the issue evolves over time and across sectors. Drawing from the literature on environmental policy integration/mainstreaming and policy process theories, we develop competing hypotheses, expecting either increasing or fluctuating attention to the biodiversity issue. We tested the hypotheses using the case of Swiss politics between 1999 and 2018. Applying a combination of computational methods, we analyze the content of a comprehensive collection of policy documents (n ≈ 440,000) attributed to 20 policy sectors. Comparing the sectors, we find that (1) a persistent increase in attention is the exception, (2) if there is an increase in attention, it is likely to be temporary, and (3) the most common pattern is that of invariant attention over time. Biodiversity integration—if it does happen at all—tends to occur in cycles rather than in steady long-term shifts. This implies that the conservation of biodiversity does not follow the cross-sectoral nature of the problem, but is subject to the dynamics of "politics," where actors, because of limited resources, engage with (aspects of) an issue only for a certain amount of time

High-Dose Enalapril Treatment Reverses Myocardial Fibrosis in Experimental Uremic Cardiomyopathy

AIMS: Patients with renal failure develop cardiovascular alterations which contribute to the higher rate of cardiac death. Blockade of the renin angiotensin system ameliorates the development of such changes. It is unclear, however, to what extent ACE-inhibitors can also reverse existing cardiovascular alterations. Therefore, we investigated the effect of high dose enalapril treatment on these alterations. METHODS: Male Sprague Dawley rats underwent subtotal nephrectomy (SNX, n = 34) or sham operation (sham, n = 39). Eight weeks after surgery, rats were sacrificed or allocated to treatment with either high-dose enalapril, combination of furosemide/dihydralazine or solvent for 4 weeks. Heart and aorta were evaluated using morphometry, stereological techniques and TaqMan PCR. RESULTS: After 8 and 12 weeks systolic blood pressure, albumin excretion, and left ventricular weight were significantly higher in untreated SNX compared to sham. Twelve weeks after SNX a significantly higher volume density of cardiac interstitial tissue (2.57±0.43% in SNX vs 1.50±0.43% in sham, p<0.05) and a significantly lower capillary length density (4532±355 mm/mm(3) in SNX vs 5023±624 mm/mm(3) in sham, p<0.05) were found. Treatment of SNX with enalapril from week 8-12 significantly improved myocardial fibrosis (1.63±0.25%, p<0.05), but not capillary reduction (3908±486 mm/mm(3)) or increased intercapillary distance. In contrast, alternative antihypertensive treatment showed no such effect. Significantly increased media thickness together with decreased vascular smooth muscles cell number and a disarray of elastic fibres were found in the aorta of SNX animals compared to sham. Both antihypertensive treatments failed to cause complete regression of these alterations. CONCLUSIONS: The study indicates that high dose ACE-I treatment causes partial, but not complete, reversal of cardiovascular changes in SNX

Everolimus after failure of one prior VEGF-targeted therapy in metastatic renal cell carcinoma : Final results of the MARC-2 trial

MARC-2, a prospective, multicenter phase IV trial, aimed to investigate clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus after failure of one initial vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy and to identify subgroups benefiting most, based on clinical characteristics and biomarkers. Patients with clear cell mRCC failing one initial VEGFR-TKI received everolimus until progression or unacceptable toxicity. Primary endpoint was 6-month progression-free survival rate (6moPFS). Secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Between 2011 and 2015, 63 patients were enrolled. Median age was 65.4 years (range 43.3-81.1). 6moPFS was 39.3% (95% confidence interval [CI], 27.0-51.3) overall, 54.4% (95% CI, 35.2-70.1) vs 23.7% (95% CI, 10.5-39.9) for patients aged ≥65 vs 25 vs ≤25 kg/m2. A Cox proportional hazards model confirmed a longer PFS for patients aged ≥65 years (hazard ratio [HR] 0.46; 95% CI, 0.26-0.80) and a longer OS for patients with BMI >25 kg/m2 (HR 0.36; 95% CI, 0.18-0.71). Median PFS and median OS were 3.8 months (95% CI, 3.2-6.2) and 16.8 months (95% CI, 14.3-24.3). ORR was 7.9% and disease control rate was 60.3%. No new safety signals emerged. Most common adverse events were stomatitis (31.7%), fatigue (31.7%), and anemia (30.2%). One patient died from treatment-related upper gastrointestinal hemorrhage. Everolimus remains a safe and effective treatment option for mRCC patients after one prior VEGFR-TKI therapy. Patients aged ≥65 years and patients with BMI >25 kg/m2 benefited most

Rheological and biological properties of a hydrogel support for cells intended for intervertebral disc repair

<p>Abstract</p> <p>Background</p> <p>Cell-based approaches towards restoration of prolapsed or degenerated intervertebral discs are hampered by a lack of measures for safe administration and placement of cell suspensions within a treated disc. In order to overcome these risks, a serum albumin-based hydrogel has been developed that polymerizes after injection and anchors the administered cell suspension within the tissue.</p> <p>Methods</p> <p>A hydrogel composed of chemically activated albumin crosslinked by polyethylene glycol spacers was produced. The visco-elastic gel properties were determined by rheological measurement. Human intervertebral disc cells were cultured <it>in vitro </it>and <it>in vivo </it>in the hydrogel and their phenotype was tested by reverse-transcriptase polymerase chain reaction. Matrix production and deposition was monitored by immuno-histology and by biochemical analysis of collagen and glycosaminoglycan deposition. Species specific <it>in situ </it>hybridization was performed to discriminate between cells of human and murine origin in xenotransplants.</p> <p>Results</p> <p>The reproducibility of the gel formation process could be demonstrated. The visco-elastic properties were not influenced by storage of gel components. <it>In vitro </it>and <it>in vivo </it>(subcutaneous implants in mice) evidence is presented for cellular differentiation and matrix deposition within the hydrogel for human intervertebral disc cells even for donor cells that have been expanded in primary monolayer culture, stored in liquid nitrogen and re-activated in secondary monolayer culture. Upon injection into the animals, gels formed spheres that lasted for the duration of the experiments (14 days). The expression of cartilage- and disc-specific mRNAs was maintained in hydrogels <it>in vitro </it>and <it>in vivo</it>, demonstrating the maintenance of a stable specific cellular phenotype, compared to monolayer cells. Significantly higher levels of hyaluronan synthase isozymes-2 and -3 mRNA suggest cell functionalities towards those needed for the support of the regeneration of the intervertebral disc. Moreover, mouse implanted hydrogels accumulated 5 times more glycosaminoglycans and 50 times more collagen than the <it>in vitro </it>cultured gels, the latter instead releasing equivalent quantities of glycosaminoglycans and collagen into the culture medium. Matrix deposition could be specified by immunohistology for collagen types I and II, and aggrecan and was found only in areas where predominantly cells of human origin were detected by species specific <it>in situ </it>hybridization.</p> <p>Conclusions</p> <p>The data demonstrate that the hydrogels form stable implants capable to contain a specifically functional cell population within a physiological environment.</p

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival