Disease marker combination enhances patient characterization in the Finnish sarcoidosis patients

Sarcoidosis is an inflammatory disease of unknown etiology and multiple clinical phenotypes. Clinical manifestations range from asymptomatic disease to severe loss-of-function leading to the hypothesis that sarcoidosis might not be just one disease, but consists of several distinct disease entities each with potentially distinct genetic associations. We have previously demonstrated that in our series HLADRB1* 03:01 and haplotype HLA-DRB1*04:01-DPB1*04:01 are associated with good prognosis sarcoidosis. In our recent work, we found a novel SNP (rs9905945) in the 50upstream region of the ACE gene to be associated with favorable disease prognosis as well. The main objective of this study was to expand the previous results and analyse combined influence of the found ACE SNP rs9905945 with the protective HLA markers HLADRB1*03:01 and HLA-DRB1*04:01-DPB1*04:01 in 188 Finnish sarcoidosis patients (resolved disease, n = 90; persistent disease, n = 98). When combining the frequencies of the rs9905945 and of the HLA markers, the strongest association was found for a combination of either/or both HLA markers and rs9905945 for good disease prognosis (37.1% in resolved vs. 11.3% in persistent, p <0.001, OR = 4.61, (95% CI 2.15-9.86)). In conclusion, we discovered that a combination of the ACE SNP rs9905945 and HLA markers enhance the accuracy for predicting disease course in Finnish sarcoidosis patients further characterizing genetic differences between Finnish sarcoidosis patients with different prognosis. (c) 2017 Elsevier Ltd. All rights reserved.Peer reviewe

Magnetic irreversibility and Verwey transition in nano-crystalline bacterial magnetite

The magnetic properties of biologically-produced magnetite nanocrystals biomineralized by four different magnetotactic bacteria were compared to those of synthetic magnetite nanocrystals and large, high quality single crystals. The magnetic feature at the Verwey temperature, $T_{V}$, was clearly seen in all nanocrystals, although its sharpness depended on the shape of individual nanoparticles and whether or not the particles were arranged in magnetosome chains. The transition was broader in the individual superparamagnetic nanoparticles for which $T_{B}<T_{V}$, where $T_{B}$ is the superparamagnetic blocking temperature. For the nanocrystals organized in chains, the effective blocking temperature $T_{B}>T_{V}$ and the Verwey transition is sharply defined. No correlation between the particle size and $T_{V}$ was found. Furthermore, measurements of $M(H,T,time)$ suggest that magnetosome chains behave as long magnetic dipoles where the local magnetic field is directed along the chain and this result confirms that time-logarithmic magnetic relaxation is due to the collective (dipolar) nature of the barrier for magnetic moment reorientation

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11

Agonism Reloaded: Potentia, Renewal and Radical Democracy

This article focuses on the agonistic account of renewal and discusses its place within the broader horizon of radical democracy. It suggests that while the emphasis which agonistic theorists place on difference and popular struggles (particularly social movement politics) ensures some common ground with other theories of radical democracy, their account of renewal also displays some marked differences. The article explores these differences and discusses whether agonism is sufficient to address the limits of the current neoliberal order

Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: The CLARINET open-label extension study

In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 %) nonfunctioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection

Distinct crustal structure of the North American Midcontinent Rift from P wave receiver functions

Eighty-two broadband seismic stations of the Superior Province Rifting Earthscope Experiment (SPREE) collected 2.5 years of continuous seismic data in the area of the high gravity anomaly associated with the Midcontinent Rift (MCR). Over 100 high-quality teleseismic earthquakes were used for crustal P wave receiver function analysis. Our analysis reveals that the base of the sedimentary layer is shallow outside the MCR, thickens near the flanks where gravity anomalies are low, and shallows again in the MCR's center where the gravity anomalies peak. This pattern is similar to that found from local geophysical studies and is consistent with reverse faulting having accompanied the cessation of rifting at 1.1 Ga. Intermittent intracrustal boundaries imaged by our analysis might represent the bottom of the MCR's mostly buried dense volcanic layers. Outside the MCR, the Moho is strong, sharp, and relatively flat, both beneath the Archean Superior Province and the Proterozoic terranes to its south. Inside the MCR, two weaker candidate Mohos are found at depths up to 25 km apart in the rift's center. The intermediate layer between these discontinuities tapers toward the edges of the MCR. The presence of this transitional layer is remarkably consistent along the strike of the MCR, including beneath its jog in southern Minnesota, near the Belle Plaine Fault. We interpret these results as evidence for extensive underplating as a defining characteristic of the rift, which remains continuous along the Minnesota jog, where due to its orientation, it is minimally affected by the reverse faulting that characterizes the NNE striking parts of the rift

Glucose-6-phosphate dehydrogenase-derived NADPH fuels superoxide production in the failing heart.

In the failing heart, NADPH oxidase and uncoupled NO synthase utilize cytosolic NADPH to form superoxide. NADPH is supplied principally by the pentose phosphate pathway, whose rate-limiting enzyme is glucose 6-phosphate dehydrogenase (G6PD). Therefore, we hypothesized that cardiac G6PD activation drives part of the excessive superoxide production implicated in the pathogenesis of heart failure. Pacing-induced heart failure was performed in eight chronically instrumented dogs. Seven normal dogs served as control. End-stage failure occurred after 28 +/- 1 days of pacing, when left ventricular end-diastolic pressure reached 25 mm Hg. In left ventricular tissue homogenates, spontaneous superoxide generation measured by lucigenin (5 microM) chemiluminescence was markedly increased in heart failure (1338 +/- 419 vs. 419 +/- 102 AU/mg protein, P < 0.05), as were NADPH levels (15.4 +/- 1.5 vs. 7.5 +/- 1.5 micromol/gww, P < 0.05). Superoxide production was further stimulated by the addition of NADPH. The NADPH oxidase inhibitor gp91(ds-tat) (50 microM) and the NO synthase inhibitor L-NAME (1 mM) both significantly lowered superoxide generation in failing heart homogenates by 80% and 76%, respectively. G6PD was upregulated and its activity higher in heart failure compared to control (0.61 +/- 0.10 vs. 0.24 +/- 0.03 nmol/min/mg protein, P < 0.05), while superoxide production decreased to normal levels in the presence of the G6PD inhibitor 6-aminonicotinamide. We conclude that the activation of myocardial G6PD is a novel mechanism that enhances NADPH availability and fuels superoxide-generating enzymes in heart failure

Physical activity and risk of colon adenoma: A meta-analysis

BACKGROUND: Little evidence is available on the relation of physical activity with colon adenomas, a colon cancer precursor. METHODS: We conducted a systematic literature review and meta-analysis of published studies (in English) through April 2010, examining physical activity or exercise and risk or prevalence of colon adenoma or polyp. Random effects models were used to estimate relative risks (RRs) and corresponding confidence intervals (CIs). A total of 20 studies were identified that examined the association and provided RRs and corresponding 95% CIs. RESULTS: A significant inverse association between physical activity and colon adenomas was found with an overall RR of 0.84 (CI: 0.77–0.92). The association was similar in men (RR=0.81, CI: 0.67–0.98) and women (RR=0.87, CI: 0.74–1.02). The association appeared slightly stronger in large/advanced polyps (RR=0.70, CI: 0.56–0.88). CONCLUSION: This study confirms previous reports of a significant inverse association of physical activity and colon adenoma, and suggests that physical activity can have an important role in colon cancer prevention