Intraperitoneal bevacizumab for control of malignant ascites due to advanced-stage gastrointestinal cancers: A multicentre double-blind, placebo-controlled phase II study - AIO SUP-0108

PURPOSE: Malignant ascites is debilitating for patients with advanced cancer. As shown previously, tumour cell production of vascular endothelial growth factor might be a major cause of the formation of malignant ascites. Intraperitoneal bevacizumab could therefore be an option for symptom control in refractory ascites. PATIENTS AND METHODS: Patients with advanced gastrointestinal cancer and malignant ascites who had undergone paracentesis at least twice within the past 4 weeks were randomly assigned in a 2:1 ratio to intraperitoneal bevacizumab (400 mg absolute) or placebo after paracentesis. During the 8-week treatment period, a minimum interval of 14 d was kept between the applications of the study drug. Primary end-point was paracentesis-free survival (ParFS). RESULTS: Fifty-three patients (median age 63 years) were randomised. Forty-nine patients received at least one study drug application and qualified for the main analysis. The proportion of patients with at least one common toxicity criteria grade III-V event was similar with 20/33 (61%) on bevacizumab and 11/16 (69%) on placebo. Median ParFS was 14 d (95% confidence interval [CI]: 11-17) in the bevacizumab arm and 10.5 d (95% CI: 7-21) on placebo (hazard ratio 0.74, 95% CI: 0.40-1.37; P = 0.16). The longest paracentesis-free period was 19 d on bevacizumab (range 6-66 d) and 17.5 d in the placebo arm (range 4-42) (P = 0.85). Median overall survival was 64 d (95% CI: 45-103) on bevacizumab compared to 31.5 d (95% CI: 20-117) on placebo (P = 0.31). CONCLUSION: Intraperitoneal bevacizumab was well tolerated. Overall, treatment did not result in a significantly better symptom control of malignant ascites. However, patients defined by specific immune characteristics may benefit

BIOHYBRID – Biohybrid templates for peripheral nerve regeneration

[Excerpt] Peripheral nerve injuries represent a major cause for morbidity and disability in affected patients and cause substantial costs for society in a global perspective. It has been estimated that peripheral nerve injuries affect 2.8% of trauma patients,many of whom acquire life-long disability (Noble et al., 1998). With respect to an incidence of nerve injuries of 13.9/100,000 inhabitants per year (Asplund et al., 2009) and the number of inhabitants in the EU (495,000,000 inhabitants in 2007), the number of peripheral nerve injuries requiring repair and reconstruction, excluding nerve injuries by amputations, may be 70,000 annually only in EU countries. Related to peripheral nerve injuries, the costs for society are substantial and consist of direct (costs for surgery, outpatient visits and rehabilitation) and indirect (lost production) costs. Individual median and ulnar nerve injuries in the forearm have total costs of EUR 51,000 and 31,000, respectively, where around 85% of the costs consist of loss of production (Rosberg et al., 2005), still excluding costs for adjusted quality of life ( Eriksson et al., 2011) . Thus, one may estimate that the annual costs only in the EU may be as high as EUR 2.2 billion, indicating that improved treatment strategies for peripheral nerve injuries may not only improve the situation for patients, but may also significantly reduce costs for society. [...](undefined

Statistical mechanics of secondary structures formed by random RNA sequences

The formation of secondary structures by a random RNA sequence is studied as a model system for the sequence-structure problem omnipresent in biopolymers. Several toy energy models are introduced to allow detailed analytical and numerical studies. First, a two-replica calculation is performed. By mapping the two-replica problem to the denaturation of a single homogeneous RNA in 6-dimensional embedding space, we show that sequence disorder is perturbatively irrelevant, i.e., an RNA molecule with weak sequence disorder is in a molten phase where many secondary structures with comparable total energy coexist. A numerical study of various models at high temperature reproduces behaviors characteristic of the molten phase. On the other hand, a scaling argument based on the extremal statistics of rare regions can be constructed to show that the low temperature phase is unstable to sequence disorder. We performed a detailed numerical study of the low temperature phase using the droplet theory as a guide, and characterized the statistics of large-scale, low-energy excitations of the secondary structures from the ground state structure. We find the excitation energy to grow very slowly (i.e., logarithmically) with the length scale of the excitation, suggesting the existence of a marginal glass phase. The transition between the low temperature glass phase and the high temperature molten phase is also characterized numerically. It is revealed by a change in the coefficient of the logarithmic excitation energy, from being disorder dominated to entropy dominated.Comment: 24 pages, 16 figure

In vitro evaluation of cell-seeded chitosan films for peripheral nerve tissue engineering

Natural biomaterials have attracted an increasing interest in the field of tissue-engineered nerve grafts, representing a possible alternative to autologous nerve transplantation. With the prospect of developing a novel entubulation strategy for transected nerves with cell-seeded chitosan films, we examined the biocompatibility of such films in vitro. Different types of rat Schwann cells (SCs)-immortalized, neonatal, and adult-as well as rat bone-marrow-derived mesenchymal stromal cells (BMSCs) were analyzed with regard to their cell metabolic activity, proliferation profiles, and cell morphology after different time points of mono-and cocultures on the chitosan films. Overall the results demonstrate a good cytocompatibility of the chitosan substrate. Both cell types were viable on the biomaterial and showed different metabolic activities and proliferation behavior, indicating cell-type-specific cell-biomaterial interaction. Moreover, the cell types also displayed their typical morphology. In cocultures adult SCs used the BMSCs as a feeder layer and no negative interactions between both cell types were detected. Further, the chitosan films allow neurite outgrowth from dissociated sensory neurons, which is additionally supported on film preseeded with SC-BMSC cocultures. The presented chitosan films therefore demonstrate high potential for their use in tissue-engineered nerve grafts.This work was supported by the European Community's Seventh Framework Programme (FP7-HEALTH-2011) under grant agreement No. 278612. This work was also co-funded by Programa Operacional Regional do Norte (ON.2-O Novo Norte), ao abrigo do Quadro de Referencia Estrategico Nacional (QREN), and atraves do Fundo Europeu de Desenvolvimento Regional (FEDER). The authors gratefully acknowledge the delivery of the chitosan raw material by Altakitin S.A., Portugal, and the fabrication of chitosan films by Medovent GmbH, Germany

Effect of phentolamine on perfusate flow characteristics during renal preservation

Studies of the intrarenal distribution of perfusate during pulsatile hypothermic renal preservation have shown that donor agonal anoxia produces decreased perfusion flow to the cortex and an increase in medullary flow which is reversed by intraarterial infusion of phentolamine. Kidneys subjected to donor anoxia plus 40-50 min of warm ischemia also show similar cortical-medullary perfusion changes which are refractory to intraarterial phentolamine. The potential clinical consequences of changes in intrarenal perfusion and its treatment are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21730/1/0000123.pd

Witterungsextreme und ihre Bedeutung für die jährlichen Ertragsabweichungen von Winterweize

KlimafolgenFür die Landwirtschaft stellen Witterungsereignisse mit signifikanten Abweichungen von langjährigen Mittel eine große Herausforderung dar. Witterungsextreme wie Starkregen, Hitzeperioden während kritischer phänologischer Phasen wie beispielsweise der Blüte oder längere niederschlagsfreie Zeiten haben oftmals direkte Auswirkungen auf den Ertrag und die Qualität der Ernteprodukte. Durch den Klimawandel werden zudem die Wiederkehr von Extremereignissen und die Intensität von Witterungsereignissen beeinflusst. Die Bedeutung der Witterungsextreme für die jährlichen Ertragsschwankungen von Winterweizen wurde durch die Auswertung der Langzeitversuche des JKI in Dahnsdorf, Brandenburg untersucht. Die Klimadaten entstammen der Wetterstation auf dem Versuchsfeld und fehlende Daten sind durch Interpolation von umliegenden Klimastationen auf diesen Standort für die Zeit von 1993-2013 erzeugt worden. Während des Untersuchungszeitraums betrug die jährliche Durchschnittstemperatur 9.6°C und der Jahresniederschlag lag bei 587 mm. Die Anzahl aufeinanderfolgender Tage ohne Niederschlag (NCDWP) von April-September und die Temperatur >25°C (NHD) zur Blüte von Winterweizen im Zeitraum vom 1.-21.Juni in Kombination mit unterschiedlichen Pflanzenschutzstrategien wurde hinsichtlich der Bedeutung für die jährlichen Ertragsschwankungen analysiert. Sowohl bei den NCDWP als auch bei den NHD konnte für den Betrachtungszeitraum für die Werte oberhalb des 80%-igen Perzentils eine leichte Zunahme beider Extrema für diesen Standort gefunden werden (Zunahme von 5 auf 6 bei NHD und 14 auf 15 bei NCDWP). Eine Regressionsanalyse für den Zeitraum von 1996-2007 ergab für beide Extrema ertragsrelevante Auswirkungen auf die jährlichen Ertragsschwankungen. Hierbei zeigten die NHD eine deutlich stärkere ertragsrelevante Auswirkung als die NCDWP bei Winterweizen, abhängig von den jeweiligen Pflanzenschutzstrategien

Overlapping political budget cycle

We advance the literature on political budget cycles by testing for cycles in expenditures for elections to the legislative and the executive branches. Using municipal data, we identify cycles independently for the two branches, evaluate the effects of overlaps, and account for general year effects. We find sizable effects on expenditures before legislative elections and even larger effects before joint elections to the legislature and the office of mayor. In the case of coincident elections, we show that it is important whether the incumbent chief executive seeks reelection. To account for the potential endogeneity of that decision, we apply an IV approach using age and pension eligibility rules