An amphiphilic graft copolymer-based nanoparticle platform for reduction-responsive anticancer and antimalarial drug delivery

Medical applications of anticancer and antimalarial drugs often suffer from low aqueous solubility, high systemic toxicity, and metabolic instability. Smart nanocarrier-based drug delivery systems provide means of solving these problems at once. Herein, we present such a smart nanoparticle platform based on self-assembled, reduction-responsive amphiphilic graft copolymers, which were successfully synthesized through thiol–disulfide exchange reaction between thiolated hydrophilic block and pyridyl disulfide functionalized hydrophobic block. These amphiphilic graft copolymers self-assembled into nanoparticles with mean diameters of about 30–50 nm and readily incorporated hydrophobic guest molecules. Fluorescence correlation spectroscopy (FCS) was used to study nanoparticle stability and triggered release of a model compound in detail. Long-term colloidal stability and model compound retention within the nanoparticles was found when analyzed in cell media at body temperature. In contrast, rapid, complete reduction-triggered disassembly and model compound release was achieved within a physiological reducing environment. The synthesized copolymers revealed no intrinsic cellular toxicity up to 1 mg mL−1. Drug-loaded reduction-sensitive nanoparticles delivered a hydrophobic model anticancer drug (doxorubicin, DOX) to cancer cells (HeLa cells) and an experimental, metabolically unstable antimalarial drug (the serine hydroxymethyltransferase (SHMT) inhibitor (±)-1) to Plasmodium falciparum-infected red blood cells (iRBCs), with higher efficacy compared to similar, non-sensitive drug-loaded nanoparticles. These responsive copolymer-based nanoparticles represent a promising candidate as smart nanocarrier platform for various drugs to be applied to different diseases, due to the biocompatibility and biodegradability of the hydrophobic block, and the protein-repellent hydrophilic block

Epidemic Microclusters of Blood-Culture Proven Sepsis in Very-Low-Birth Weight Infants: Experience of the German Neonatal Network

INTRODUCTION: We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009-2010. METHODS: Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. RESULTS: In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01-55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% -6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient's Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1-27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. DISCUSSION: Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care

Energy Storage as Part of a Secure Energy Supply

The current energy system is subject to a fundamental transformation: A system that is oriented towards a constant energy supply by means of fossil fuels is now expected to integrate increasing amounts of renewable energy to achieve overall a more sustainable energy supply. The challenges arising from this paradigm shift are currently most obvious in the area of electric power supply. However, it affects all areas of the energy system, albeit with different results. Within the energy system, various independent grids fulfill the function of transporting and spatially distributing energy or energy carriers, and the demand-oriented supply ensures that energy demands are met at all times. However, renewable energy sources generally supply their energy independently from any specific energy demand. Their contribution to the overall energy system is expected to increase significantly. Energy storage technologies are one option for temporal matching of energy supply and demand. Energy storage systems have the ability to take up a certain amount of energy, store it in a storage medium for a suitable period of time, and release it in a controlled manner after a certain time delay. Energy storage systems can also be constructed as process chains by combining unit operations, each of which cover different aspects of these functions. Large-scale mechanical storage of electric power is currently almost exclusively achieved by pumped-storage hydroelectric power stations. These systems may be supplemented in the future by compressed-air energy storage and possibly air separation plants. In the area of electrochemical storage, various technologies are currently in various stages of research, development, and demonstration of their suitability for large-scale electrical energy storage. Thermal energy storage technologies are based on the storage of sensible heat, exploitation of phase transitions, adsorption/desorption processes, and chemical reactions. The latter offer the possibility of permanent and loss-free storage of heat. The storage of energy in chemical bonds involves compounds that can act as energy carriers or as chemical feedstocks. Thus, they are in direct economic competition with established (fossil fuel) supply routes. The key technology here – now and for the foreseeable future – is the electrolysis of water to produce hydrogen and oxygen. Hydrogen can be transformed by various processes into other energy carriers, which can be exploited in different sectors of the energy system and/or as raw materials for energy-intensive industrial processes. Some functions of energy storage systems can be taken over by industrial processes. Within the overall energy system, chemical energy storage technologies open up opportunities to link and interweave the various energy streams and sectors. Chemical energy storage not only offers means for greater integration of renewable energy outside the electric power sector, it also creates new opportunities for increased flexibility, novel synergies, and additional optimization. Several examples of specific energy utilization are discussed and evaluated with respect to energy storage applications. The article describes various technologies for energy storage and their potential applications in the context of Germany’s Energiewende, i.e. the transition towards a more sustainable energy system. Therefore, the existing legal framework defines some of the discussions and findings within the article, specifically the compensation for renewable electricity providers defined by the German Renewable Energy Sources Act, which is under constant reformation. While the article is written from a German perspective, the authors hope this article will be of general interest for anyone working in the areas of energy systems or energy technology

A Constitutional Translocation t(1;17)(p36.2;q11.2) in a Neuroblastoma Patient Disrupts the Human NBPF1 and ACCN1 Genes

The human 1p36 region is deleted in many different types of tumors, and so it probably harbors one or more tumor suppressor genes. In a Belgian neuroblastoma patient, a constitutional balanced translocation t(1;17)(p36.2;q11.2) may have led to the development of the tumor by disrupting or activating a gene. Here, we report the cloning of both translocation breakpoints and the identification of a novel gene that is disrupted by this translocation. This gene, named NBPF1 for Neuroblastoma BreakPoint Family member 1, belongs to a recently described gene family encoding highly similar proteins, the functions of which are unknown. The translocation truncates NBPF1 and gives rise to two chimeric transcripts of NBPF1 sequences fused to sequences derived from chromosome 17. On chromosome 17, the translocation disrupts one of the isoforms of ACCN1, a potential glioma tumor suppressor gene. Expression of the NBPF family in neuroblastoma cell lines is highly variable, but it is decreased in cell lines that have a deletion of chromosome 1p. More importantly, expression profiling of the NBPF1 gene showed that its expression is significantly lower in cell lines with heterozygous NBPF1 loss than in cell lines with a normal 1p chromosome. Meta-analysis of the expression of NBPF and ACCN1 in neuroblastoma tumors indicates a role for the NBPF genes and for ACCN1 in tumor aggressiveness. Additionally, DLD1 cells with inducible NBPF1 expression showed a marked decrease of clonal growth in a soft agar assay. The disruption of both NBPF1 and ACCN1 genes in this neuroblastoma patient indicates that these genes might suppress development of neuroblastoma and possibly other tumor types

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

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

Tactile illusory movement: Effects of spatio-temporal stimulus characteristics on the integrative processing of saltatory and successively activated stimulus patterns

Saltation and apparent movement are related phenomena: Both generate illusory stimuli in-between the actually activated stimulus sites. This dissertation examines spatio-temporal stimulus parameters where both phenomena create equivalent percepts. In these cases it is assumed that cortical representations adapt identically to the properties of both stimulus patterns – saltation and apparent movement. Furthermore it is tested whether repetitive stimulation results in plastic changes of the cortical map and related perceptual changes. Another focus lies on the integration of the stimulus patterns over both body halves. We used varying numbers of vibrotactile point stimuli that were presented on a horizontal array around the trunk. In two pilot studies and three main studies with a total of 139 subjects we reached the following conclusions: In accordance with neural network models stimuli presented close together in time are expected to belong together. Therefore both stimulus patterns generate indistinguishable percepts at short interstimulus intervals (<100 ms); the same applies for short stimulus durations (<50 ms). Increasing the number of tactors – and thus decreasing inter-tactor distance – tends to improve the integration of both stimulus patterns into a percept of continuous movement. Vibration frequency affects the quality of illusory movement as well as the similarity of both patterns. Further studies exploring the spatial resolution of low- and high-frequency vibrotactile stimulus patterns on hairy skin are needed to clearly explain this result. An effect of repetitive stimulation on the comparability of both stimulus patterns could not be found – presumably because plastic changes in the cortical map of body sites like the trunk – which are less innervated and rarely used to explore the environment compared to the fingers – might require more stimulus repetitions. Crossing the body midline impairs comparability of both stimulus patterns, however in the majority of cases saltation and apparent movement generate indiscriminable percepts when presented unilaterally or bilaterally indicating that integration of spatio-temporal stimuli occurred over the body midline – yet interstimulus intervals might differ due to interhemispheric transmission time. The results of this dissertation shed further light on the processing of spatio-temporal stimuli and might also be used in the design of tactile torso displays

Attempted Suicide Short Intervention Program Influences Coping Among Patients with a History of Attempted Suicide

Background: The development of individual coping strategies for suicidal crises is essential for suicide prevention. However, the influence of a brief intervention and the effect on coping strategies is largely unknown. This study aimed to investigate the influence of the Attempted Suicide Short Intervention Program on the development of coping strategies, in comparison to a control group. Method: In this secondary analysis of a 24-month follow-up randomised controlled study, 120 patients (55% female; mean age of 36) with a history of suicide attempts were randomly allocated to either the ASSIP group or to a control group, in addition to treatment as usual. Results: The present study identified 11% less dysfunctional coping in the ASSIP group and 6% more problem-focussed coping compared to the control group after 24-months. The analysis of broader strategies showed a significant group difference regarding self-distraction (after 12-months) and self-blame (after 24-months). In regard to the long-term association between coping strategies and suicidal ideation, active coping and substance use were negatively associated with suicidal ideation in the ASSIP group. Whereas, in the control group, behavioural disengagement and positive reframing were positively and self-distraction was negatively related to suicidal ideation. Limitation: The receipt of a clinical interview and suicide risk assessment in the control group could have potentially had an effect on participants’ coping mechanisms. Conclusion: These results indicate that ASSIP may have an impact on the development of problem-focussed coping strategies. Although a reduction in dysfunctional coping seems to be essential in overcoming suicidal crises. Keywords: attempted suicide, coping behaviour, Attempted Suicide Short Intervention Program, brief therapy, suicidal ideatio

Pathways Responsible for Human Autoantibody and Therapeutic Intravenous IgG Activity in Humanized Mice

Immunoglobulin G (IgG) antibodies are major drivers of autoimmune pathology, but they are also used in the form of intravenous IgG (IVIg) therapy to suppress autoantibody activity. To identify the pathways underlying human autoantibody and IVIg activity, we established a humanized mouse model of an autoantibody-dependent autoimmune disease responding to treatment with IVIg preparations. We show that the human IgG subclass strongly impacts autoantibody activity and that the Fc-receptor genotype of the human donor immune system further modulates autoantibody activity. Human mononuclear phagocytes were responsible for autoantibody activity, and IVIg therapy was able to suppress disease pathology in an Fc-fragment-dependent manner. While highly sialylated IgG glycovariants were essential for IVIg activity, it was independent of the Fc-receptor genotype and did not result in a general block of activating or the neonatal Fc-receptor. These findings may help in the development of strategies to block autoantibody and enhance therapeutic IVIg activity in humans